tbuckley/cabot-search huggingface dataset:
A systematic literature review and indirect treatment comparison of PARP inhibitors in combination with next-generation hormonal agents in BRCA-mutated metastatic castration-resistant prostate cancer.
Authors: Neal D. Shore, Jack Williams, Derek L. Clouthier, Stephanie L. Swift, Sophie Tatman, Shona Lang, Robert Hettle
Journal: Journal of Clinical Oncology (2024)

e17029 Background: In the USA, several poly(ADP-ribose) polymerase inhibitors (PARPi) are approved in combination with next-generation hormonal agents (NHAs) for metastatic castration resistant-prostate cancer (mCRPC), including olaparib plus abiraterone acetate with prednisone/prednisolone (OLA+AA/P) and niraparib plus AA/P (NIRA+AA/P) for mCRPC with BRCA1 and/or BRCA2 mutations (BRCAm), and talazoparib plus enzalutamide (TALA+ENZ) for mCRPC with homologous recombination repair mutations, including BRCAm. All approvals were based on placebo (PBO)-controlled Phase III trials. To support clinical decision-making, we performed a systematic literature review and indirect treatment comparison (ITC) to assess the comparative efficacy and safety of regimens. Methods: Published clinical trials were identified by searching Embase, MEDLINE, Evidence-Based Medicine Reviews database, conferences and registries up to September 2023. Studies reporting radiographic progression-free survival (rPFS), overall survival (OS), and/or safety outcomes for mCRPC were included. The feasibility of performing anchored or unanchored ITCs using BRCAm subgroup data was assessed. Where feasible, Bayesian ITCs were performed using BRCAm subgroup hazard ratios (HRs) for investigator-assessed rPFS, blinded independent central review (BICR) rPFS, and OS. Safety ITCs were performed using overall study data and reported as risk differences (RD) for adverse events (AEs). Results: Thirty-nine studies were identified, of which three reported BRCAm-specific data, including PBO-controlled studies for OLA+AA/P, NIRA+AA/P, and TALA+ENZ. An anchored ITC was feasible for OLA+AA/P and NIRA+AA/P using PBO+AA/P as a common comparator. ITC results showed a significant improvement in rPFS and OS, and a numerical reduction in AE risk for OLA+AA/P vs NIRA+AA/P (Table). TALA+ENZ was excluded from the ITC as it was not possible to form a network with OLA+AA/P or NIRA+AA/P due to differences in NHA use (ENZ vs AA/P) in PBO-control arms, whilst data limitations prevented unanchored ITCs. Conclusions: In BRCAm mCRPC, ITC results suggest that OLA+AA/P has improved efficacy and a favorable safety profile vs NIRA+AA/P. Current evidence does not allow for a robust comparison of OLA+AA/P or NIRA+AA/P with TALA+ENZ in BRCAm mCRPC. [Table: see text]
Dosimetry of lutetium-177 PSMA-targeted radiopharmaceutical therapies for prostate cancer patients: A comparative systematic review and meta-analysis.
Authors: Zachary Ells, Magnus Dahlbom, Johannes Czernin, Tristan Grogan, Jeremie Calais
Journal: Journal of Clinical Oncology (2024)

