Cancer Biology and Radiation Therapy

Using next-generation sequencing (NGS), we investigated DNA mutations in the plasma tumor cell-free circulating DNA (ctDNA) of 38 patients with inoperable squamous cell head neck cancer (SCHNC) before and after the completion of chemoradiotherapy (CRT). Baseline mutations of the TP53 were recorded in 10/38 (26.3%) and persisted in 4/10 patients after CRT. ΤP53 mutations were further detected post CRT in 7/38 additional patients with undetectable mutations at baseline (overall rate 44.7%). Furthermore, 4/38 patients exhibited baseline mutations of the EGFR, AR, FGFR3, and FBXW3, and four new gene mutations were detected after CRT (MTOR, EGFR3, ALK, and SF3B1). Τ4 stage was related with a significantly higher rate of mutations (TP53 and overall). Mutations were observed in 8/30 (26.6%) responders (complete/partial response) vs. in 6/8 (75%) of the rest of the patients (p = 0.03). Significant poorer LRFS was noted for patients with mutations detected before and after CRT (p = 0.02). Patients who had detectable mutations either before or after CRT had significantly worse DMFS (p = 0.04 overall, and p = 0.02 for TP53 mutations). It was concluded that assessment of mutations before and after the end of CRT is essential to characterize patients with a high risk of locoregional recurrence or metastatic progression. Full article

Since EXTRA, a non-randomized phase II trial with 31 patients, explored the use of capecitabine, mitomycin and radiation therapy (RT) in the treatment of localized squamous cell carcinoma of the anal canal (SCCAC), this treatment has been considered as an acceptable alternative to infusional 5-FU. However, the differences in efficacy between capecitabine and 5-FU in chemoradiation therapy (CRT) with simultaneous integrated boost (SIB) radiation therapy (SIB-IMRT) for local SCCAC are not well documented. Patients included in this prospective monocentric cohort study were treated with SIB-RapidArc (a unique RT method treatment for all patients: identical technique, volume and constraints for at-risk organs), mitomycin C and 5-FU each day of RT for 7 weeks (group 1) or capecitabine each day of RT (group 2). Patients treated between July 2009 and August 2017 (group 1) and between November 2012 and April 2018 (group 2) for local SCCAC T2-4 classified as N, M0 or T, N1-3, M0 were included. Primary endpoints were progression-free survival (PFS) and acute toxicities. Results: One hundred forty-seven patients were included, 91 in group 1 and 56 in group 2. The two groups were statistically comparable in terms of sex, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and TNM. With a median duration of follow-up of 53.5 months, the PFS rate at 3 years was 80% for group 1 and 75% for group 2 (p = 0.32). The 3-year colostomy-free survival rate was 92% for group 1 and 85% for group 2 (p = 0.11). The rate of patients with at least one grade 3 or higher acute toxicity was 35.5% in group 1 and 21.4% in group 2 (p = 0.10), with a trend of fewer acute toxicities with capecitabine. Conclusion: Capecitabine/mitomycin in combination with SIB RapidArc radiation therapy for anal cancer seems as effective as 5-FU-based chemotherapy and is well tolerated with minimal toxicity. Full article

Soft tissue sarcomas of the extremities are rare tumors with various prognostic factors. Their management is debatable due to their inconsistent results within the literature and the lack of large prospective studies. The objective of this systematic review is to analyze the available scientific data on prognostic factors concerning the characteristics of the patients, the disease and the treatments performed, as well as their potential complications, on studies with a median follow-up of 5 years at minimum. A search of articles following the “PRISMA method” and using the PubMed search engine was conducted to select the most relevant studies. Twenty-five articles were selected, according to preestablished criteria. This review provides a better understanding of the prognosis and disease outcome of these tumors. Many factors were described comparing the frequency of occurrence according to the studies, which remain heterogeneous between them. Significant factors that could orient patients to radiotherapy were highlighted. These positive prognostic factors provide valuable insight to optimize radiotherapy treatments for patients treated for soft tissue sarcoma of the extremities. Full article

Background: The treatment paradigm for locally advanced cervical cancer (LACC) has shifted from two-dimensional-brachytherapy (2D-BT) to three-dimensional-image-guided adaptive BT (3D-IGABT). In this retrospective study, we report our experience with the change from 2D-BT to 3D-IGABT. Methods: We reviewed 146 LACC patients (98 3D-IGABT and 48 2D-BT) who received chemoradiation between 2004 and 2019. The multivariable odds ratio (OR) for treatment-related toxicities and hazard ratios (HR) for locoregional control (LRC), distant control (DC), failure-free survival (FFS), cancer-specific survival (CSS) and overall survival (OS) are reported. Results: The median follow-up was 50.3 months. There was a significant decrease in overall late toxicities in the 3D-IGABT group compared to the 2D-BT group (OR 0.22[0.10–0.52]), late gastrointestinal (OR 0.31[0.10–0.93]), genitourinary (OR 0.31[0.09–1.01]) and vaginal toxicities (0% vs. 29.6%). Grade ≥ 3 toxicity was low in both groups (2D-BT: 8.2% acute, 13.3% late vs. 3D-IGABT: 6.3% acute, 4.4% late, NS). The five-year LRC, DC, FFS, CSS and OS for 3D-IGABT were 92.0%, 63.4%, 61.7%, 75.4% and 73.6%, compared to 87.3%, 71.8%, 63.7%, 76.3% and 70.8% for 2D-BT (NS). Conclusions: 3D-IGABT for the treatment of LACC is associated with a decrease in overall late gastrointestinal, genitourinary and vaginal toxicities. The disease control or survival outcomes were comparable to contemporary 3D-IGABT studies. Full article

