Cancers

11 pages, 1343 KiB

Open AccessArticle

Use of Proton Pump Inhibitors and the Risk for the Development of Gastric Cancers: A Nationwide Population-Based Cohort Study Using Balanced Operational Definitions

by Eun Jeong Gong, Chang Seok Bang, Dong-Kyu Kim, Jae Jun Lee and Gwang Ho Baik

Cancers 2022, 14(20), 5172; https://doi.org/10.3390/cancers14205172 - 21 Oct 2022

Cited by 5 | Viewed by 1482

Abstract

Objectives: Previous cohort studies using national claim data in Korea have shown conflicting results about the association between the use of proton pump inhibitors (PPIs) and the risk of gastric cancer. This may be due to differences in the inclusion criteria or index [...] Read more.

Objectives: Previous cohort studies using national claim data in Korea have shown conflicting results about the association between the use of proton pump inhibitors (PPIs) and the risk of gastric cancer. This may be due to differences in the inclusion criteria or index dates of each study. This study aims to evaluate the association between PPI use and the risk of gastric cancer using balanced operational definitions. Design: A population-based cohort analysis was conducted using the Korean National Health Insurance Service database. Subjects who used PPIs or histamine-2 receptor antagonist (H₂RA) for more than 60 days after Helicobacter pylori eradication were included. The study subjects were those who had never used H₂RAs (PPI users) and controls were those who had never used PPIs (H₂RA users). For comparison, the index dates of previous studies were adopted and analyzed. The subjects were followed until the development of gastric cancer, death, or study end. Results: A total of 10,012 subjects were included after propensity score matching. During a median follow-up of 6.56 years, PPI was not associated with an increased risk of gastric cancer (Hazard ratio: 1.30, 95% confidence interval: 0.75–2.27). This was consistent if the cumulative daily dose was adjusted (90/120/180 days), or if the index date was changed to the first day of PPI prescription or the last day of Helicobacter pylori eradication. There was no significant difference in mortality between both groups. Conclusion: PPI use was not associated with an increased risk of gastric cancer. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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11 pages, 547 KiB

Open AccessSystematic Review

“Intestinal-Type” Vulvar Adenocarcinoma: A Review of the MITO Rare Tumors Group

by Miriam Dellino, Stefania Cicogna, Francesca Falcone, Marco Mitidieri, Roberta Mazzeo, Sandro Pignata, Giorgia Mangili and Gennaro Cormio

Cancers 2022, 14(20), 5171; https://doi.org/10.3390/cancers14205171 - 21 Oct 2022

Cited by 3 | Viewed by 1787

Abstract

Intestinal-type adenocarcinoma (VAIt) represents a sporadic variant of vulvar carcinoma. It appears frequently localized to epithelial glands in the vulvar region, and it probably derives from cloacal remnants persisting in the adult. We performed a systematic review of the limited cases reported in [...] Read more.

Intestinal-type adenocarcinoma (VAIt) represents a sporadic variant of vulvar carcinoma. It appears frequently localized to epithelial glands in the vulvar region, and it probably derives from cloacal remnants persisting in the adult. We performed a systematic review of the limited cases reported in the literature, with the intent to assess the specific peculiarities of this rare neoplasia and to state consistent management recommendations. The principal histological VAIt characteristic is that it resembles mucinous colonic carcinomas. Therefore, immunohistochemical workup, with different tumor markers including CK20, CDX2, and CK7 staining, is needed. To confirm vulvar origin, a thorough diagnostic, and radiological examination is required to rule out other primary malignancies. The gold standard of treatment for VAIt is surgery, with local excision with tumor-free margins. Lymph node staging is an option advised if the tumor size is >2 cm or if lymph node metastases are suspected on imaging. On the other hand, the role of neoadjuvant therapy is still in doubt, but a good response to adjuvant chemotherapy treatments has been described in both advanced and recurrent diseases. Sometimes, VAIt behavior can be unpredictable, with relapses even after many years, so more experiences and longer follow-up periods are needed to elucidate the best therapeutic management and its long-term prognosis. Full article

(This article belongs to the Special Issue Rare Gynecological Cancers)

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12 pages, 2163 KiB

Open AccessArticle

Induction Regimen in High-Risk Neuroblastoma: A Pilot Study of Highly Effective Continuous Exposure of Tumor Cells to Radio-Chemotherapy Sequence for 1 Month. The Critical Role of Iodine-131-Metaiodobenzylguanidine

by Stefano Mastrangelo, Giorgio Attinà, Luca Zagaria, Alberto Romano and Antonio Ruggiero

Cancers 2022, 14(20), 5170; https://doi.org/10.3390/cancers14205170 - 21 Oct 2022

Cited by 3 | Viewed by 1222

Abstract

The prognosis of high-risk neuroblastoma (NB) continues to be poor. The early development of resistance often leads to disease recurrence. In the present study, an innovative induction regimen, including an intensive initial radio-chemotherapy sequence based on the use of iodine-131-metaiodobenzylguanidine (131-I-MIBG), was investigated. [...] Read more.

The prognosis of high-risk neuroblastoma (NB) continues to be poor. The early development of resistance often leads to disease recurrence. In the present study, an innovative induction regimen, including an intensive initial radio-chemotherapy sequence based on the use of iodine-131-metaiodobenzylguanidine (131-I-MIBG), was investigated. The duration of the regimen lasted only one month. Fifteen newly diagnosed patients aged >18 months with high-risk NB were treated with cisplatin, etoposide, cyclophosphamide, and vincristine, followed on day 10 by 131-I-MIBG (dose: 12–18.3 mCi/kg). Cisplatin and vincristine were administered on day 20 and 21 followed by the re-administration of vincristine, cyclophosphamide, and doxorubicin on day 29 and 30. Non-hematologic toxicity was not observed. Moderate hematologic toxicity was present probably attributable to chemotherapy. The evaluation of response was performed approximately 50 days after the initiation of treatment, yielding four complete responses, eight very good partial responses, one partial response, and two non-responses. Importantly, a complete metastatic response was achieved in 87% of patients. The present pilot study, which includes 131-I-MIBG, allows for a highly effective continuous exposure of tumor cells to both chemotherapy and radiotherapy. Furthermore, early high-dose chemotherapy followed by stem cell rescue may achieve high levels of tumor cell clearance and improve the prognosis of high-risk NB. Full article

(This article belongs to the Special Issue Rare Tumors in Children: Trends in Diagnosis, Treatment and Prevention)

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13 pages, 2395 KiB

Open AccessArticle

NGS-Based Molecular Karyotyping of Multiple Myeloma: Results from the GEM12 Clinical Trial

by Juan Manuel Rosa-Rosa, Isabel Cuenca, Alejandro Medina, Iria Vázquez, Andrea Sánchez-delaCruz, Natalia Buenache, Ricardo Sánchez, Cristina Jiménez, Laura Rosiñol, Norma C. Gutiérrez, Yanira Ruiz-Heredia, Santiago Barrio, Albert Oriol, Maria-Luisa Martin-Ramos, María-Jesús Blanchard, Rosa Ayala, Rafael Ríos-Tamayo, Anna Sureda, Miguel-Teodoro Hernández, Javier de la Rubia, Gorka Alkorta-Aranburu, Xabier Agirre, Joan Bladé, María-Victoria Mateos, Juan-José Lahuerta, Jesús F. San-Miguel, María-José Calasanz, Ramón Garcia-Sanz and Joaquín Martínez-Lopez Show full author list Hide full author list

Cancers 2022, 14(20), 5169; https://doi.org/10.3390/cancers14205169 - 21 Oct 2022

Cited by 3 | Viewed by 2008

Abstract

Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to [...] Read more.

Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to identify, in a single assay, known genetic alterations for the prognostic stratification of MM. The NGS panel was designed for the simultaneous study of single nucleotide and copy number variations, insertions and deletions, chromosomal translocations and V(D)J rearrangements. The panel was validated using a cohort of 149 MM patients enrolled in the GEM2012MENOS65 clinical trial. The results showed great global accuracy, with positive and negative predictive values close to 90% when compared with available data from fluorescence in situ hybridization and whole-exome sequencing. While the treatments used in the clinical trial showed high efficacy, patients defined as high-risk by the panel had shorter progression-free survival (p = 0.0015). As expected, the mutational status of TP53 was significant in predicting patient outcomes (p = 0.021). The NGS panel also efficiently detected clonal IGH rearrangements in 81% of patients. In conclusion, molecular karyotyping using a targeted NGS panel can identify relevant prognostic chromosomal abnormalities and translocations for the clinical management of MM patients. Full article

(This article belongs to the Section Cancer Biomarkers)

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11 pages, 244 KiB

Open AccessReview

Recent Advances in Combination of Immunotherapy and Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma

by Ruixi Wang, Shiliang Liu, Baoqing Chen and Mian Xi

Cancers 2022, 14(20), 5168; https://doi.org/10.3390/cancers14205168 - 21 Oct 2022

Cited by 12 | Viewed by 2932

Abstract

Esophageal cancer has a high mortality rate and a poor prognosis, with more than one-third of patients receiving a diagnosis of locally advanced cancer. Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype of esophageal cancer in Asia and Eastern Europe. Although [...] Read more.

Esophageal cancer has a high mortality rate and a poor prognosis, with more than one-third of patients receiving a diagnosis of locally advanced cancer. Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype of esophageal cancer in Asia and Eastern Europe. Although neoadjuvant or definitive chemoradiotherapy (CRT) has been the standard treatment for locally advanced ESCC, patient outcomes remain unsatisfactory, with recurrence rates as high as 30–50%. The combination of immune checkpoint inhibitors (ICIs) and CRT has emerged as a novel strategy to treat esophageal cancer, and it may have a synergistic action and provide greater efficacy. In the phase III CheckMate-577 trial, one year of adjuvant nivolumab after neoadjuvant CRT improved disease-free survival in patients with residual disease on pathology. Moreover, several phase I and II studies have shown that ICIs combined with concurrent CRT may increase the rate of pathologic complete response for resectable ESCC, but they lack long-term follow-up results. In unresectable cases, the combination of camrelizumab and definitive CRT showed promising results against ESCC in a phase Ib trial. Phase III randomized trials are currently ongoing to investigate the survival benefits of ICIs combined with neoadjuvant or definitive CRT, and they will clarify the role of immunotherapy in locally advanced ESCC. Additionally, valid biomarkers to predict tumor response and survival outcomes need to be further explored. Full article

(This article belongs to the Special Issue Advanced Squamous Cell Carcinoma)

14 pages, 295 KiB

Open AccessReview

Precision Medicine in the Treatment of Locally Advanced or Metastatic Urothelial Cancer: New Molecular Targets and Pharmacological Therapies

by Antonio Vitiello, Francesco Ferrara, Ruggero Lasala and Andrea Zovi

Cancers 2022, 14(20), 5167; https://doi.org/10.3390/cancers14205167 - 21 Oct 2022

Cited by 6 | Viewed by 2028

Abstract

Many variants of urothelial cancer present diagnostic challenges and carry clinical implications that influence prognosis and treatment decisions. The critical issues of treatment-resistant clones are a crucial barrier to care in individuals affected by urothelial carcinoma. Laying the foundations for the resistance evolution, [...] Read more.

Many variants of urothelial cancer present diagnostic challenges and carry clinical implications that influence prognosis and treatment decisions. The critical issues of treatment-resistant clones are a crucial barrier to care in individuals affected by urothelial carcinoma. Laying the foundations for the resistance evolution, a wide mutational heterogeneity characterizes urothelial carcinoma, noticeable also in patients affected by a early stage disease. In recent years the growing knowledge of the pathogenesis and molecular paths underlying the onset and progression of urothelial cancer are leading to the development of new therapies based on immune checkpoints. Chemotherapy and immunotherapy both operate selectively by shaping the developmental trajectory of urothelial carcinoma in the course of the illness. To date, a promising new therapeutic treatment is represented by antibody-drug conjugates, therapeutic tools that exploit the targeted ability of an antibody to administer cytotoxic drugs directly to the tumor. Indeed, nowadays in the clinical setting there are several treatments available for the treatment of locally advanced or metastatic urothelial cancer, from classic chemotherapeutics such as Gemcitabine, Cisplatin and Carboplatin, Paclitaxel and Docetaxel, to Programmed cell death protein 1 (PD-1) or Programmed death-ligand 1 (PD-L1) inhibitors such as Atezolizumab, Avelumab, Nivolumab, Pembrolizumab, up to anti-nectin 4 Enfortumab Vedotin and Sacituzumab govitecan, which binds Tumor-associated calcium signal transducer 2 (Trop-2) and activates as a topoisomerase inhibitor. The aim of this work is to describe the molecular mechanisms underlying the onset of the urothelial cancer and provide an overview of the immunotherapies that can be used in the clinical setting to counteract it, deepening the efficacy and safety results of the pivotal studies and the place in therapy of these treatments. Full article

(This article belongs to the Special Issue Pathology of Urogenital Cancers)

14 pages, 3100 KiB

Open AccessArticle

Stereotactic Body Radiotherapy Boost with the CyberKnife for Locally Advanced Cervical Cancer: Dosimetric Analysis and Potential Clinical Benefits

by Jiaxiang Gao, Benhua Xu, Yibin Lin, Zhenhang Xu, Miaoyun Huang, Xiaobo Li, Xiaodong Wu and Yuangui Chen

Cancers 2022, 14(20), 5166; https://doi.org/10.3390/cancers14205166 - 21 Oct 2022

Cited by 5 | Viewed by 2150

Abstract

(1) Aim: To compare the treatment plans of stereotactic body radiotherapy (SBRT) with CyberKnife (CK) and high-dose-rate (HDR) intracavitary/interstitial brachytherapy (IC/ISBT) and examine the feasibility of CK-SBRT as a viable alternative to BT in patients with locally advanced cervical cancer (LACC). (2) Methods: [...] Read more.

(1) Aim: To compare the treatment plans of stereotactic body radiotherapy (SBRT) with CyberKnife (CK) and high-dose-rate (HDR) intracavitary/interstitial brachytherapy (IC/ISBT) and examine the feasibility of CK-SBRT as a viable alternative to BT in patients with locally advanced cervical cancer (LACC). (2) Methods: A BT plan of 28 Gy in four fractions delivered previously to 20 patients with LACC was compared with a CK plan based on the same CT images with structures delineation for BT. The SBRT treatment plan was further divided according to two different approaches, with the high-risk planning target volume (HR-PTV) defined by the high-risk clinical target volume (HR-CTV) without and with a 5 mm margin, which were named CK-CTV plan and CK-PTV plan, respectively. The dose distributions and dosimetric parameters of the target volumes and organs at risk (OARs) were recorded and compared for the three boost plans. Radiobiological metrics were calculated based on the EUD for the hybrid plans. Additionally, the relationship between tumor volume and tolerance doses for the OARs in the BT plan and CK-PTV plan was investigated. (3) Results: Target coverage was better with the CK plan than with the BT plan, as the D95%, D98%, HI and CI of the CK-CTV plan and CK-PTV plan were higher than those of the BT plan; an exception was the D50%. Similarly, the TCP of the target was also significantly in favor of the CK hybrid plans (p < 0.01). For the OARs, the CK-CTV plan was superior to the BT plan as regards the rectum D2cc, bladder D2cc and bladder Dmax. The CK-PTV plan could achieve dosimetric parameters comparable to those of the BT plan for OARs concerning the small residual tumor volume. The NTCP of the rectum for the WPI+CK-CTV plans was significantly lower than that of the WPI+BT plans (p < 0.01). (4) Conclusions: CK-based SBRT can achieve better target coverage, dose sparing for the OARs and radiobiological effects compared with the BT plan for tumors that are not excessively large. CK-based SBRT could be an alternative option to administer a radiation boost for patients with LACC. Full article

(This article belongs to the Section Cancer Therapy)

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13 pages, 1481 KiB

Open AccessArticle

Ixazomib, Lenalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma in Routine Clinical Practice: Extended Follow-Up Analysis and the Results of Subsequent Therapy

by Jiri Minarik, Jakub Radocha, Alexandra Jungova, Jan Straub, Tomas Jelinek, Tomas Pika, Ludek Pour, Petr Pavlicek, Lubica Harvanova, Lenka Pospisilova, Petra Krhovska, Denisa Novakova, Pavel Jindra, Ivan Spicka, Hana Plonkova, Martin Stork, Jaroslav Bacovsky, Vladimir Maisnar and Roman Hajek

Cancers 2022, 14(20), 5165; https://doi.org/10.3390/cancers14205165 - 21 Oct 2022

Cited by 6 | Viewed by 2890

Abstract

Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis [...] Read more.

Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis of the outcomes in lenalidomide (LEN) pretreated and LEN refractory patients. Methods: We assessed 344 patients with RRMM, treated with IRD (N = 127) or RD (N = 217). The data were acquired from the Czech Registry of Monoclonal Gammopathies (RMG). With prolonged follow-up (median 28.5 months), we determined the new primary endpoints OS, PFS and PFS-2. Secondary endpoints included the next therapeutic approach and the survival measures in LEN pretreated and LEN refractory patients. Results: The final overall response rate (ORR) was 73.0% in the IRD cohort and 66.8% in the RD cohort. The difference in patients reaching ≥VGPR remained significant (38.1% vs. 26.3%, p = 0.028). Median PFS maintained significant improvement in the IRD cohort (17.5 vs. 12.5 months, p = 0.013) with better outcomes in patients with 1–3 prior relapses (22.3 vs. 12.7 months p = 0.003). In the whole cohort, median OS was for IRD vs. RD patients 40.9 vs. 27.1 months (p = 0.001), with further improvement within relapse 1-3 (51.7 vs. 27.8 months, p ˂ 0.001). The median PFS of LEN pretreated (N = 22) vs. LEN naive (N = 105) patients treated by IRD was 8.7 vs. 23.1 months (p = 0.001), and median OS was 13.2 vs. 51.7 months (p = 0.030). Most patients in both arms progressed and received further myeloma-specific therapy (63.0% in the IRD group and 53.9% in the RD group). Majority of patients received pomalidomide-based therapy or bortezomib based therapy. Significantly more patients with previous IRD vs. RD received subsequent monoclonal antibodies (daratumumab—16.3% vs. 4.3%, p = 0.0054; isatuximab 5.0% vs. 0.0%, p = 0.026) and carfilzomib (12.5 vs. 1.7%, p = 0.004). The median PFS-2 (progression free survival from the start of IRD/RD therapy until the second disease progression or death) was significantly longer in the IRD cohort (29.8 vs. 21.6 months, p = 0.016). There were no additional safety concerns in the extended follow-up. Conclusions: The IRD regimen is well tolerated, easy to administer, and with very good therapeutic outcomes. The survival measures in unsorted real-world population are comparable to the outcomes of the clinical trial. As expected, patients with LEN reatment have poorer outcomes than those who are LEN-naive. The PFS benefit of IRD vs. RD translated into significantly better PFS-2 and OS, but the outcomes must be accounted for imbalances in pretreatment group characteristics (especially younger age and stem cell transplant pretreatment), and in subsequent therapies. Full article

(This article belongs to the Special Issue Immunomodulatory Agents for Multiple Myeloma)

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13 pages, 1251 KiB

Open AccessArticle

Risk and Status of Gastrointestinal Cancer According to the International Standard Industrial Classification in Korean Workers

by Soonsu Shin, Jun-Hyeok Choi, Kyung-Eun Lee, Jin-Ha Yoon and Wanhyung Lee

Cancers 2022, 14(20), 5164; https://doi.org/10.3390/cancers14205164 - 21 Oct 2022

Cited by 1 | Viewed by 1294

Abstract

To compare the risk of developing gastrointestinal (GI) cancer according to industrial groups, we performed a retrospective cohort study using the database of the Korea National Health Insurance Service (NHIS). We calculated the age-standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) [...] Read more.

To compare the risk of developing gastrointestinal (GI) cancer according to industrial groups, we performed a retrospective cohort study using the database of the Korea National Health Insurance Service (NHIS). We calculated the age-standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) for the types of GI cancers according to the Korean Standard Industrial Classification (KSIC) compared with the whole employee population. The highest SIR for all GI cancer was found in the “Mining and quarrying” section (SIR, 1.30; 95% CI, 1.14–1.47), followed by the “Transportation and storage” section (SIR, 1.27; 95% CI, 1.24–1.30). Miners and quarriers had the highest risk of developing gastric cancer (SIR, 1.29; 95% CI, 1.06–1.55) and cancer of the liver and intrahepatic bile ducts (SIR, 1.48; 95% CI, 1.17–1.86). Transportation workers had the highest SIR of cancer of the lip, oral cavity, and pharynx (SIR, 1.27; 95% CI, 1.13–1.43) and cancers of the rectum, anus, and anal canal (SIR, 1.27; 95% CI, 1.19–1.35). There were distinct GI cancers with an elevated risk in each industry group. Our findings imply that distinct cancer prevention programs should be developed for each industrial sector. Full article

(This article belongs to the Special Issue Occupational Cancers)

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14 pages, 889 KiB

Open AccessReview

Neoantigen Vaccines; Clinical Trials, Classes, Indications, Adjuvants and Combinatorial Treatments

by Jenni Viivi Linnea Niemi, Aleksandr V. Sokolov and Helgi B. Schiöth

Cancers 2022, 14(20), 5163; https://doi.org/10.3390/cancers14205163 - 21 Oct 2022

Cited by 15 | Viewed by 3066

Abstract

Personalized neoantigen vaccines are a highly specific cancer treatment designed to induce a robust cytotoxic T-cell attack against a patient’s cancer antigens. In this study, we searched ClinicalTrials.gov for neoantigen vaccine clinical trials and systematically analyzed them, a total of 147 trials. Peptide [...] Read more.

Personalized neoantigen vaccines are a highly specific cancer treatment designed to induce a robust cytotoxic T-cell attack against a patient’s cancer antigens. In this study, we searched ClinicalTrials.gov for neoantigen vaccine clinical trials and systematically analyzed them, a total of 147 trials. Peptide vaccines are the largest neoantigen vaccine type, comprising up to 41% of the clinical trials. However, mRNA vaccines are a growing neoantigen vaccine group, especially in the most recent clinical trials. The most common cancer types in the clinical trials are glioma, lung cancer, and malignant melanoma, being seen in more than half of the clinical trials. Small-cell lung cancer and non-small-cell lung cancer are the largest individual cancer types. According to the results from the clinical trials, neoantigen vaccines work best when combined with other cancer treatments, and popular combination treatments include immune checkpoint inhibitors, chemotherapy, and radiation therapy. Additionally, half of the clinical trials combined neoantigen vaccines with an adjuvant to boost the immune effects, with poly-ICLC being the most recurrent adjuvant choice. This study clarifies the rapid clinical trial development of personalized neoantigen vaccines as an emerging class of cancer treatment with increasingly diversified opportunities in classes, indications, and combinatorial treatments. Full article

(This article belongs to the Special Issue Research in Personalized Cancer Vaccine)

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16 pages, 2735 KiB

Open AccessArticle

Longitudinally Heterogeneous Tumor Dose Optimizes Proton Broadbeam, Interlaced Minibeam, and FLASH Therapy

by Matthias Sammer, Aikaterini Rousseti, Stefanie Girst, Judith Reindl and Günther Dollinger

Cancers 2022, 14(20), 5162; https://doi.org/10.3390/cancers14205162 - 21 Oct 2022

Cited by 2 | Viewed by 1388

Abstract

The prerequisite of any radiation therapy modality (X-ray, electron, proton, and heavy ion) is meant to meet at least a minimum prescribed dose at any location in the tumor for the best tumor control. In addition, there is also an upper dose limit [...] Read more.