e17033 Background: Novel theranostic approaches using radiopharmaceuticals targeting PSMA have emerged for treating metastatic castrate resistant prostate cancer (mCRPC). The physical properties and commercial availability of Lutetium-177 (Lu177) makes it one of the most used radionuclides for radiopharmaceutical therapy (RPT). In this review we aimed at comparing the dosimetry of the most used Lu177-PSMA RPT compounds. Methods: This is a systematic review and meta-analysis of Lu177-PSMA RPT (617, I&amp;T, and J591) dosimetry for prostate cancer. Absorbed doses in Gy/GBq for each organ (kidney, parotid and submandibular glands, bone marrow, liver, lacrimal glands) and for tumor lesions (bone and non- bone lesions) were extracted. These were used to estimate the pooled average absorbed dose of each RPT, and normalize each to the respective injected activity (Gy/cycle) as determined by the dose per cycles used in VISION (7.4 GBq), SPLASH (6.8 GBq), and PROSTACT Trials (5.8 GBq). Results: 29 published manuscripts comprising 535 patients were included in the meta-analysis. The pooled dose was calculated for kidney based on (28 studies, 485 patients), parotid (20, 309), submandibular (7, 100) and lacrimal glands (9, 174), bone marrow (18, 293), and liver (14, 245) were 4.04 and 4.70, 5.85 and 2.62, 5.15 and 4.35, 11.03 and 19.23, 0.24 and 0.19 and 1.11 and 0.56 Gy respectively for Lu177-PSMA-617 and Lu177-PSMA-I&amp;T. Lu177-PSMA-J591 reported absorbed doses to the kidney, bone marrow and liver were 3.95, 0.90, and 5.88 Gy respectively. There was no significant difference between Lu177-PSMA-I&amp;T and Lu177-PSMA-617 for the dose to kidneys (p=0.10), submandibular glands (p=0.56), bone marrow (p=0.31), lacrimal glands (p=0.20), or tumors (p=0.16). However, parotid dose from Lu177-PSMA-617 was higher than that of Lu177-PSMA-I&amp;T (p=&lt;0.01). Average tumor doses tended to be higher for Lu177-PSMA-617 than for Lu177-PSMA-I&amp;T, (27.94 vs. 21.31 Gy); p=0.16. Lu177-PSMA-J591 exposed the bone marrow and liver, to a significantly higher dose while resulting in a lower dose to the kidney than either of the two small molecule compounds. Absorbed doses to the salivary glands, lacrimal glands, and tumors after the treatment with Lu177-PSMA-J591 have not been published yet. Conclusions: The clinical impact of higher tumor to kidney dose ratio for Lu177-PSMA-617 than Lu177-PSMA-I&amp;T has yet to be determined. Data for Lu177-PSMA-J591 are thus far too limited to draw firm conclusions.
Emergency treatment for primary intracranial germ cell tumours (PICGCTs).
Authors: Ravindhi Murphy, Jodie Russell, Thomas Talbot, Mark Lythgoe, Gina Sherpa, Eunice Yun Xing, Sanjay Khanna, Ling Li, Terry Tin, Sabrina Kalam, Victoria Singh-Curry, Ehsan Ghorani, Reece Caldwell, Naveed Sarwar, Michael Seckl, Michael Gonzalez
Journal: Journal of Clinical Oncology (2024)

e17020 Background: PICGCTs arise de novo in children and young adults, most frequently in the pineal or suprasellar regions. Here, we evaluate the acute pathway for patients (pts) with PICGCTs managed at our Emergency Cancer Treatment Centre. Methods: Retrospective observational study from 1984-2022 at a single institution. Data was collected from paper and electronic patient records for all PICGCT pts, including pts treated with our intracranial regimen EP-OMB (Etoposide-Cisplatin alternating every week with Vincristine-Methotrexate-Bleomycin) administered with and without intrathecal Methotrexate. Results: To date, we have identified 43 pts with intracranial disease treated at our Centre over 38 years: 25 pts (58%) with PICGCT, 18pts (42%) with germ cell tumour brain metastases treated with EP-OMB and excluded from analysis. Most PICGCT pts are male (92%, n=23) with a median age 25 (range 17-50). The majority present with symptomatic disease (88%, n=22) confined to the pineal gland (72%, n=18), with hormone dysfunction in 24% ( n=6). Only two female pts (8%) have presented with suprasellar and pituitary midline lesions causing headache, progressive visual loss and hypothalamic failure including cranial diabetes insipidus. Eloquent areas in the brain cannot be biopsied so only 60% PICGCTs ( n=15) were confirmed histologically, 47% as germinoma ( n=7), 27% dysgerminoma ( n=4), 27% unclassified ( n=4). Tumour markers (TM) were elevated in all pts with cerebrospinal fluid (CSF) evaluation ( n=5) compared to elevated serum TM in under half (44%, n=12). 68% pts required emergency treatment for a new cancer diagnosis ( n=17): neurosurgery (59%, n=10), chemotherapy (35%, n=6) or radiotherapy (6%, n=1). 88% PICGCT pts received EP-OMB ( n=22) with intrathecal Methotrexate in 63% ( n=14). For all PICGCT pts, 72% pts remain alive ( n=18) with median follow-up 3.8 years (range 0.2-27.3). For 36% pts with TM relapse or radiological progression despite treatment ( n=9), 44.4% remain alive ( n=4) with median overall survival at 6.8 years (range 1.1-18.6). Conclusions: PICGCT pts frequently require emergency surgical treatment for a new cancer diagnosis. Although rare, accurate diagnosis will affect management and prognosis in this young patient group. CSF rather than serum TM analysis is crucial for diagnostic work-up. Consensus on optimal management is warranted given the potential toxicity from multiple therapeutic interventions administered with curative intent.
Impact of hospital volume on outcomes of autologous stem cell transplant (ASCT) in patients with testicular cancer.
Authors: Paramveer Singh, Jasmeet Kaur, Tanveer Mir, Waqas Qureshi
Journal: Journal of Clinical Oncology (2024)