The leading cause of death for patients with HPV associated squamous cell carcinoma of the head and neck (SCCHN) after treatment with chemoradiotherapy (CRT) nowadays is peripheral metastasis. This study investigated whether induction chemotherapy (IC) could improve progression free survival (PFS) and impact on relapse pattern after CRT. Methods: Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18–75 years, an ECOG performance status 0–1, and adequate organ functions. Results: From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4–92.8) in arm A and 78.4% (95% CI 69.5–88.3) in arm B (HR 1.39, 95% CI 0.69–2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. Conclusions: PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient. Full article

Protein kinases, found in the nucleus and cytoplasm, play essential roles in a multitude of cellular processes, including cell division, proliferation, apoptosis, and signal transduction. STK38 is a member of the protein kinase A (PKA)/PKG/PKC family implicated in regulating cell division and morphogenesis in yeast and C. elegans. However, its function remained largely unknown in mammals. In recent years, advances in research on STK38 and the identification of its substrates has led to a better understanding of its function and role in mammals. This review discusses the structure, expression, and regulation of activity as a kinase, its role in the DNA damage response, cross-talk with other signaling pathways, and its application for radio-sensitization. Full article

Background: We sought to investigate whether serum immune and inflammatory parameters can help to predict distant metastasis (DM) in patients with unresectable hepatocellular carcinoma (HCC) undergoing curative radiation therapy (RT). Methods: A total of 76 RT courses were analyzed. The following variables were included in the analysis: systemic inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), absolute lymphocyte count, lymphocyte-to-monocyte ratio, albumin, albumin-to-alkaline phosphatase ratio, RT-related parameters, and levels of total protein, hemoglobin, α-fetoprotein, and PIVKA-II. Distant control (DC) and overall survival (OS) rates were calculated and compared. Results: The mean age was 61.4 years, and most patients were men (n = 62, 81.6%). The median RT fraction number and fractional doses were 12 (range, 4–30) and 5 (range, 2–12) Gy, respectively. With a median follow-up of 12 (range, 3.1–56.7) months, the 1-year DC and OS rates were 64.4% and 55.2%, respectively. The development of DM significantly deteriorated OS (p = 0.013). In the multivariate analysis, significant independent prognostic indicators for DC and OS rates were the highest posttreatment PLR (≤235.7 vs. >235.7, p = 0.006) and the lowest posttreatment PNI (≤25.4 vs. >25.4, p < 0.001), respectively. Conclusions: Posttreatment serum PLR might be helpfully used as a predictive biomarker of DM in unresectable HCC patients undergoing RT. Future research is necessary to confirm our findings. Full article

Intracranial metastasis is very common in adult cancer patients with an overall incidence of approximately 10–40%. The most common primary tumors responsible for this in adults are lung and breast cancer. Brain metastasis signifies a grave prognosis, with a median survival of 6 to 12 months. They are traditionally managed with palliative care and whole brain radiotherapy (WBRT). WBRT was an effective method to control brain metastases, decreasing corticosteroid use to control tumor-associated edema, and potentially improving overall survival; however, WBRT was found to be associated with a serious neurocognitive degeneration, this adverse effect (AE) follows a biphasic pattern beginning with a transient decline in mental functioning at around 4 months post-treatment, slowly leading to an irreversible neurologic impairment from months to years later. Evidence supports that WBRT can cause radiation injury to the hippocampus, which in turn will lead to a decline in neurocognitive function (NCF). Volumetric modulated arc therapy (VMAT) is a relatively new type of image-guided radiotherapy that treats multiple brain metastasis simultaneously and efficiently with less neurocognitive sequelae. Eighteen cancer patients with limited (≤5 brain tumors) or oligometastatic brain tumor were treated with a spatially fractionated VMAT technique for a total dose of 30 Gy in 10 fractions, the patients tolerated the VMAT treatment with no radiation-induced neurologic toxicities after a mean follow-up of 1 year. Local control rate was 84%, and the median survival for these 19 patients was 11.3 months (range: 9.1–22.4 months). In conclusion, the VMAT is a suitable technique that is a safe and effective treatment for brain oligometastases. Full article

Immunotherapy is increasingly being used in the treatment of tumors. Adverse effects, however, are not uncommon, with the most common immune-related adverse events (IrAEs) including rash, fatigue, anemia, diarrhea, constipation, and elevated transaminase, among others. Rare IrAEs, which may include thrombocytopenia, hypoparathyroidism, pancreatitis glomerulonephritis, Guillain-Barré syndrome, and celiac disease, may also present. Immune checkpoint inhibitor (ICI)-induced primary hyperparathyroidism (PHPT) has not yet been reported on, and no research currently exists regarding its pathogenesis. We describe how a 50-year-old man diagnosed with advanced small-cell lung cancer (SCLC) developed severe PHPT after receiving the programmed cell death (PD)-1 inhibitor camrelizumab. The patient eventually died of respiratory failure and a progressive malignancy. We speculate that the hypercalcemia and hypophosphatemia observed in this case were secondary to ICI-induced PHPT. Although fatal PHPT is rare, early intervention may reduce the risk of future complications. Therefore, further exploration of the underlying mechanisms is needed to guide solutions. Full article