The prerequisite of any radiation therapy modality (X-ray, electron, proton, and heavy ion) is meant to meet at least a minimum prescribed dose at any location in the tumor for the best tumor control. In addition, there is also an upper dose limit within the tumor according to the International Commission on Radiation Units (ICRU) recommendations in order to spare healthy tissue as well as possible. However, healthy tissue may profit from the lower side effects when waving this upper dose limit and allowing a larger heterogeneous dose deposition in the tumor, but maintaining the prescribed minimum dose level, particularly in proton minibeam therapy. Methods: Three different longitudinally heterogeneous proton irradiation modes and a standard spread-out Bragg peak (SOBP) irradiation mode are simulated for their depth-dose curves under the constraint of maintaining a minimum prescribed dose anywhere in the tumor region. Symmetric dose distributions of two opposing directions are overlaid in a 25 cm-thick water phantom containing a 5 cm-thick tumor region. Interlaced planar minibeam dose distributions are compared to those of a broadbeam using the same longitudinal dose profiles. Results and Conclusion: All longitudinally heterogeneous proton irradiation modes show a dose reduction in the healthy tissue compared to the common SOBP mode in the case of broad proton beams. The proton minibeam cases show eventually a much larger mean cell survival and thus a further reduced equivalent uniform dose (EUD) in the healthy tissue than any broadbeam case. In fact, the irradiation mode using only one proton energy from each side shows better sparing capabilities in the healthy tissue than the common spread-out Bragg peak irradiation mode with the option of a better dose fall-off at the tumor edges and an easier technical realization, particularly in view of proton minibeam irradiation at ultra-high dose rates larger than ~10 Gy/s (so-called FLASH irradiation modes). Full article

(This article belongs to the Special Issue Steps towards the Clinics in Spatially Fractionated Radiation Therapy)

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16 pages, 2023 KiB

Open AccessArticle

Higher Risk of Recurrence in Patients Treated for Head and Neck Cancer with Low BMI and Elevated Levels of C-Reactive Protein

by Diana Spiegelberg, Christer Malmberg, Ylva Tiblom Ehrsson and Göran Laurell

Cancers 2022, 14(20), 5161; https://doi.org/10.3390/cancers14205161 - 21 Oct 2022

Cited by 1 | Viewed by 1463

Abstract

This prospective study identifies high-risk groups for recurrence of head and neck cancer by BMI and circulating inflammatory response markers. Head and neck cancer patients from three Swedish hospitals were included (n = 272). Leukocyte and thrombocyte counts, CRP levels, and BMI [...] Read more.

This prospective study identifies high-risk groups for recurrence of head and neck cancer by BMI and circulating inflammatory response markers. Head and neck cancer patients from three Swedish hospitals were included (n = 272). Leukocyte and thrombocyte counts, CRP levels, and BMI were measured pre-treatment and post-treatment. Associations between the four factors and treatment failure (residual tumor, loco-regional failure, general failure/distant metastasis) were assessed using a Cox proportional hazards model adjusted for sex, age at the initial visit, smoking status, cancer stage, and hemoglobin count. CRP level was the only significant single variable, with an average increase in risk of recurrence of 74% (p = 0.018) for every doubling. The predictive power of a combined model using all variables was highest during the initial months after treatment, with AUC under the ROC curve 0.75 at the 0–3 month timepoints. Patients with elevated pre- and post-treatment CRP levels are at higher risk for recurrence of disease. Male patients with low post-treatment BMI, advanced stage, and high CRP at any time post treatment are at high risk for recurrence. The combined model may be useful for stratifying post-treatment patients into low and high-risk groups, to enable more detailed follow-up or additional treatment regimens. Full article

(This article belongs to the Special Issue Head and Neck Cancer Recurrence: Diagnosis, Treatment and Prognosis)

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20 pages, 1724 KiB

Open AccessReview

Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies

by Nannan Wang, Yuepeng Cao, Chengshuai Si, Peng Shao, Guoqing Su, Ke Wang, Jun Bao and Liu Yang

Cancers 2022, 14(20), 5160; https://doi.org/10.3390/cancers14205160 - 21 Oct 2022

Cited by 6 | Viewed by 3495

Abstract

Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, [...] Read more.

Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC. Full article

(This article belongs to the Special Issue Signaling Pathway in Gastrointestinal Cancer)

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16 pages, 287 KiB

Open AccessArticle

Associations of Dietary Intakes of Carotenoids and Vitamin A with Lung Cancer Risk in a Low-Income Population in the Southeastern United States

by Yan Sun, Jie Wu, Hyung-Suk Yoon, Maciej S. Buchowski, Hui Cai, Stephen A. Deppen, Mark D. Steinwandel, Wei Zheng, Xiao-Ou Shu, William J. Blot and Qiuyin Cai

Cancers 2022, 14(20), 5159; https://doi.org/10.3390/cancers14205159 - 21 Oct 2022

Cited by 2 | Viewed by 2126

Abstract

Observational studies found inverse associations of dietary carotenoids and vitamin A intakes with lung cancer risk. However, interventional trials among high-risk individuals showed that β-carotene supplements increased lung cancer risk. Most of the previous studies were conducted among European descendants or Asians. We [...] Read more.

Observational studies found inverse associations of dietary carotenoids and vitamin A intakes with lung cancer risk. However, interventional trials among high-risk individuals showed that β-carotene supplements increased lung cancer risk. Most of the previous studies were conducted among European descendants or Asians. We prospectively examined the associations of lung cancer risk with dietary intakes of carotenoids and vitamin A in the Southern Community Cohort Study, including 65,550 participants with 1204 incident lung cancer cases. Multivariate Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Lung cancer cases had lower energy-adjusted dietary intakes of all carotenoids and vitamin A than non-cases. However, dietary intakes of carotenoids and vitamin A were not associated with overall lung cancer risk. A significant positive association of dietary vitamin A intake with lung cancer risk was observed among current smokers (HR_{Q4 vs. Q1} = 1.23; 95% CI: 1.02–1.49; P_trend = 0.01). In addition, vitamin A intake was associated with an increased risk of adenocarcinoma among African Americans (HR_{Q4 vs. Q1} = 1.55; 95%CI: 1.08–2.21; P_trend = 0.03). Dietary lycopene intake was associated with an increased risk of lung cancer among former smokers (HR_{Q4 vs. Q1} = 1.50; 95% CI: 1.04–2.17; P_trend = 0.03). There are positive associations of dietary β-cryptoxanthin intake with squamous carcinoma risk (HR_{Q4 vs. Q1} = 1.49; 95% CI: 1.03–2.15; P_trend = 0.03). Further studies are warranted to confirm our findings. Full article

(This article belongs to the Special Issue Cancer and Nutrients)

13 pages, 1362 KiB

Open AccessArticle

The Optimal Therapy after Progression on Immune Checkpoint Inhibitors in MSI Metastatic Gastrointestinal Cancer Patients: A Multicenter Retrospective Cohort Study

by Mifen Chen, Zhenghang Wang, Zimin Liu, Ning Liu, Weijia Fang, Hangyu Zhang, Xuan Jin, Jiayi Li, Weifeng Zhao, Huajun Qu, Fanghua Song, Zhiwei Chang, Yi Li, Yong Tang, Chunlei Xu, Xiaotian Zhang, Xicheng Wang, Zhi Peng, Jinping Cai, Jian Li and Lin Shen Show full author list Hide full author list

Cancers 2022, 14(20), 5158; https://doi.org/10.3390/cancers14205158 - 21 Oct 2022

Cited by 3 | Viewed by 2022

Abstract

Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with [...] Read more.

Background: In microsatellite instability (MSI)/mismatch repair-deficient (dMMR) gastrointestinal cancers, the optimum therapy after the progression of immune checkpoint inhibitors (ICIs) is yet unknown. Here, we compared the efficacy of programmed death 1 (PD1)/programmed death ligand-1 (PD-L1) inhibitors plus other therapy and chemotherapy with or without targeted therapy in MSI/dMMR gastrointestinal cancer patients after progression on anti-PD1/PD-L1 monotherapy. Methods: We retrospectively recruited MSI/dMMR gastrointestinal cancer patients who had progressed on anti-PD1/PD-L1 monotherapy. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr) were compared between patients who received anti-PD1/PD-L1 plus other therapy (ICI-plus group) and patients who received chemotherapy with or without targeted therapy (chemo-targeted group). Results: In total, 26 and 25 patients were recruited in the ICI-plus group and chemo-targeted group, respectively. Significantly better DCR (80.8% vs. 44.0%, p = 0.007), PFS (median PFS 6.9 months vs. 3.0 months, p = 0.001), OS (median OS NR vs. 14.1 months, p = 0.043), and PFSr (2.4 vs. 0.9, p = 0.021), along with a numerically higher ORR (23.1% vs. 12.0%, p = 0.503) were observed in the ICI-plus group compared with the chemo-targeted group. Multivariate analyses identified the therapy regimen as an important prognostic factor in gastrointestinal cancers. Conclusions: Compared to conventional chemotherapy with or without targeted therapy, continuing anti-PD1/PD-L1 in combination with other treatments showed better clinical outcomes in MSI/dMMR gastrointestinal cancer patients who progressed on PD1/PD-L1 blockade, which should be validated prospectively in clinical trials. Full article

(This article belongs to the Section Cancer Therapy)

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19 pages, 4757 KiB

Open AccessArticle

Effect of Tertiary Lymphoid Structures on Prognosis of Patients with Hepatocellular Carcinoma and Preliminary Exploration of Its Formation Mechanism

by Jianhui Li, Ye Nie, Weili Jia, Wenlong Wu, Wenjie Song and Yongxiang Li

Cancers 2022, 14(20), 5157; https://doi.org/10.3390/cancers14205157 - 21 Oct 2022

Cited by 6 | Viewed by 2141

Abstract

Background: Tertiary lymphoid structures (TLSs) are formed by the aggregation of tumour-infiltrating lymphocytes (TILs), which is driven by chemokines or cytokines in the tumour microenvironment. Studies have shown that TLSs are associated with good prognosis in patients with various solid tumours and can [...] Read more.