e17021 Background: ASCT has a potential to achieve cure in relapsed refractory testicular cancers (TC). A large volume hospital (LVH) is generally recommended but the impact of hospital volume on the outcomes of this therapy is not clearly known. Methods: We included 39435 adult (&gt;18 years) patients with TC from national inpatient sample database from 2016 – 2018. Patients were stratified based on hospital volume. Based on the weighted number of ASCT performed annually, LVH were defined as &gt;45 annual cases, and small volume hospitals (SVH) were defined &lt;25 annual cases. Subgroup analysis was performed for the patients with brain metastasis. Results: A total of 1,225 patients (3.1%) with TC underwent ASCTs between 2016 and 2020. Baseline characteristics are summarized in the table. Patients treated at LVH exhibited a significantly higher median age (p &lt; 0.01), had more proportion with private insurance (p =0.003). Patients treated at SVH experienced significantly higher rates of pneumonia (p &lt; 0.01), vtach (p = 0.02), and neurologic complications (p = 0.02) compared to those at medium volume (MVH) or LVH. Length of stay exceeding 18 days (LOS18) was significantly longer in SVH compared to LVH (p = 0.02). No significant differences in in-hospital mortality were observed based on hospital volume (p = 0.86), even among patients with brain metastases (p = 0.78). LVH had a significantly higher proportion of patients with private insurance compared to MVH and SVH (p = 0.003). Health care costs were significantly higher in SVH and MVH for patients with brain metastases undergoing ASCT compared to LVH (p &lt; 0.01). In adjusted analysis, significant predictors for mortality included liver disease (OR: 6.12, (95% CI: 4.1 to 266); p &lt; 0.01), and electrolyte imbalance (OR: 19, 95% CI (1.6 to 233); p = 0.02). Predictors for LOS18 included AKI (IRR: 1.8, 95% CI (1.17 to 3.05); p = 0.009) and vtach (IRR: 1.04, (1.28 to 8.3); p &lt; 0.01). In LVH, LOS18 was significantly lower (IRR: 0.40, (0.20 to 0.78); p = 0.008). Conclusions: ASCT-related complication rates and length of stay were higher in small volume hospitals that treated testicular cancer which also correlated with higher costs. The study suggests that ASCT should be considered in large volume hospitals. [Table: see text]
Population-based germline breast cancer gene association studies and meta-analysis to inform wider mainstream testing.
Authors: C.F. Rowlands, S. Allen, J. Balmaña, S.M. Domchek, D.G. Evans, H. Hanson, N. Hoogerbrugge, P.A. James, K.L. Nathanson, M. Robson, M. Tischkowitz, W.D. Foulkes, C. Turnbull
Journal: Annals of Oncology (2024)