Background: After stereotactic body radiation therapy (SBRT) for lung tumors, follow-up CT scans remain a pitfall. The early detection of local relapse is essential to propose a new treatment. We aim to create a local recurrence predictive score using pre- and post-therapeutic imaging criteria and test it on a validation cohort. Methods: Between February 2011 and July 2016, lung tumors treated by SBRT with available pretreatment fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) and follow-up CT scans were retrospectively analyzed. The risk factors associated with relapse were identified by univariate logistic regression on a train cohort. The score was created using these factors, merging clinical and imaging criteria associated with local relapse, and then tested on an independent validation cohort. Overall and local relapse-free survival at 1 and 3 years were recorded. Results: Twenty-eight patients were included in the train cohort and ten in the derivation cohort (male 74%, median age 70 ± 12 years). Five variables significantly associated with local recurrence (female gender; sequential enlargement; craniocaudal growing; bulging margins; standardized uptake value (SUV_max > 5.5)) were combined to create the score on five points. With the threshold >2.5/5, the sensitivity and specificity of the score on the validation cohort were 100% and 88%, respectively. Overall survival and local relapse-free survival at 1 and 3 years were 89% and 42%, and 89% and 63%, respectively. Conclusion: The local recurrence risk score created has high sensitivity (100%) and specificity (88%), upon independent validation cohort, to detect local relapse. This score is easy to use in daily clinical practice. Full article

The purpose of the study was to calibrate and commission optically-stimulated luminescence dosimeters (OSLDs) for in vivo measurements in contact-based ¹⁹²Ir treatments for superficial high dose rate (HDR) brachytherapy in place of metal-oxide-semiconductor field-effect transistors (MOSFETs). Dose linearity and dose rate dependence were tested by varying source-to-OSLD distance and dwell time. Angular dependence was measured using a solid water phantom setup for OSLD rotation. A group of OSLDs were readout 34 consecutive times to test readout depletion while OSLDs were optically annealed using a mercury lamp for 34.7 h. End-to-end tests were performed using a Freiburg flap and Valencia applicator. OSLD measurements were compared to MOSFETs and treatment planning system (TPS) doses. OSLD response was supralinear for doses above 275 cGy. They were found to be independent of dose rate and dependent on the incident angle in edge-on scenarios. OSLDs exhibited minimal readout depletion and were successfully annealed after 24 h of illumination. Freiburg flap measurements agreed well with the TPS. For the Valencia, OSLDs showed to be the more accurate system over MOSFETs, with a maximum disagreement with the TPS being 0.09%. As such, OSLDs can successfully be used in place of MOSFETs for in vivo dosimetry for superficial HDR brachytherapy. Full article

Survival, recurrence, and xerostomia are considerable problems in the treatment of oral squamous carcinoma patients. In this study, we investigated the role of DMA (5-(4-methylpiperazin-1-yl)-2-[2′-(3,4-dimethoxyphenyl)5″benzimidazoyl]benzimidazole) as a salivary gland cytoprotectant in a patient-derived xenograft mouse model. A significant increase in saliva secretion was observed in the DMA-treated xenograft compared to radiation alone. Repeated doses of DMA with a high dose of radiation showed a synergistic effect on mice survival and reduced tumor growth. The mean survival rate of tumor-bearing mice was significantly enhanced. The increased number of Ki-67-stained cells in the spleen, intestine, and lungs compared to the tumor suggests DMA ablates the tumor but protects other organs. The expression of aquaporin-5 was restored in tumor-bearing mice injected with DMA before irradiation. The reduced expression of αvβ3 integrin and CD44 in DMA alone and DMA with radiation-treated mice suggests a reduced migration of cells and stemness of cancer cells. DMA along with radiation treatment results in the activation of the Ras/Raf/MEK/ERK pathway in the tumor, leading to apoptosis through caspase upregulation. In conclusion, DMA has strong potential for use as an adjuvant in radiotherapy in OSCC patients. Full article

External auditory canal (EAC) cancer is a rare disease for which there are no adequate evidence-based treatment strategies. Radiotherapy is often used as the initial treatment to preserve the organ. This study aimed to elucidate the efficacy of radiotherapy for EAC squamous cell carcinoma (SCC). Patients with T1 disease were treated with radiotherapy alone. Patients with T2–4 disease were treated with chemoradiotherapy. The median follow-up period was 30.4 months. The 3-year local control (LC) rate for all patients was 51%, the disease-free survival (DFS) rate was 44%, and the overall survival (OS) rate was 73%. For T1–3 disease, the 3-year LC rate was 74%, DFS was 62%, and OS was 89%. However, for T4 disease, the 3-year LC rate was 17%, DFS was 17%, and OS was 50%. In a univariate analysis, only the T-category was a significant factor for LC and DFS (p = 0.006 and 0.02, respectively). All local recurrences were within the high-dose irradiated area. The results of this study suggest chemoradiotherapy can be an alternative to a combination of surgery and postoperative radiation for T1–3 SCC of the EAC. However, the efficacy of chemoradiotherapy in T4 cases was inadequate. Full article

