bluuebunny/crossref_metadata_2025 huggingface dataset:
Experience of seven Spanish centres with echoendoscopically implanted 32P microparticles associated with chemotherapy in locally advanced pancreatic adenocarcinoma.
Authors: Guillen-Ponce Carmen , Lopez-Gomez Victoria , Juez Ignacio , Navales Ignacio , Ponz-Sarvise Mariano , Adeva Jorge , Rodriguez Cernuda Maria Purificacion , Garrido Maria , Garcia Garcia De Paredes Ana , Zamora Javier
Published: July 2024

e16358

Background: 32P brachytherapy delivered by echoendoscopy (EUS) represents an innovative therapy in locally advanced pancreatic cancer (LAPC). The device to implant it is approved in unresectable LAPC in combination with gemcitabine-based chemotherapy. Our aim is to present the preliminary efficacy and safety results of a series that brings together the experience of seven centres in Spain. Methods: After being assessed by a multidisciplinary committee and meeting eligibility criteria (Table 1), patients signed consent to receive intratumoural 32P by EUS within the international observational registry OSPREY (March 2022-February 2024). Complications associated with intratumoural 32P injection via EUS, associated adverse events (AEs) and preliminary efficacy results (progression-free survival [PFS], distant and locoregional, and overall survival [OS]) were analysed. Results: Thirteen patients (7 females; age 65 years [range 48, 79]; 10 ECOG 1) with unresectable LAPC (7 in head, 3 in uncinate and 3 in body; tumour size 36.8 mm [range 25, 60]) were included. The median time from tumour diagnosis to procedure was 5 months [1.4, 28.9]. Only 4 patients (30 %) had received a previous line of treatment. Eleven patients (85%) received gemcitabine-based chemotherapy concomitant with intratumoural 32P (8 gemcitabine plus nabpaclitaxel; 3 gemcitabine monotherapy). There were no complications or AEs related to 32P injection or EUS. A total of 7 patients (54%) had chemotherapy-related AEs, with 2 cases of G3 neutropenia; 6 had G1-2 toxicities: neutropenia (1), thrombopenia (2), anaemia (1), nausea (1), asthenia (1), diarrhoea (1) and constipation (1). Two patients underwent surgery after intratumoural treatment. With a median follow-up of 17.3 months after injection, 8 patients (61.5 %) have progressed, all of them distantly, and three also locoregionally. The median PFS since 32P injection is 8.4 months (95% CI 2.7, NR). Six patients are alive at the end of follow-up (46.2 %) with a median OS since 32P injection of 13.8 months 95% CI [10, NR]. At data cut-off, five patients remain on-treatment. Conclusions: Our initial experience suggests that intratumoural 32P associated with gemcitabine-based chemotherapy is safe. Patients after 32P injection achieve long overall survival. Our ongoing prospective registry will allow evaluation of the oncological outcomes of this therapy at longer follow-up times. [Table: see text]
Analyzing imbalance of short tandem repeats for pancreatic cancer detection.
Authors: Levine Jonathan , Finkelstein Sydney , Timmaraju Venkata Arun
Published: July 2024

e16359

Background: Short tandem repeats (STRs), alternatively known as microsatellites, encompass repeat units of 1 to 6 base pairs (bp) in the genome and function as regulators of gene expression, impacting plasticity and complex traits. STRs are prone to hypermutation with alterations correlated to pathogenicity in multiple Mendelian and acquired disorders. STR variant classes include insertions, mobile element insertions (MEIs), deletions, and multi-allelic copy number variants (mCNVs). These can lead to repeat expansions, allelic imbalance (AI), and microsatellite instability (MSI) observed in diseases such as Huntington's disease, hereditary ataxia, and multiple cancers. In pancreatic cancer, AI and associated loss-of-heterozygosity (LOH) at tumor suppressor loci flanked by hypervariable STR regions correspond to a pathogenic phenotype with a risk of aggressive disease. Consequently, it is critical to develop accurate and robust methods to precisely identify and genotype pancreatic samples with varying specimen quality in a clinical setting to aid in diagnosis. Methods: Capillary electrophoresis (CE) and Sanger sequencing have been used to analyze STRs. The availability of newer tools such as 2nd generation short-read (NGS) and 3rd generation long-read (TGS) sequencers could allow for high throughput scaling, however, informatics challenges associated with analyzing repetitive regions remain. Here we developed amplification and enrichment methods for targeted analysis for detection by CE, NGS and TGS. Results: Amplification and enrichment strategies for detecting 17 short tandem repeat regions that play a role in pancreatic carcinogenesis were developed. Methods were optimized for detecting STR alterations in cell-free nucleic acids isolated from endoscope-guided pancreatic fine needle aspirate biopsies. Furthermore, informatics tools were developed to analyze short-read and long-read sequencing data to accurately analyze repeat regions. Conclusions: Here we compared 3 platforms (CE, NGS, and TGS) and found that CE remains the gold standard for analyzing AI/LOH with data comparable to long-read TGS, while short-read NGS is not always amenable to accurate analysis dependent on the region of interest. Additionally, we found that artifacts of amplification persist, irrespective of the 3 platforms analyzed.
Recurrence patterns and surveillance strategies in long-term survivors of resected pancreatic cancer.
Authors: May Michael S. , Stanton Liam James , Jamison Jacob K. , May Benjamin , Michel Alissa M. , Raufi Alexander G. , Wong Winston , Kastrinos Fay , Accordino Melissa Kate , Hershman Dawn L. , Manji Gulam Abbas , Wu Linda
Published: July 2024