Germline genetic testing, previously restricted to familial and young-onset breast cancer, is now offered increasingly broadly to patients with 'population-type' breast cancer in mainstream oncology clinics, with wide variation in the genes included.
The role of TROP-2 in the progression and target therapy in penile squamous cell carcinoma.
Authors: Yi Tang, Xingliang Tan, Zhicheng Liu, Qianghua Zhou, Wensu Wei, Gangjun Yuan, Kai Yao
Journal: Journal of Clinical Oncology (2024)

e17023 Background: Penile squamous cell carcinoma(PSCC) is a devastating malignancy of urogenitary system. However, current chemotherapy treatments including TIP regimen has showed limited effects but strong side effects in advanced PSCC. Trophoblast cell-surface antigen-2 (Trop-2) is a novel target for Antibody-drug conjugates (ADC) drugs and is proved to be effective in several human cancers, but its role in PSCC has not been clearly certified. Methods: 198 PSCC tumor tissue specimens and clinicopathological data were collected. TROP-2 expression was detected by IHC experiments and the correlation between TROP-2 expression and clinicopathological data of patients was analyzed through statistical methods. Then a series of in vivo and in vitro experiments were conducted to investigate the mechanism that how TROP-2 promote PSCC cell proliferation. Results: IHC results showed that TROP-2 was highly expressed in 60.2% of tumor specimens, and statistical analysis revealed a positive association of TROP-2 expression with advanced pT, pN stages and extranodal extension (ENE), as well as poor prognosis. Knockdown of TROP-2 expression inhibited the proliferation of PSCC cells both in vivo and in vitro. Further experiments identified that TROP-2 promoted PSCC cell proliferation via AKT-mediated PKCα signaling pathway. TROP-2 ADC drugs could inhibited PSCC cell proliferation both in vitro and in vivo. Conclusions: TROP-2 promotes PSCC cell proliferation, and TROP-2 targeted ADC-drug is a promising agent for PSCC treatment in future.
Analysis of glycemia during olaparib therapy in patients with ovarian cancer.
Authors: Joanna Stanislawiak-Rudowicz, Edyta Szalek, Andrzej Czyrski, Edmund Grzeskowiak, Radoslaw Madry
Journal: Journal of Clinical Oncology (2024)

e17559 Background: Olaparib (poly(ADP-ribose) polymerase inhibitor) is a relatively new anticancer drug and some of its metabolic side effects, such as its effect on blood glucose, are not yet well defined. The aim of the study was a retrospective analysis to investigate olaparib-induced changes in glucose levels in patients with ovarian cancer (OC). Methods: The study was conducted on 32 OC patients with normoglycemia (3.9–5.5 mmol/l) confirmed before olaparib treatment. The fasting glucose (FG) levels were estimated after I (one month), II (two months), and III (three months) courses of olaparib treatment. The severity of hyperglycemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Results: During treatment with olaparib, grade 1 hyperglycemia was found in 18 patients (56.2%), therefore hemoglobin A1C level measurement was recommended. The number of patients with impaired fasting glucose (5.6–6.9 mmol/l), characteristic of a pre-diabetic state, was 17 (53.1%), while glycemia indicative of diabetes (≥7.0 mmol/l) were found in 1 patient (3.1%). The statistically significant increase in glycemia was observed after I course of treatment (p&lt; 0.0001), then after the second (p=0.0003), and III course (p=0.0025). Conclusions: During olaparib therapy, hyperglycemia was observed in 56.2% of the analyzed OC patients, implying the need for glycemic monitoring during monthly routine check-ups to implement effective behavioral and therapeutic management.
Association of homologous recombination repair mutation defined with a 15-gene panel with the prognosis of epithelial ovarian cancer: A Chinese multicenter retrospective study.
Authors: Yi Liu, Xiaojun Chen, Huaiwu Lu, Xin Wu, Xuehan Liu, Fei Xu, Dongdong Ye, Bo Ding, Xiaoyan Lu, Ling Qiu, Jing Zhu, Yingying Wang, Xinya Huang, Zhen Shen, Tao Zhu, Yang Shen, Ying Zhou
Journal: Journal of Clinical Oncology (2024)