Background: Tertiary lymphoid structures (TLSs) are formed by the aggregation of tumour-infiltrating lymphocytes (TILs), which is driven by chemokines or cytokines in the tumour microenvironment. Studies have shown that TLSs are associated with good prognosis in patients with various solid tumours and can improve patient responses to immunotherapy. However, the role of TLSs in hepatocellular carcinoma (HCC) remains controversial, and the underlying molecular mechanism is unclear. Methods: According to haematoxylin-eosin (HE) staining results, HCC patients in Xijing Hospital data and TCGA data were divided into TLS+ and TLS- groups, and Kaplan–Meier (KM) analysis was performed to assess overall survival (OS) and recurrence-free survival (RFS). Immunofluorescence (IF) and immunohistochemistry (IHC) were used to identify TILs in the TLS+ group. Lymphocyte-specific protein tyrosine kinase (LCK), a molecule involved in TLS formation, was explored in LinkedOmics. TILs were divided into two groups by drawing receiver operating characteristic (ROC) curves to calculate cut-off values. Spearman correlation analysis was used to calculate the correlation between LCK and TILs, and the molecular pathways by which LCK regulates immunotherapy were clarified through enrichment analysis. The half-maximal inhibitory concentration (IC50) distribution of sorafenib was observed in groups that varied in LCK expression. Results: According to the HE results, 61 cases in the Xijing Hospital cohort and 195 cases in the TCGA cohort had TLSs, while 89 cases and 136 cases did not. The KM results showed that TLSs had no effect on the OS of HCC patients but significantly affected RFS. The IF/IHC results showed that higher TIL numbers in TLSs were correlated with better prognosis in HCC patients. Spearman correlation analysis showed that LCK expression was positively correlated with TIL numbers. Enrichment analysis showed that upregulation of LCK expression mainly regulated the cytokine signalling pathway, the chemokine signalling pathway and T-cell activation. The IC50 scores of sorafenib in HCC patients with high LCK expression were lower, and the sensitivity was higher. Conclusion: TLSs mainly affected the early RFS of HCC patients but had no effect on OS. The high expression of the TLS formation-related gene LCK can increase the sensitivity of HCC patients to ICIs. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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10 pages, 1027 KiB

Open AccessArticle

Ultrasound-Guided Needle Aspiration Biopsy of Superficial Metastasis of Lung Cancer with and without Rapid On-Site Evaluation: A Randomized Trial

by Vanina Livi, Giovanni Sotgiu, Alessandra Cancellieri, Daniela Paioli, Fausto Leoncini, Daniele Magnini and Rocco Trisolini

Cancers 2022, 14(20), 5156; https://doi.org/10.3390/cancers14205156 - 21 Oct 2022

Cited by 1 | Viewed by 1391

Abstract

Background and Objective: Studies which evaluated the role of an ultrasound-guided needle aspiration biopsy (US-NAB) of metastases from lung cancer located in “superficial” organs/tissues are scant, and none of them assessed the possible impact of rapid on-site evaluation (ROSE) on diagnostic accuracy and [...] Read more.

Background and Objective: Studies which evaluated the role of an ultrasound-guided needle aspiration biopsy (US-NAB) of metastases from lung cancer located in “superficial” organs/tissues are scant, and none of them assessed the possible impact of rapid on-site evaluation (ROSE) on diagnostic accuracy and safety outcomes. Methods: Consecutive patients with suspected superficial metastases from lung cancer were randomized 1:1 to US-NAB without (US-NAB group) or with ROSE (ROSE group). The diagnostic yield for a tissue diagnosis was the primary outcome. Secondary outcomes included the diagnostic yield for cancer genotyping, the diagnostic yield for PD-L1 testing, and safety. Results: During the study period, 136 patients were randomized to receive an US-NAB with (n = 68) or without ROSE (n = 68). We found no significant differences between the ROSE group and the US-NAB group in terms of the diagnostic yields for tissue diagnosis (94.1% vs. 97%, respectively; p = 0.68), cancer genotyping (88% vs. 91.8%, respectively; p = 0.56), and PD-L1 testing (93.5% vs. 90.6%, respectively; p = 0.60). Compared to the diagnostic US-NAB procedures, the non-diagnostic procedures were characterized by less common use of a cutting needle (66.6% vs. 96.9%, respectively; p = 0.0004) and less common retrieval of a tissue core (37.5% vs. 98.5%; p = 0.0001). Only one adverse event (vasovagal syncope) was recorded. Conclusion: US-NAB of superficial metastases is safe and has an excellent diagnostic success regardless of the availability of ROSE. These findings provide a strong rationale for using US-NAB as the first-step method for tissue acquisition whenever a suspected superficial metastatic lesion is identified in patients with suspected lung cancer. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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14 pages, 3149 KiB

Open AccessArticle

Low-Dose Computed Tomography Scanning Protocols for Online Adaptive Proton Therapy of Head-and-Neck Cancers

by Konrad P. Nesteruk, Mislav Bobić, Gregory C. Sharp, Arthur Lalonde, Brian A. Winey, Lena Nenoff, Antony J. Lomax and Harald Paganetti

Cancers 2022, 14(20), 5155; https://doi.org/10.3390/cancers14205155 - 21 Oct 2022

Cited by 4 | Viewed by 1913

Abstract

Purpose: To evaluate the suitability of low-dose CT protocols for online plan adaptation of head-and-neck patients. Methods: We acquired CT scans of a head phantom with protocols corresponding to CT dose index volume CTDI_vol in the range of 4.2–165.9 mGy. The highest [...] Read more.

Purpose: To evaluate the suitability of low-dose CT protocols for online plan adaptation of head-and-neck patients. Methods: We acquired CT scans of a head phantom with protocols corresponding to CT dose index volume CTDI_vol in the range of 4.2–165.9 mGy. The highest value corresponds to the standard protocol used for CT simulations of 10 head-and-neck patients included in the study. The minimum value corresponds to the lowest achievable tube current of the GE Discovery RT scanner used for the study. For each patient and each low-dose protocol, the noise relative to the standard protocol, derived from phantom images, was applied to a virtual CT (vCT). The vCT was obtained from a daily CBCT scan corresponding to the fraction with the largest anatomical changes. We ran an established adaptive workflow twice for each low-dose protocol using a high-quality daily vCT and the corresponding low-dose synthetic vCT. For a relative comparison of the adaptation efficacy, two adapted plans were recalculated in the high-quality vCT and evaluated with the contours obtained through deformable registration of the planning CT. We also evaluated the accuracy of dose calculation in low-dose CT volumes using the standard CT protocol as reference. Results: The maximum differences in D₉₈ between low-dose protocols and the standard protocol for the high-risk and low-risk CTV were found to be 0.6% and 0.3%, respectively. The difference in OAR sparing was up to 3%. The Dice similarity coefficient between propagated contours obtained with low-dose and standard protocols was above 0.982. The mean 2%/2 mm gamma pass rate for the lowest-dose image, using the standard protocol as reference, was found to be 99.99%. Conclusion: The differences between low-dose protocols and the standard scanning protocol were marginal. Thus, low-dose CT protocols are suitable for online adaptive proton therapy of head-and-neck cancers. As such, considering scanning protocols used in our clinic, the imaging dose associated with online adaption of head-and-neck cancers treated with protons can be reduced by a factor of 40. Full article

(This article belongs to the Special Issue Proton Therapy for Cancer in the Era of Precision Medicine)

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15 pages, 912 KiB

Open AccessReview

Squalamines in Blockade of Tumor-Associated Angiogenesis and Cancer Progression

by Colin Sterling, Jr., Diana Márquez-Garbán, Jaydutt V. Vadgama and Richard J. Pietras

Cancers 2022, 14(20), 5154; https://doi.org/10.3390/cancers14205154 - 21 Oct 2022

Cited by 1 | Viewed by 1659

Abstract

Mechanisms of action of squalamine in human vascular endothelial cells indicate that this compound attaches to cell membranes, potentially interacting with calmodulin, Na⁺/H⁺ exchanger isoform NHE3 and other signaling pathways involved in the angiogenic process. Thus, squalamine elicits blockade of [...] Read more.

