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Background: Germline genetic testing is traditionally carried out in patients suspected with hereditary cancer syndrome for enhanced cancer surveillance and/or preventive strategies, but is increasingly carried out for therapeutic indications., Materials and Methods: We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their clinical utility., Results: From 2000 to 2022, 1154 cancer patients underwent germline testing, with the majority (945/1154) tested with multi-gene panels. Four hundred and eleven (35.6%) patients harboured a PGV and 334 (81%) were clinically actionable. BRCA1/2 accounted for 62.3% of actionable mutations, followed by mismatch repair (18%), and other homologous recombination repair (HRR) genes (19.7%). One hundred and fifty-two germline-positive patients have advanced cancers, and 79 received germline-directed therapies (poly ADP ribose polymerase inhibitors = 75; immunotherapy = 4). Median duration of immunotherapy and poly ADP ribose polymerase were 20.5 months (range 5-40 months) and 8 months (range 1-76 months), respectively. Among BRCA/HRR mutation carriers who received platinum-based chemotherapy, pathological complete response rate in the neoadjuvant setting was 53% (n = 17 breast cancers) and objective response rate was >80% in the advanced setting (n = 71)., Conclusions: One-third of cancer patients tested carried a PGV and ∼80% were clinically actionable. Three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study investigates the differences in diagnostic performance between diffuse-weighted imaging (DWI) and dynamic contrast-enhanced imaging (DCE), either alone or in combination with T2-weighted imaging (T2WI), for diagnosing deep myometrial invasion (dMI) of endometrial cancers (EC)., Methods: We performed a comprehensive search for published studies comparing DWI and DCE for preoperatively diagnosing dMI of EC. The overall diagnostic accuracy of each test was calculated using the areas under the summary receiver operating characteristic curves (AUCs). The sensitivities and specificities were compared using bivariate meta-regression., Results: Pooled analysis of nineteen studies with 961 patients (main group) showed that DWI had a larger AUC (0.943, 95% confidence interval (CI) = 0.921-0.967) than DCE (0.922, 95% CI = 0.893-0.953). For the subgroup comprising 7 studies, DWI combined with T2WI and DCE combined with T2WI showed AUCs of 0.959 (95% CI, 0.932-0.986) and 0.929 (95% CI, 0.847-1.000), respectively. None of the differences in AUCs were statistically significant. All comparisons of the sensitivities and specificities of the main group and subgroup also showed no significant differences., Conclusion: This meta-analysis found no significant difference in diagnostic performance between DWI and DCE for diagnosis of dMI in EC. DWI may be preferred for its ease of use in clinical practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC)., Methods and Materials: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m 2 , concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m 2 ) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity., Results: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP., Conclusions: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m 2 . Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Current recommendation for locally advanced cervical cancer includes pelvic external beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy. Involvement of pelvic lymph nodes is an important prognostic factor in locally advanced cervical cancer and recurrence commonly occurs despite definitive treatment. To date, there is no standard guideline on whether an EBRT boost should be applied to involved pelvic lymph nodes. Our study aims to assess if pelvic EBRT boost would reduce recurrence, benefit survival, and affect associated toxicities., Methods: We conducted a retrospective review of locally advanced cervical cancer cases treated with definitive treatment at our institution. Involvement of pelvic lymph nodes were assessed on CT, MRI (> 10 mm or suspicious features) or PET scan (SUVmax > 2.5). EBRT dose ranged from 45 to 50.4 Gy with nodal boost ranging from 3.6-19.8 Gy., Results: Between 2008 to 2015, 139 patients with locally advanced cervical cancer underwent treatment. Sixty-seven patients had positive pelvic lymph nodes, of which 53.7% received a nodal boost. Five-year recurrence free survival was 48.6% with vs. 64.5% without nodal boost (P = 0.169) and 5-year overall survival in those with positive pelvic lymph nodes was 74.3% with vs. 80.6% without nodal boost (P = 0.143). There was no significant difference in toxicity with nodal boost., Conclusions: EBRT boost to pelvic lymph nodes does not reduce recurrence or improve survival in locally advanced cervical cancer with lymph node involvement at diagnosis.

Background: Developing multiple cancers is an indicator of underlying hereditary cancer predisposition, but there is a paucity of data regarding the clinical genetic testing outcomes of these patients., Methods: We compared cancer index patients with ≥2 primary malignancies versus 1 primary cancer who underwent clinical evaluation and testing with multi-gene panels comprising up to 49 genes from 1998-2016., Results: Among 1191 cancer index patients, 80.6%, 17.2%, and 2.2% respectively had 1, 2, and ≥3 primary malignancies. For patients with 2 primary cancers (n=205), the most common cancer pairs were bilateral breast (37.5%), breast-ovary (11.7%), endometrium-ovary (9.2%), colon-endometrium (3.9%) and colon-colon (3.4%). 42.3% patients underwent gene testing including 110/231 (47.6%) with multiple malignancies. Pathogenic variants were found more frequently in younger patients, in those with a family history of cancer related to the suspected syndrome, and a trend towards significance in those with multiple primary cancers (35.5% vs. 25.6%, p = 0.09). In patients with multiple cancers, pathogenic variants were most commonly identified in BRCA1 (38.5%), BRCA2 (17.9%), and the mismatch repair genes (20.5%), while 23.1% of pathogenic mutations were in other moderate- to high-penetrance cancer predisposition genes including APC, ATM, MUTYH, PALB2, RAD50 and TP53., Conclusion: Patients with multiple cancers were more likely to carry pathogenic mutations than those with single cancer. About three-quarters of deleterious mutations in patients with multiple primary cancers were in BRCA1/2 and the mismatch repair genes, but multi-gene panel testing facilitated the detection of mutations in another 6 genes and is warranted in this high-risk population., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Non-Hodgkin lymphoma of vulva is exceedingly rare and it often poses a diagnostic challenge if their existence is not suspected. We report a patient who has primary cutaneous anaplastic large cell (C-ALCL) with an unusual presentation as a vulvar ulcer. She received a brief course of chemotherapy followed by local irradiation and has remained disease-free more than a year from the time of diagnosis. To our knowledge, primary C-ALCL involving the vulva has never been reported. Despite its typical cutaneous manifestation of C-ALCL, the uncommon presenting site of this entity warrants recognition because of its prognostic and therapeutic implication.