e17556 Background: There was no consensus regarding the optimal homologous recombination repair (HRR) gene panel to predict prognosis of epithelial ovarian cancer (EOC). Methods: The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centres were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors and progression-free survival (PFS) with 15-gene panel mutation status was assessed. Results: 43.2% (133/308) of patients were determined to carry 144 deleterious HRR mutations (HRRm), among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. Patients who received PARP inhibitors (PARPis) were 29.1% (37/127) and 50.5% (46/91) in the HRR wild-type (HRRwt) group and HRRm group at IIIC-IV stages, respectively. A prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. In univariate analysis, significant predictors of relapse included nonresidual status (HR, 0.62; 95% CI, 0.39-0.98; P = 0.0287), 15-gene panel mutation (HR, 0.42; 95% CI, 0.28-0.64; P = 0.0001), platinum sensitivity (HR, 0.07; 95% CI, 0.02-0.22; P &lt; 0.001) and maintenance therapy (PARPi) (HR, 0.48; 95% CI, 0.31-0.74; P = 0.0028) (Figure 5). In multivariate Cox analysis, nonresidual (HR, 0.63; 95% CI, 0.40-0.99; P = 0.046), 15-gene panel mutation (HR, 0.49; 95% CI, 0.28-0.88; P = 0.016) and platinum sensitivity (HR, 0.02; 95% CI, 0.01-0.05; P &lt; 0.001) remained independent prognostic factors. Conclusions: This study provides evidence that HRRm with a 15-gene panel can predict the prognosis of EOC, among which only BRCA1/2 mutations contribute to prognosis prediction. [Table: see text]
Homologous recombination deficiency score for predicting efficacy of platinum-based chemotherapy and PARPi maintenance therapy in ovarian cancer.
Authors: Jinhua Wang, Jing Shen, Zhe Zhang, Lei Ye, Jin Lu, Ziyi Xiao, Lihua Zhang, Xiaojian Liu, Chan Zhu, Xiaoxuan Wang, Chao Zhang, Xing Zhang, Dong-sheng Chen, Xinyu Xu
Journal: Journal of Clinical Oncology (2024)

e17543 Background: Currently, homologous recombination deficiency (HRD) has been confirmed to be a predictive biomarker for poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer, while its effects on the clinical outcomes of platinum-based chemotherapy and PARPi maintenance therapy are not assessed rigorously in ovarian cancer. We developed an HRD assay to evaluate the effect of HRD scores on the platinum-based chemotherapy and PARPi maintenance therapy in Chinese patients with ovarian cancer. Methods: HRD testing was performed on the samples obtained at primary cytoreductive surgery. The progression-free survival (PFS) was observed among the BRCA-mutated/HRD-positive and BRCA wild-type/HRD-negative patients. Univariate and multivariate COX analyses were performed to test the association of PFS with different variables, and hazards ratios (HR) and 95% confidence interval (CI) were calculated. The two-tailed p value less than 0.05 was considered statistically significant. Results: Totally 74 patients who received platinum-based chemotherapy were eligible for the study, among whom 81.1% responded to the initial platinum-based chemotherapy, 33.8% harbored BRCA1/2 mutations and 74.3% were HRD-positive. The median HRD score of platinum-sensitive patients (n=60) was 48.5, significantly higher than the 31 of platinum-resistant patients (n=14, p=0.0035). Analysis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) between platinum-sensitive and platinum-resistant patients showed significant differences in TAI ( p=0.0012) and LST ( p=0.004). Compared with HRD-negative patients, HRD-positive patients had a significantly longer median PFS (10 vs. 15 months, p=0.017), and multivariate analysis further indicated that HRD-positive status (HR, 0.423, 95%CI: 0.191-0.939, p=0.035) was a significant predictor for the improvement of PFS. Conclusions: The HRD assay developed in our study can accurately predict the response to platinum-based chemotherapy and PARPi efficacy in patients with ovarian cancer, providing powerful evidence for implementation of genetic testing and guidance of clinical treatment in ovarian cancer.
Clinical characteristics and treatment outcomes of advanced penile squamous cell carcinoma: Real-world evidence from a tertiary cancer center in Brazil.
Authors: Vinicius Cruz Parrela, Gabriel Berlingieri Polho, Matheus de Oliveira Andrade, Rogerio Almeida Moreno Santos, Gustavo Luis Alves, Matheus Henrique Juliani Arneiro, Vitor Hugo Felix, Cassio Murilo Hidalgo Filho, Murilo Cazellato Pacheco de Mello, Jose Mauricio Mota
Journal: Journal of Clinical Oncology (2024)