Mechanisms of action of squalamine in human vascular endothelial cells indicate that this compound attaches to cell membranes, potentially interacting with calmodulin, Na⁺/H⁺ exchanger isoform NHE3 and other signaling pathways involved in the angiogenic process. Thus, squalamine elicits blockade of VEGF-induced endothelial tube-like formation in vitro. Further, squalamine reduces growth of several preclinical models of human cancers in vivo and acts to stop metastatic tumor spread, actions due largely to blockade of angiogenesis induced by the tumor and tumor microenvironment. Squalamine in Phase I/II trials, alone or combined with standard care, shows promising antitumor activity with limited side-effects in patients with advanced solid cancers. Increased attention on squalamine regulation of signaling pathways with or without combination treatments in solid malignancies deserves further study. Full article

(This article belongs to the Special Issue Advances in Tumor Angiogenesis)

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29 pages, 13313 KiB

Open AccessArticle

Construction of a Prognostic and Early Diagnosis Model for LUAD Based on Necroptosis Gene Signature and Exploration of Immunotherapy Potential

by Baizhuo Zhang, Yudong Wang, Xiaozhu Zhou, Zhen Zhang, Haoyu Ju, Xiaoqi Diao, Jiaoqi Wu and Jing Zhang

Cancers 2022, 14(20), 5153; https://doi.org/10.3390/cancers14205153 - 20 Oct 2022

Cited by 1 | Viewed by 2002

Abstract

Necroptosis is a type of programmed necrosis that is different from apoptosis and necrosis. Lung cancer has the highest incidence and mortality worldwide, and lung adenocarcinoma is the most common subtype of lung cancer. However, the role of necroptosis in the occurrence and [...] Read more.

Necroptosis is a type of programmed necrosis that is different from apoptosis and necrosis. Lung cancer has the highest incidence and mortality worldwide, and lung adenocarcinoma is the most common subtype of lung cancer. However, the role of necroptosis in the occurrence and development of LUAD remains largely unexplored. In this paper, four NRGs and nine NRGs determined by big data analysis were used to effectively predict the risk of early LUAD (AUC = 0.994) and evaluate the prognostic effect on LUAD patients (AUC = 0.826). Meanwhile, ESTIMATE, single-sample gene set enrichment analysis (ssGSEA), genomic variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune checkpoint analysis were used to explore the enrichment characteristics and immune research related to the prognostic model. In deep data mining, we were surprised to find that prognostic models also regulate the immune microenvironment, cell cycle, and DNA damage repair mechanisms. Thus, we demonstrated a significant correlation between model evaluation results, ICI treatment, and chemotherapeutic drug sensitivity. The low-risk population has a stronger tumor immune response, and the potential for ICI treatment is greater. People at high risk respond less to immunotherapy but respond well to chemotherapy drugs. In addition, PANX1, a core gene with important value in immune regulation, prognosis assessment, and early diagnosis, has been identified for the first time, which provides a new target for the immunotherapy of LUAD as well as a new theoretical basis for the basic research, clinical diagnosis, and individualized treatment of LUAD. Full article

(This article belongs to the Collection Application of Bioinformatics in Cancers)

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13 pages, 1746 KiB

Open AccessArticle

Genetic Stability of Driver Alterations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type and Their Relapses: A Rationale for the Use of Molecular-Based Methods for More Effective Disease Monitoring

by Anne M. R. Schrader, Ruben A. L. de Groen, Rein Willemze, Patty M. Jansen, Koen D. Quint, Arjen H. G. Cleven, Tom van Wezel, Ronald van Eijk, Dina Ruano, J. Hendrik Veelken, Cornelis P. Tensen, Karen J. Neelis, Laurien A. Daniels, Esther Hauben, F. J. Sherida H. Woei-A-Jin, Anne-Marie Busschots, Maarten H. Vermeer and Joost S. P. Vermaat

Cancers 2022, 14(20), 5152; https://doi.org/10.3390/cancers14205152 - 20 Oct 2022

Cited by 3 | Viewed by 1597

Abstract

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory [...] Read more.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a rare, aggressive cutaneous lymphoma with a 5-year disease-specific survival of only ~55%. Despite high response rates to initial immune-polychemotherapy, most patients experience a disease relapse. The genetic evolution of primary and relapsed/refractory disease has only scarcely been studied in PCDLBCL-LT patients. Therefore, in this retrospective cohort study, 73 primary/pre-treatment and relapsed/refractory biopsies of 57 patients with PCDLBCL-LT were molecularly characterized with triple FISH and targeted next-generation sequencing for 52 B-cell-lymphoma-relevant genes, including paired analysis in 16 patients. In this cohort, 95% of patients harboured at least one of the three main driver alterations (mutations in MYD88/CD79B and/or CDKN2A-loss). In relapsed/refractory PCDLBCL-LT, these oncogenic aberrations were persistently present, demonstrating genetic stability over time. Novel alterations in relapsed disease affected mostly CDKN2A, MYC, and PIM1. Regarding survival, only MYC rearrangements and HIST1H1E mutations were statistically significantly associated with an inferior outcome. The stable presence of one or more of the three main driver alterations (mutated MYD88/CD79B and/or CDKN2A-loss) is promising for targeted therapies addressing these alterations and serves as a rationale for molecular-based disease monitoring, improving response evaluation and early identification and intervention of disease relapses in these poor-prognostic PCDLBCL-LT patients. Full article

(This article belongs to the Special Issue Treatment Resistance and Predictive Biomarkers in Lymphoid Malignancies)

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13 pages, 1388 KiB

Open AccessArticle

R1 Vascular or Parenchymal Margins: What Is the Impact after Resection of Intrahepatic Cholangiocarcinoma?

by Andrea Mabilia, Alessandro D. Mazzotta, Fabien Robin, Mohammed Ghallab, Eric Vibert, René Adam, Daniel Cherqui, Antonio Sa Cunha, Daniel Azoulay, Chady Salloum, Gabriella Pittau, Oriana Ciacio, Marc Antoine Allard, Karim Boudjema, Laurent Sulpice and Nicolas Golse

Cancers 2022, 14(20), 5151; https://doi.org/10.3390/cancers14205151 - 20 Oct 2022

Cited by 3 | Viewed by 1661

Abstract

Background: to date, long-term outcomes of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) have been examined in only one study which did not find significant difference. Patients and Methods: we analyzed consecutive patients [...] Read more.