Preoperative concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced rectal cancer patients, but 20–30% do not benefit from the desired therapeutic effects. Previous reports indicate that high levels of ERCC1 reduce the effectiveness of cisplatin-based CCRT; however, it remains unclear as to whether ERCC1 overexpression increases radiation resistance. To clarify the correlation between ERCC1 levels and radiation (RT) resistance, we established two cell lines (HCT116-Tet-on and COLO205-Tet-on), induced them to overexpress ERCC1, detected cell survival following exposure to radiation, established HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models, and detected tumor volume following exposure to radiation. We found that ERCC1 overexpression increased radiation resistance. After regulating ERCC1 levels and radiation exposure to verify the correlation, we noted that increased radiation resistance was dependent on ERCC1 upregulation in both cell lines. For further verification, we exposed HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models to radiation and observed that ERCC1 overexpression increased colorectal cancer tumor radioresistance in both. Combined, our results suggest that ERCC1 overexpression may serve as a suitable CCRT prognostic marker for colorectal cancer patients. Full article

To evaluate the efficacy of proton beam therapy (PBT) as an initial treatment in treatment-naïve hepatocellular carcinoma (HCC) patients and to assess the prognostic significance of albumin-bilirubin (ALBI) grade, 46 treatment-naïve HCC patients treated with PBT were analyzed. The ALBI grade distribution was grade 1 in 11 (23.9%) patients, grade 2 in 34 (73.9%) patients, and grade 3 in 1 (2.2%) patient. The median duration of follow-up was 56.5 months (95% confidence interval [CI], 48.2–64.7). Among the 46 patients, disease progression was observed in 23 (50%) patients: local progression in 3 (6.5%) patients; intrahepatic progression in 22 (47.8%); and extrahepatic progression in 5 (10.9%). The 5-year freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) rates were 92.7% (95% CI, 84.7–100.7), 43.3% (95% CI, 28.2–58.4), and 69.2% (95% CI, 54.9–83.5), respectively. In multivariate analysis, there were no independent factors for FFLP (p > 0.05 each), but tumor stage and ALBI grade were independent factors for PFS and OS (p < 0.05 each). PBT could result in comparable OS in treatment-naïve HCC patients to other recommended first-line treatments, and ALBI grade, in addition to tumor stage, could be useful for predicting OS. Full article

Background: The aim of this study was to evaluate the impact of irradiation and time of irradiation on the ossification of jaws reconstructed with free bone grafts. Methods: In total, 100 reconstructions of the jaw were retrospectively evaluated for ossification between bone segments by two raters based on postoperative panoramic radiographs (immediate postOP, approximately 6, 12 and 24 months follow-up). Three subgroups were divided according to the time of irradiation: preoperative radiation therapy (n = 41), postoperative radiation therapy (n = 26) and patients without any radiation therapy (n = 33) as the control group. Ossification time and influencing factors were documented. Results: The fastest ossification with a median of 304 ± 37 days was observed (p < 0.001) in the nonirradiated control group. No significant difference (p = 0.087) in ossification was found between the pre- (447 ± 136 days) and postoperative (510 ± 112 days) radiation groups. Ossification between two graft segments (336 ± 38 days) showed significantly (p < 0.001) faster ossification than between the original and grafted bone (448 ± 85 days). Moreover, closer initial contact between the segments resulted in faster ossification (p < 0.001). When analyzing cofactors, tobacco consumption was the only negative factor aggravating ossification (p = 0.006). Conclusion: Head and neck radiation corresponded with the impaired and prolonged ossification of jaw reconstructions with free bone grafts. There was no difference in ossification if radiotherapy was performed before or after reconstructive surgery. A close bony contact was particularly important for ossification between the original and grafted bone. Full article