e17025 Background: Penile cancer is a rare disease worldwide. However, Brazil has an annual incidence of 1.5 cases per 100,000 inhabitants, representing 2% of male cancers. This study aims to evaluate clinical characteristics and treatment outcomes of patients (pts) with advanced penile squamous cell carcinoma (SCC) in a large tertiary cancer center in Brazil. Methods: We performed a retrospective database analysis of pts with advanced penile squamous cell carcinoma (SCC) treated at Instituto do Cancer do Estado de Sao Paulo between January 2008 and October 2023. Medical records were reviewed for demographic, clinicopathological features and treatment outcomes data. Cumulative survival probabilities were computed using the Kaplan-Meier method. Prognostic factors associated with survival were evaluated through univariate analyses, using the Cox regression model. Results: We identified 91 pts with advanced penile SCC eligible for analysis. Median age was 62 years (IQR 44.5-64.5), most were married (53.8%), diagnosed with stage T3/T4 (60.4%), and N2/N3 (64.9%) SCC. At diagnosis, 65% were classified as stage IV (T4, N3, or M1 disease). De novo metastasis occurred in 35% pts. Neoadjuvant chemotherapy was given to 30.8%, mainly ITP regimen containing paclitaxel, ifosfamide, and cisplatin (46.4%). First-line palliative chemotherapy was given to 50.5%, being carboplatin and paclitaxel the predominant choice (47.8%). Disease progression occurred in 54% pts, after a median follow-up of 21.8 months. At the last follow-up, 61.5% had nodal disease. Most common sites of metastasis were lung (50.5%) and liver (19.8%). Overall survival (OS) was 12.9 months (95% CI 9.8 - 18.3). Prognostic factors significantly correlated with OS were ECOG 0-1 (HR 0.40, 95% CI 0.21 - 0.74, p=0.003) and complete response post-chemotherapy (HR 0.14; 95% CI 0.02 - 0.80, p=0.02). No association with survival was found for region/state of origin, distance from patient’s home to the hospital, marital status, education level, and age. Conclusions: Advanced penile squamous cell carcinoma (SCC) presents significant challenges in Brazil, with high rates of advanced disease at diagnosis. OS correlated with complete response to chemotherapy and performance status.
Vaccine effectiveness and impact of meningococcal vaccines against gonococcal infections: A systematic review and meta-analysis
Authors: Bing Wang, Hassen Mohammed, Prabha Andraweera, Mark McMillan, Helen Marshall
Journal: Journal of Infection (2024)

To systematically review and synthesis the evidence of vaccine effectiveness (VE) and impact (VI) of meningococcal vaccines in preventing gonorrhoea.
Copper impairs the intestinal barrier integrity in Wilson disease
Authors: Adriana Fontes, Hannah Pierson, Joanna B. Bierła, Carola Eberhagen, Jennifer Kinschel, Banu Akdogan, Tamara Rieder, Judith Sailer, Quirin Reinold, Joanna Cielecka-Kuszyk, Sylwia Szymańska, Frauke Neff, Katja Steiger, Olga Seelbach, Andree Zibert, Hartmut H. Schmidt, Stefanie M. Hauck, Christine von Toerne, Bernhard Michalke, Jeremy D. Semrau, Ana M. DiSpirito, João Ramalho-Santos, Guido Kroemer, Roman Polishchuk, Anabela Marisa Azul, Alan DiSpirito, Piotr Socha, Svetlana Lutsenko, Hans Zischka
Journal: Metabolism (2024)

In Wilson disease (WD), liver copper (Cu) excess, caused by mutations in the ATPase Cu transporting beta (ATP7B), has been extensively studied. In contrast, in the gastrointestinal tract, responsible for dietary Cu uptake, ATP7B malfunction is poorly explored. We therefore investigated gut biopsies from WD patients and compared intestines from two rodent WD models and from human ATP7B knock-out intestinal cells to their respective wild-type controls. We observed gastrointestinal (GI) inflammation in patients, rats and mice lacking ATP7B. Mitochondrial alterations and increased intestinal leakage were observed in WD rats, Atp7b