Background: to date, long-term outcomes of R1 vascular (R1vasc) and R1 parenchymal (R1par) resections in the setting of intrahepatic cholangiocarcinoma (iCCA) have been examined in only one study which did not find significant difference. Patients and Methods: we analyzed consecutive patients who underwent iCCA resection between 2000 and 2019 in two tertiary French medical centers. We report overall survival (OS) and disease-free-survival (DFS). Univariate and multivariate analyses were performed to determine associated factors. Results: 195 patients were analyzed. The number of R0, R1par and R1vasc patients was 128 (65.7%), 57 (29.2%) and 10 (5.1%), respectively. The 1- and 2-year OS rates in the R0, R1par and R1vasc groups were 83%, 87%, 57% and 69%, 75%, 45%, respectively (p = 0.30). The 1- and 2-year DFS rates in the R0, R1par and R1vasc groups were 58%, 50%, 30% and 43%, 28%, 10%, respectively (p = 0.019). Resection classification (HR 1.56; p = 0.003) was one of the independent predictors of DFS in multivariate analysis. Conclusions: the survival outcomes after R1par resection are intermediate to those after R0 or R1vasc resection. R1vasc resection should be avoided in patients with iCCA as it does not provide satisfactory oncological outcomes. Full article

(This article belongs to the Section Cancer Therapy)

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17 pages, 4463 KiB

Open AccessArticle

Doped Ferrite Nanoparticles Exhibiting Self-Regulating Temperature as Magnetic Fluid Hyperthermia Antitumoral Agents, with Diagnostic Capability in Magnetic Resonance Imaging and Magnetic Particle Imaging

by Federica Vurro, Marco Gerosa, Alice Busato, Matilde Muccilli, Emil Milan, Jeff Gaudet, Patrick Goodwill, James Mansfield, Enrico Forlin, Alessandro Negri, Filippo Gherlinzoni, Giovanni Morana, Michele Gottardi, Paolo Matteazzi, Max Wintermark, Adolfo Speghini and Pasquina Marzola

Cancers 2022, 14(20), 5150; https://doi.org/10.3390/cancers14205150 - 20 Oct 2022

Cited by 6 | Viewed by 1706

Abstract

This paper reports a comprehensive investigation of a magnetic nanoparticle (MNP), named M55, which belongs to a class of innovative doped ferrite nanomaterials, characterized by a self-limiting temperature. M55 is obtained from M48, an MNP previously described by our group, by implementing an [...] Read more.

This paper reports a comprehensive investigation of a magnetic nanoparticle (MNP), named M55, which belongs to a class of innovative doped ferrite nanomaterials, characterized by a self-limiting temperature. M55 is obtained from M48, an MNP previously described by our group, by implementing an additional purification step in the synthesis. M55, after citrate and glucose coating, is named G-M55. The present study aimed to demonstrate the properties of G-M55 as a diagnostic contrast agent for MRI and magnetic particle imaging (MPI), and as an antitumoral agent in magnetic fluid hyperthermia (MFH). Similar specific absorption rate values were obtained by standard MFH and by an MPI apparatus. This result is of interest in relation to the application of localized MFH by MPI apparatus. We demonstrated the biocompatibility of G-M55 in a triple-negative human breast cancer line (MDA-MB-231), and its efficacy as an MFH agent in the same cell line. We also demonstrated the efficacy of MFH treatment with G-M55 in an experimental model of breast cancer. Overall, our results pave the way for the clinical application of G-M55 as an MFH agent in breast cancer therapy, allowing not only efficient treatment by both standard MFH apparatus and MPI but also temperature monitoring. Full article

(This article belongs to the Collection Hyperthermia in Cancer Therapy)

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30 pages, 1177 KiB

Open AccessEditor’s ChoiceReview

Dietary Interventions in Cancer Treatment and Response: A Comprehensive Review

by Benjamin D. Mercier, Eemon Tizpa, Errol J. Philip, Qianhua Feng, Ziyi Huang, Reeny M. Thomas, Sumanta K. Pal, Tanya B. Dorff and Yun R. Li

Cancers 2022, 14(20), 5149; https://doi.org/10.3390/cancers14205149 - 20 Oct 2022

Cited by 9 | Viewed by 6130

Abstract

Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient’s quality of life and even life-threatening. Diet is a [...] Read more.

Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient’s quality of life and even life-threatening. Diet is a modifiable risk factor that has been shown to affect cancer risk, recurrence, and treatment toxicity, but little information is known how diet interacts with cancer treatment modalities. Although dietary interventions, such as intermittent fasting and ketogenic diets, have shown promise in pre-clinical studies by reducing the toxicity and increasing the efficacy of chemotherapeutics, there remains a limited number of clinical studies in this space. This review surveys the impact of dietary interventions (caloric restriction, intermittent and short-term fasting, and ketogenic diet) on cancer treatment outcomes in both pre-clinical and clinical studies. Early studies support a complementary role for these dietary interventions in improving patient quality of life across multiple cancer types by reducing toxicity and perhaps a benefit in treatment efficacy. Larger, phase III, randomized clinical trials are ultimately necessary to evaluate the efficacy of these dietary interventions in improving oncologic or quality of life outcomes for patients that are undergoing chemotherapy or radiotherapy. Full article

(This article belongs to the Special Issue The Mechanisms of Physical Activity, Diet, and Body Composition in Cancer Prevention and Control)

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18 pages, 2915 KiB

Open AccessArticle

The METTL3 RNA Methyltransferase Regulates Transcriptional Networks in Prostate Cancer

by Daisy B. Haigh, Corinne L. Woodcock, Jennifer Lothion-Roy, Anna E. Harris, Veronika M. Metzler, Jenny L. Persson, Brian D. Robinson, Francesca Khani, Mansour Alsaleem, Atara Ntekim, Srinivasan Madhusudan, Melissa B. Davis, Kristian B. Laursen, Lorraine J. Gudas, Catrin S. Rutland, Michael S. Toss, Nathan Archer, Zsuzsanna Bodi, Emad A. Rakha, Rupert G. Fray, Jennie N. Jeyapalan and Nigel P. Mongan Show full author list Hide full author list

Cancers 2022, 14(20), 5148; https://doi.org/10.3390/cancers14205148 - 20 Oct 2022

Cited by 10 | Viewed by 2674

Abstract

Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are [...] Read more.

Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa. Full article

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14 pages, 1218 KiB

Open AccessArticle

Longitudinal Body Composition Changes Detected by [¹⁸F]FDG PET/CT during and after Chemotherapy and Their Prognostic Role in Elderly Hodgkin Lymphoma

by Domenico Albano, Francesco Dondi, Giorgio Treglia, Alessandra Tucci, Marco Ravanelli, Davide Farina and Francesco Bertagna

Cancers 2022, 14(20), 5147; https://doi.org/10.3390/cancers14205147 - 20 Oct 2022

Cited by 5 | Viewed by 1660

Abstract

The aim of this retrospective study was to investigate the longitudinal body changes in terms of muscle and adipose areas and their prognostic role in elderly (>65 years) patients affected by Hodgkin lymphoma (HL). Skeletal muscle area (SMA), skeletal muscle index (SMI), visceral [...] Read more.

The aim of this retrospective study was to investigate the longitudinal body changes in terms of muscle and adipose areas and their prognostic role in elderly (>65 years) patients affected by Hodgkin lymphoma (HL). Skeletal muscle area (SMA), skeletal muscle index (SMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intramuscular adipose tissue (IMAT), and total dispose tissue (TAT) were measured using the computed tomography (CT) of fluorine-18-fluorodeoxyglucose positron emission tomography/CT ([18F]FDG PET/CT) in 88 patients who undertook baseline, interim (after two cycles of chemotherapy), and end-of-treatment (after 6 cycles of chemotherapy) PET/CT scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured at pre-treatment PET/CT. Metabolic response applying Deauville score was evaluated at interim and end-of-treatment PET/CT. Survival curves, such as progression free survival (PFS) and overall survival (OS), were calculated for the whole population. Fifty-eight (66%) patients had sarcopenia at baseline and sarcopenia rate increased at interim scan with 68 (77%) cases and at end-of-treatment scan with 73 (83%) cases. Muscular areas (SMA and SMI) declined significantly during the treatment (p < 0.001), decreasing from baseline by 5% and 7% at interim and end-of-treatment evaluation, respectively. Instead, VAT, SAT, IMAT, and TAT increased significantly over this time (p < 0.001). Sarcopenia was significantly related with comprehensive geriatric assessment. PET/CT response at interim and end-of-treatment, MTV, TLG, and baseline sarcopenia were independent prognostic factors for PFS. Instead, metabolic response at interim and end-of-treatment PET, baseline sarcopenia, ΔSMI at interim, and ΔSMI at end-of-treatment for OS were independent prognostic factors. Full article

(This article belongs to the Topic Lymphoma: Update on the Role of Imaging in the Understanding, Diagnosis, Treatment and Management)

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19 pages, 3353 KiB

Open AccessArticle

Role of N-Cadherin in Epithelial-to-Mesenchymal Transition and Chemosensitivity of Colon Carcinoma Cells

by Veronika Skarkova, Barbora Vitovcova, Petra Matouskova, Monika Manethova, Petra Kazimirova, Adam Skarka, Veronika Brynychova, Pavel Soucek, Hana Vosmikova and Emil Rudolf

Cancers 2022, 14(20), 5146; https://doi.org/10.3390/cancers14205146 - 20 Oct 2022

Cited by 2 | Viewed by 1481

Abstract

(1) Background: N-cadherin expression, epithelial-to-mesenchymal transition (EMT) and aggressive biological phenotype of tumor cells are linked although the underlying mechanisms are not entirely clear. (2) Methods: In this study, we used two different in vitro cell models with varying N-cadherin expression (stabilized lines [...] Read more.