(1) Background: To report the long-term clinical outcomes of computer-tomography (CT)-guided brachytherapy (BT) for locally advanced cervical cancer. (2) Methods: A total of 135 patients with FIGO stage IB-IVA cervical cancer treated with definitive radiotherapy +/− chemotherapy with an IGABT boost at Queen Mary Hospital, Hong Kong, between November 2013 and December 2019 were included. Treatment included pelvic radiotherapy 40 Gy/20 Fr/4 weeks +/− chemotherapy then CT-guided BT (7 Gy × 4 Fr) and a sequential parametrial boost. The primary outcome was local control. Secondary outcomes were pelvic control, distant metastasis-free survival, overall survival (OS) and late toxicities. (3) Results: The median follow-up was 53.6 months (3.0–99.6 months). The five-year local control, pelvic control, distant metastasis-free survival and OS rates were 90.7%, 84.3%, 80.0% and 87.2%, respectively. The incidence of G3/4 long-term toxicities was 6.7%, including proctitis (2.2%), radiation cystitis (1.5%), bowel perforation (0.7%), ureteric stricture (0.7%) and vaginal stenosis and fistula (0.7%). Patients with adenocarcinomas had worse local control (HR 5.82, 95% CI 1.84–18.34, p = 0.003), pelvic control (HR 4.41, 95% CI 1.83–10.60, p = 0.001), distant metastasis-free survival (HR 2.83, 95% CI 1.17–6.84, p = 0.021) and OS (HR 4.38, 95% CI: 1.52–12.67, p = 0.003) rates. Distant metastasis-free survival was associated with HR-CTV volume ≥ 30 cm³ (HR 3.44, 95% CI 1.18–9.42, p = 0.025) and the presence of pelvic lymph node (HR 3.44, 95% CI 1.18–9.42, p = 0.025). OS was better in patients with concurrent chemotherapy (HR 4.33, 95% CI: 1.40–13.33, p = 0.011). (4) Conclusions: CT-guided BT for cervical cancer achieved excellent long-term local control and OS. Adenocarcinoma was associated with worse clinical outcomes. (4) Conclusion: CT-guided BT for cervical cancer achieved excellent long-term local control and OS. Adenocarcinoma was associated with worse clinical outcomes. Full article

The recurrence rate of cervical cancer after primary treatment can reach 60%, and a poor prognosis is reported in most cases. Treatment options for the recurrence of cervical cancer mainly depend on the prior treatment regimen and the location of recurrent lesions. Re-irradiation is still considered as a clinical challenge, owing to a high incidence of toxicity, especially in in-field recurrence within a short period of time. Recent advances in radiotherapy have preliminarily revealed encouraging outcomes of re-irradiation. Several centers have concentrasted on stereotactic body radiation therapy (SBRT) for the treatment of well-selected cases. Meanwhile, as the image-guiding techniques become more precise, a better dose profile can also be achieved in brachytherapy, including high-dose-rate interstitial brachytherapy (HDR-ISBT) and permanent radioactive seed implantation (PRSI). These treatment modalities have shown promising efficacy with a tolerable toxicity, providing further treatment options for recurrent cervical cancer. However, it is highly unlikely to draw a definite conclusion from all of those studies due to the large heterogeneity among them and the lack of large-scale prospective studies. This study mainly reviews and summarizes the progress of re-irradiation for recurrent cervical cancer in recent years, in order to provide potential treatment regimens for the management of re-irradiation. Full article

Background: This study evaluated the outcome, toxicity and predictive factors in patients unfit for concurrent chemo-radiotherapy (CT-RT) treated with hypofractionated sequential CT-RT or exclusive radiotherapy (RT) for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: We included patients affected by LA-NSCLC (stage IIA-IVA) treated with a total dose of 50–60 Gy in 20 fractions. The primary outcomes were local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS) and overall survival (OS). Univariate analysis was used to correlate outcomes with prognostic factors. Results: Between 2011 and 2019, 210 patients were treated, 113 (53.8%) with sequential CT-RT and 97 (46.2%) with exclusive RT. After a median follow-up of 15.3 months, 74 patients (35.2%) had a local progression and 133 (63.3%) had a distant progression. The one-, two- and five-year LC were 73.6%, 55.3% and 47.9%, respectively. At the time of analysis, 167 patients (79.5%) died. The one-, two- and five-year OS were 64.7%, 36% and 20%, respectively. PTV volume correlated with PFS (p = 0.001) and LC (p = 0.005). Acute and late toxicity occurred in 82% and 26% of patients. Conclusions: Albeit with the known limitations of a retrospective and heterogeneous study, our work shows that hypofractionated sequential CT-RT or exclusive RT offer a good local control and toxicity profile and a promising survival rate in LA-NSCLC patients unfit for the concurrent CT-RT scheme. Full article

The taxane family of microtubule poisons and chemotherapeutics have been studied for over 50 years and are among the most frequently used antineoplastic agents today. Still, limited research exists characterizing taxane-induced sex-specific mechanisms of action and toxicities in cancer and non-cancerous tissue. Such research is important to advance cancer treatment outcomes as well as to address clinically observed sex-differences in short- and long-term taxane-induced toxicities that have disproportionate effects on female and male cancer patients. To gain more insight into these underlying differences between the sexes, the following review draws from pre-clinical and clinical paclitaxel and taxane oncology literature, examines sex-discrepancies, and highlights uncharacterized sex-dependent mechanisms of action and clinical outcomes. To our knowledge, this is the first literature review to provide a current overview of the basic and clinical sex dimorphisms of taxane-induced effects. Most importantly, we hope to provide a starting point for improving and advancing sex-specific personalized chemotherapy and cancer treatment strategies as well as to present a novel approach to review sex as a biological variable in basic and clinical biology. Full article

Metastatic ureteral tumors arising from a primary breast carcinoma are extremely rare. They present with hematuria and radiological findings compatible with obstructive ureteral phenomena. We present a case of an 87-year-old woman with a history of lymphoma and triple negative breast cancer (TNBC), during an emergency admission for peptic ulcer, developed macroscopic hematuria. Radiologic and endoscopic investigations revealed a remarkable stenosis at the lower segment of the right ureter, attributed to metastases from her breast carcinoma. We report this case with the aim to make both oncologists and urologists aware of this rare condition. Full article

Radiotherapy (RT) is an essential part of breast cancer (BC) treatments. Unfortunately, heart exposure to radiation can also impair the long-term survival of patients. Our study aimed to quantify the oncological benefit and the cardiovascular (CV) risk associated with modern RT in a real-world cohort of BC patients. Our descriptive study enrolled BC patients who received adjuvant RT. Ten-year overall survival (OS) was estimated using Predict^® version 2.1 (National Health Service, London, UK). The basal risk of CV events was estimated using the American Heart Association (ACC/AHA) CV score. Treatment volumes and mean cardiac doses were obtained from RT treatment plan records. The increased risk of CV events due to RT was estimated using a model proposed by Darby. The risk of acute myocardial infarction or stroke mortality was estimated using HeartScore^® (European Society of Cardiology, Brussels, Belgium). A total of 256 BC patients were included in the study. The average age of patients was 57 years old (range: 25–91); 49.6% had left BC. The mean cardiac dose was 166 cGy (interquartile range (IQR) 94–273); the estimated hazard ratio (HR) for CV disease was HR 1.12 (confidence interval (CI) 1.04–1.24). The estimated baseline 10-year CV risk was 5.6% (0.2 to 51.2); CV risk increased by 0.9% (range 0.02–35.47%) after RT. The absolute risk of 10-year mortality from CV disease was 2.5% (0.1–9); RT was associated with an estimated 4.9% survival benefit (3.73–6.07) against BC death and a 0.23% (0.17–0.29) estimated increase in CV mortality. Modern RT decreased 10-year BC mortality by 4% but increased CV mortality by 0.2% in this cohort. Our findings encourage the implementation of personalized adjuvant RT treatments that balance risks and benefits to improve long-term BC patient survival. Full article

Background and Objectives: The development of radioresistance is a fundamental barrier to successful glioblastoma therapy. Autophagy is thought to play a role in facilitating the DNA repair of DNA damage foci in radiation-exposed tumor cells, thus, potentially contributing to their restoration of proliferative capacity and development of resistance in vitro. However, the effect of autophagy inhibitors on DNA damage repair is not fully clear and requires further investigation. Materials and Methods: In this work, we utilized M059K (DNA-PKcs proficient) and M059J (DNA-PKcs deficient) glioma cell lines to investigate the role of autophagy inhibitors in the DNA repair of radiation-induced DNA damage. Cell viability following radiation was determined by trypan blue exclusion in both cell lines. Cell death and autophagy assays were performed to evaluate radiation-induced cell stress responses. DNA damage was measured as based on the intensity of phosphorylated γ-H2AX, a DNA double-stranded breaks (DSBs) marker, in the presence or absence of autophagy inhibitors. Results: The cell viability assay showed that M059J cells were more sensitive to the same dose of radiation (4 Gy) than M059K cells. This observation was accompanied by an elevation in γ-H2AX formation in M059J but not in M059K cells. In addition, the DAPI/TUNEL and Senescence-associated β-galactosidase (SA-β-gal) staining assays did not reveal significant differences in apoptosis and/or senescence induction in response to radiation, respectively, in either cell line. However, acridine orange staining demonstrated clear promotion of acidic vesicular organelles (AVOs) in both cell lines in response to 4 Gy radiation. Moreover, DNA damage marker levels were found to be elevated 72 h post-radiation when autophagy was inhibited by the lysosomotropic agent bafilomycin A1 (BafA1) or the PI3K inhibitor 3-methyl adenine (3-MA) in M059K cells. Conclusions: The extent of the DNA damage response remained high in the DNA-PKcs deficient cells following exposure to radiation, indicating their inability to repair the newly formed DNA-DSBs. On the other hand, radioresistant M059K cells showed more DNA damage response only when autophagy inhibitors were used with radiation, suggesting that the combination of autophagy inhibitors with radiation may interfere with DNA repair efficiency. Full article

Microenvironmental conditions control the entrance and thriving of cytotoxic lymphocytes in tumors, allowing or preventing immune-mediated cancer cell death. We investigated the role of tumor-infiltrating lymphocyte (TIL) density in the outcome of radiotherapy in a series of squamous cell head–neck tumors (HNSCC). Moreover, we assessed the link between markers of hypoxia and TIL density. One-hundred twenty-one patients with HNSCC treated prospectively with radical radiotherapy/chemo-radiotherapy were analyzed. The assessment of TIL density was performed on hematoxylin and eosin biopsy sections before radiotherapy. TIL density ranged from 0.8 to 150 lymphocytes per ×40 optical field (median 27.5). Using the median value, patients were grouped into two categories of low and high TIL density. Early T-stage tumors had a significantly higher TIL density (p < 0.003), but we found no association with N-stage. Overexpression of HIF1α, HIF2α, and CA9 was significantly linked with poor infiltration by TILs (p < 0.03). A significant association of high TIL density with better disease-specific overall survival and improved locoregional relapse-free survival was noted (p = 0.008 and 0.02, respectively), which was also confirmed in multivariate analysis. It is concluded that HNSCC phenotypes that allow for the intratumoral accumulation of lymphocytes have a better outcome following radical radiotherapy/chemo-radiotherapy. Intratumoral-activated HIF- and CA9-related pathways characterize immunologically cold tumors and may be used as targets for therapeutic interventions. Full article