(1) Background: N-cadherin expression, epithelial-to-mesenchymal transition (EMT) and aggressive biological phenotype of tumor cells are linked although the underlying mechanisms are not entirely clear. (2) Methods: In this study, we used two different in vitro cell models with varying N-cadherin expression (stabilized lines and primocultures) and investigated their select biological features including the degree of their chemoresistance both in vitro as well as in vivo. (3) Results: We report that although enforced N-cadherin expression changes select morphological and behavioral characteristics of exposed cells, it fails to successfully reprogram cells to the aggressive, chemoresistant phenotype both in vitro as well as in vivo as verified by implantation of those cells into athymic mice. Conversely, primocultures of patient-colonic cells with naturally high levels of N-cadherin expression show fully aggressive and chemoresistant phenotype pertinent to EMT (in vitro and in vivo), with a potential to develop new mutations and in the presence of dysregulated regulatory pathways as represented by investigated miRNA profiles. (4) Conclusions: The presented results bring new facts concerning the functional axis of N-cadherin expression and related biological features of colon cancer cells and highlight colon cancer primocultures as a useful model for such studies. Full article

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13 pages, 4787 KiB

Open AccessArticle

by Ken Kudura, Lucas Basler, Lukas Nussbaumer and Robert Foerster

Cancers 2022, 14(20), 5145; https://doi.org/10.3390/cancers14205145 - 20 Oct 2022

Cited by 5 | Viewed by 1280

Abstract

Objectives: We aimed to investigate sex-related differences in patients with advanced melanoma treated with ICI by linking the assessment of inflammatory response in peripheral blood, onset of immune-related adverse events IRAEs during therapy and treatment response in short- and long-term. Methods: For the [...] Read more.

Objectives: We aimed to investigate sex-related differences in patients with advanced melanoma treated with ICI by linking the assessment of inflammatory response in peripheral blood, onset of immune-related adverse events IRAEs during therapy and treatment response in short- and long-term. Methods: For the purpose of this single-center retrospective study metastatic melanoma patients treated with ICI were included. Baseline patient characteristics, blood sample tests and the onset of immune-related adverse events IRAEs were documented based on clinical records. The short-term treatment response was assessed with ¹⁸F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT scans performed six months after initiation of ICI. The overall survival OS and progression-free survival PFS were used as endpoints to assess the long-term response to immunotherapy. Results: In total, 103 patients with advanced melanoma (mean age 68 ± 13.83 years) were included, 29 women (mean age 60.41 ± 14.57 years) and 74 men (mean age 65.66 ± 13.34 years). The primary tumor was located on a lower extremity in one out of three women and on the head/neck in one out of three men (p < 0.001). While the superficial spreading (41%) and nodular (36%) melanoma subtypes represented together 77% of the cases in male population, women showed a more heterogenous distribution of melanoma subtypes with the superficial spreading (35%), nodular (23%), acral lentiginous (19%) and mucosal (12%) melanoma subtypes being most frequent in female population (p < 0.001). Most differences between women and men with regards to inflammatory parameters were observed six months after initiation of ICI with a higher median NLR (p = 0.038), lower counts of lymphocytes (p = 0.004) and thrombocytes (p = 0.089) in addition to lower counts of erythrocytes (p < 0.001) and monocytes (p < 0.001) in women towards men. IRAEs were more frequent in women towards men (p = 0.013). Women were more likely to display endocrinological IRAEs, such as thyroiditis being the most frequent adverse event in women. Interestingly IRAEs of the gastrointestinal tract were the most frequent ones in men. Finally, men with advanced melanoma showed a significantly better response to immunotherapy in short- (p = 0.015) and long-term (OS p = 0.015 and PFS p < 0.001) than women. In fact, every fourth man died during the course of the disease, while every second woman did not survive. (p = 0.001). Conclusion: Men with advanced melanoma showed a significantly better response to immunotherapy in short- and long-term than women. Higher immune activation in peripheral blood before and after initiation ICI might be linked to favorable treatment response during and after ICI in favor of men and decoupled from the onset of IRAEs. Given the significantly higher immunotoxicity and worse outcome experienced by women compared to men the use of ICI should be chosen carefully in women with advanced melanoma. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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24 pages, 1257 KiB

Open AccessReview

The Role of Genomics and Proteomics in Lung Cancer Early Detection and Treatment

by Mohammad Hadi Abbasian, Ali M. Ardekani, Navid Sobhani and Raheleh Roudi

Cancers 2022, 14(20), 5144; https://doi.org/10.3390/cancers14205144 - 20 Oct 2022

Cited by 8 | Viewed by 3242

Abstract

Lung cancer is the leading cause of cancer-related death worldwide, with non-small-cell lung cancer (NSCLC) being the primary type. Unfortunately, it is often diagnosed at advanced stages, when therapy leaves patients with a dismal prognosis. Despite the advances in genomics and proteomics in [...] Read more.

Lung cancer is the leading cause of cancer-related death worldwide, with non-small-cell lung cancer (NSCLC) being the primary type. Unfortunately, it is often diagnosed at advanced stages, when therapy leaves patients with a dismal prognosis. Despite the advances in genomics and proteomics in the past decade, leading to progress in developing tools for early diagnosis, targeted therapies have shown promising results; however, the 5-year survival of NSCLC patients is only about 15%. Low-dose computed tomography or chest X-ray are the main types of screening tools. Lung cancer patients without specific, actionable mutations are currently treated with conventional therapies, such as platinum-based chemotherapy; however, resistances and relapses often occur in these patients. More noninvasive, inexpensive, and safer diagnostic methods based on novel biomarkers for NSCLC are of paramount importance. In the current review, we summarize genomic and proteomic biomarkers utilized for the early detection and treatment of NSCLC. We further discuss future opportunities to improve biomarkers for early detection and the effective treatment of NSCLC. Full article

(This article belongs to the Special Issue PI3K Pathway in Cancer)

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17 pages, 1471 KiB

Open AccessReview

Mapping Lymph Node during Indocyanine Green Fluorescence-Imaging Guided Gastric Oncologic Surgery: Current Applications and Future Directions

by Yiqun Liao, Jiahao Zhao, Yuji Chen, Bin Zhao, Yongkun Fang, Fei Wang, Chen Wei, Yichao Ma, Hao Ji, Daorong Wang and Dong Tang

Cancers 2022, 14(20), 5143; https://doi.org/10.3390/cancers14205143 - 20 Oct 2022

Cited by 2 | Viewed by 2273

Abstract

Huge strides have been made in the navigation of gastric cancer surgery thanks to the improvement of intraoperative techniques. For now, the use of indocyanine green (ICG) enhanced fluorescence imaging has received promising results in detecting sentinel lymph nodes (SLNs) and tracing lymphatic [...] Read more.

Huge strides have been made in the navigation of gastric cancer surgery thanks to the improvement of intraoperative techniques. For now, the use of indocyanine green (ICG) enhanced fluorescence imaging has received promising results in detecting sentinel lymph nodes (SLNs) and tracing lymphatic drainages, which make it applicable for limited and precise lymphadenectomy. Nevertheless, issues of the lack of specificity and unpredictable false-negative lymph nodes were encountered in gastric oncologic surgery practice using ICG-enhanced fluorescence imaging (ICG-FI), which restrict its application. Here, we reviewed the current application of ICG-FI and assessed potential approaches to improving ICG-FI. Full article

(This article belongs to the Special Issue Artificial Intelligence and MRI Characterization of Tumors)

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Cancers, Volume 14, Issue 20 (October-2 2022) – 205 articles

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