Sarcoma can present as locally advanced disease involving pleura for which extra-pleural pneumonectomy (EPP) may be the only surgical option to ensure adequate local control. Data were collected on patients who underwent EPP between January 2009 and August 2021 at Princess Margret Hospital and SickKids (Toronto) using the CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration). Ten patients with locally advanced sarcoma involving the pleura, aged 4 to 59 years (median 19.5 years) underwent EPP. Nine (90%) received pre-operative chemotherapy and eight (80%) achieved an R0 resection. Hemithoracic radiation was administered preoperatively (n = 6, 60%) or postoperatively (n = 4, 40%). Five (50%) patients were alive without disease at last follow-up (median 34.2 months) and time from EPP to last FU was median 29.2 months (range 2.2–87.5). Two patients (20%) had local recurrence, 4.3 and 5.8 months from EPP, and both died from progressive disease, 13.1 and 8.2 months from EPP, respectively. One patient died from brain metastasis (17 months), one died from radiation associated osteosarcoma (66 months), and one died from surgical complications (heart failure from constrictive pericarditis). EPP offers a feasible and life-prolonging surgical consideration for patients with locally advanced sarcoma involving the pleura in combination with chemotherapy and radiation. Consequently, EPP should be considered during multi-disciplinary tumor board discussions at high-volume centers. Full article

Background and Objectives: Reducing time of treatment during COVID-19 outbreaks has been recommended by the leading Radiation Oncology societies. Still minimizing radiation induced tissue toxicity is one of the most important issues in breast cancer patients. The study aimed to investigate compliance, clinical and dosimetry normal tissue toxicity, and cosmetic results between moderated and ultra-fractionated regimes for breast cancer patients during COVID-19 pandemic. Materials and Methods: This pilot prospective randomized study included 60 patients with early breast cancer after preserving surgery, 27 patients advocated to ultra-hypofractionated whole-breast three dimensional (3D) conformal radiotherapy of 26 Gy in 5 fractions over 1 week and 33 patients with moderate fractionated breast 3D conformal radiotherapy patients between March 2020 and July 2020, during the COVID pandemic outbreak. The compliance to treatment, dosimetric parameters, acute and late skin toxicity, subcutaneous tissue toxicity, cosmetic results and clinical follow up for 18 months for the two regimes were analyzed and compared. Results: When two regimes were compared 5 fraction group had significantly lower prevalence of newly infected cases of SARS-CoV-2 and thus delayed/interrupted treatment (p = 0.05), comparable grade 1 CTCAE v5, acute skin toxicity (p = 0.18), Grade 1 Radiation Morbidity Scoring Scheme (RESS) subcutaneous tissue toxicity (p = 0.18), Grade 1 RESS late skin toxicity (p = 0.88) and cosmetic results (p = 0.46). Dosimetric results reveled that patients in 5 fraction group received significantly lower median ipsilateral lung doses (p < 0.01) in addition to left breast cancer patients that received significantly lower median heart dose (p < 0.01) and median left anterior descending artery (LAD) dose (p < 0.01). Conclusion: Ultra-hypofractionated radiotherapy for breast cancer is comparable to moderate hypofractionation regimen regarding grade 1 acute skin toxicity, grade 1 subcutaneous tissue toxicity, late skin toxicity and cosmetic results. Application of ultra-hypofractionated radiotherapy with significantly lower radiation doses for lung and heart could be crucial in reducing the risk of acute/late pulmonary and heart radiation-induced toxicity. Full article

Background and objectives: The multidrug resistance protein 4 (MRP4) is a member of the ABC transporter, which has been extensively related to many types of cancer including leukemia. MRP4 overexpression and activity over the efflux of some chemotherapeutic drugs are the main causes of chemoresistance. 6-mercaptopurine (6-MP) is a chemotherapeutic drug widely used in the consolidation and maintenance phases of leukemia treatment. However, 6-MP is a substrate of MRP4, which decreases its chemotherapeutic efficacy. Current research is focused on the development of MRP4 inhibitors to combat chemoresistance by allowing the accumulation of the drug substrates inside the cells. To date, the only specific MRP4 inhibitor that has been developed is ceefourin-1, which has been reported to inhibit MRP4 in many cancer cells and which makes it an excellent candidate to enhance the activity of 6-MP in a combined treatment in vitro of leukemic cells. Materials and methods: in the present work, we determined the enhancing activity of ceefourin-1 on the antiproliferative and apoptotic effect of 6-MP in leukemic Jurkat cells by trypan blue assay and flow cytometry. Besides, we determined the 6-MP and ceefourin-1 binding sites into MRP4 by molecular docking and molecular dynamics. Results: ceefourin-1 enhanced the apoptotic activity of 6-MP in Jurkat cells, while in CRL-1991 cells both antiproliferative and apoptotic effect were significantly lower. Ceefourin-1 additively cooperates with 6-MP to induce apoptosis in leukemic cells, but normal lymphoblast CRl-1991 showed resistance to both drugs. Conclusion: ceefourin-1 and 6-MP cooperates to trigger apoptosis in leukemic Jurkat cells, but the full mechanism needs to be elucidated in further works. In addition, our perspective is to test the cooperation between ceefourin-1 and 6-MP in samples from patients and healthy donnors. Full article

The purpose of this study was to assess organ dosimetry and clinical use of [¹²⁴I]I-NM404, a radiotheranostic alkylphosphocholine (APC) analog, for accurate detection and characterization of a wide variety of solid primary and metastatic malignancies anywhere in the body. Methods: Patterns of [¹²⁴I]I-NM404 uptake were quantitatively analyzed and qualitatively compared with [¹⁸F]FDG PET/CT in 14 patients (median age, 61.5 years; 7 males, 7 females) with refractory metastatic cancer who were enrolled in one of two Phase I imaging studies. Primary cancer types included bronchogenic (n = 7), colorectal (n = 1), prostate (n = 1), triple-negative breast (n = 1), head and neck (n = 2), pancreatic (n = 1) carcinoma, and melanoma (n = 1). Patients were administered [¹²⁴I]I-NM404 and imaged via PET/CT at 1–2, 4–6, 24, and 48 h and at 5–10 days post injection, from top of the skull to mid-thigh. Volumes of interest were drawn over lungs, heart, liver, kidneys, and whole body for dosimetry estimation using OLINDA 1.1 Representative metastatic index lesions were chosen when applicable for each case with active sites of disease to calculate maximum and mean tumor-to-background ratios (TBRmax, TBRmean), using the adjacent normal organ parenchyma as background when possible. Results: Administrations of [¹²⁴I]-NM404 were safe and well-tolerated. The organs with the highest estimated absorbed dose (mean ± SD) were the lungs (1.74 ± 0.39 mSv/MBq), heart wall (1.52 ± 0.29 mSv/MBq), liver (1.28 ± 0.21 mSv/MBq) and kidneys (1.09 ± 0.20 mSv/MBq). The effective dose was 0.77 ± 0.05 mSv/MBq. Preferential uptake within metastatic foci was observed with all cancer subtypes, TBRmax ranged from 1.95 to 15.36 and TBRmean ranged from 1.63 to 6.63. Robust sensitive imaging of lesions was enhanced by delayed timing (2–6 days after single injection of [¹²⁴I]I-NM404, respectively) due to persistent tumor retention coupled with progressive washout of background activity. NM404 uptake was evident in pulmonary, nodal, skeletal, CNS, and other metastatic sites of disease. Radiation related injury or necrosis were NM404 negative, whereas certain small number of metastatic brain lesions were false negative for NM404. Conclusions: In addition to being well tolerated, selective tumor uptake of NM404 with prolonged retention was demonstrated within a broad spectrum of highly treated metastatic cancers. Full article

A crucial issue in radical radiation therapy for non-small-cell lung cancer is how to define the clinical target volume (CTV). Although the scope of microscopic extension (ME) and microscopic proximal bronchial extension (PBE) from a primary tumor should be considered when defining the CTV, there has been limited research on ME and PBE. Therefore, we conducted this systematic review. The PubMed, ICHUSHI (Japanese database), and Cochrane Library databases were searched, and 816 articles were initially retrieved. After primary and secondary screenings, eight articles were ultimately selected. The results of this systematic review suggest the importance of a 0 mm margin in stereotactic radiotherapy for early-stage cancer and a 5–8 mm margin in curative irradiation for locally advanced cancer. Regarding PBE, this review yielded the conclusion that it is appropriate to consider the addition of an approximately 15 mm margin from the bronchial vasculature. Although there were few articles with a high level of evidence, this systematic review enabled us to collate results from previous studies and to provide recommendations, to some extent, regarding the CTV margin in the current clinical environment, where high-precision radiation therapy, such as image-guided radiotherapy and intensity-modulated radiotherapy, is predominant. Full article

Background: Proton beam therapy (PBT), as a neoadjuvant chemoradiotherapy (nCRT) modality, is expected to result in better outcomes than photon-based radiotherapy (RT) for esophageal cancer, particularly adenocarcinoma. This study reports the results of nCRT for locally advanced esophageal squamous cell carcinoma (ESCC) using both modalities. Methods: We retrospectively reviewed the records of patients who underwent nCRT for ESCC between 2001 and 2020. A median of 41.4 Gy or cobalt gray equivalents of radiation was delivered using either photons or protons, with concurrent chemotherapy. Dosimetric and clinical parameters were compared between the two groups. Results: Of the 31 patients, the lungs and heart of the proton group (n = 15) were exposed to significantly less radiation compared to the photon group (n = 16). No significant differences in short-term postoperative outcomes or lymphocyte count were observed between the groups, and there were no significant differences between the photon and proton groups in 2-year overall survival (67.8% vs. 68.6%, p = 0.867) or 2-year disease-free survival (33.3% vs. 34.5%, p = 0.749), with a median follow-up of 17 months. Conclusions: PBT provided a significant dosimetric benefit over photon-based RT during nCRT for ESCC; however, it did not improve clinical outcomes. Full article