e16361

Background: Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related mortality in the United States. After resection, the 2-year disease-free survival is < 50%. Surveillance guidelines after resection vary significantly between expert groups. The level of evidence is particularly weak for patients who are alive and disease-free after 2 years. Our objective was to report rates and predictors of recurrence in this population. Methods: We reviewed all patients who underwent resection of stage I-III PDA at Columbia University Irving Medical Center from 2011-2022. Eligibility criteria included patients who were alive and disease-free at 2 years after diagnosis. Demographic, surgical, and treatment characteristics were recorded. Imaging studies and tumor markers were reviewed and median time between studies after 2 years of follow up was determined. Recurrence was confirmed histologically or radiologically. Follow up and survival times were calculated using Kaplan Meier statistics. Associations between patient characteristics and recurrence risk were evaluated using a Cox proportional-hazards regression adjusted for demographic and treatment characteristics. Results: We reviewed 743 patients and 225 met eligibility criteria. The median age at diagnosis was 67.5 years. Median interval between surveillance imaging was 59 days and median interval between CA 19-9 draws was 41 days. After a median follow-up of 5.2 years from diagnosis, 84/225 (37%) patients experienced a late recurrence. Of these, 35% (29/84) had local recurrence, and 65% (55/84) had distant recurrence. The most common distant sites were lung (51%) and liver (27%). Lymph node positivity at resection was associated with late recurrence risk (p = 6x10-6), but T-stage (p = 0.5), margins (p = 0.9), age (p = 0.2) and chemotherapy receipt (p = 0.3) were not. Of the 72 patients with CA 19-9-producing tumors (baseline CA 19-9 > 37 U/mL) and complete normalization of CA 19-9 postoperatively, 30 patients had recurrence with CA 19-9 checked in the 9 months preceding recurrence. CA 19-9 re-elevation preceded recurrence in 83% (25/30) of late recurrences. Median time from CA 19-9 elevation to confirmation of recurrence was 5 months. Conclusions: The rate of recurrence for patients with PDA who are disease-free 2 years after diagnosis is lower than that for patients in their first 2 years. The most common sites of late recurrence are local and lung. For long-term PDA survivors with CA 19-9 producing tumors, serial CA 19-9 monitoring may be used to guide imaging. Positive lymph nodes at resection identify patients who are at highest risk for late recurrence.
Improved germline screening for patients with pancreatic cancer through provider driven testing.
Authors: Frazier Heather , Toyon Sewanu Anjolaoluwa , Coleman DeJuana , Thomas Martha , Kunk Paul Raymond , Le Tri Minh , Rehman Muneeb , Reilley Matthew
Published: July 2024

e16366

Background: National guidelines recommend germline genetic screening for all pancreatic cancer patients. Results provide meaningful insights into pathogenic variants and impacts both treatment selection and family screening recommendations. We previously reported on current state and the need to improve germline screening rates. Since implementing a provider-driven approach, we have seen a significant increase in testing. Our findings demonstrate the feasibility and ongoing need for novel approaches to germline screening. Methods: This is a retrospective review of 223 patients with pancreatic adenocarcinoma evaluated at the University of Virginia Health System within the calendar year of 2022 compared to the 2021 calendar year. Primary endpoints include the rate of genetic counseling referral placement, the rate of attendance of outpatient genetic counseling, and the rate of individuals who completed germline screening. Our primary data points will be compared with outcomes obtained from a prior study evaluating 210 patients with pancreatic adenocarcinoma in the calendar year of 2021 at the same academic medical center. Results: Of the 223 patients with pancreatic adenocarcinoma, only 30% (69/223) had genetic counseling referrals present in the electronic health record system (EHR). This was an improvement from the 2021 calendar year, where 19% (39/210) had referrals present in the EHR. Of those with referrals present, an improvement in the rate of genetic counseling attendance was found, from 51% (20/39) in 2021 to 58% (40/69) in 2022. There was also an improvement in the rate of germline screening completion rates; 38% (85/223) of patients evaluated in 2022 completed testing, compared to 21% (44/210) in 2021. Six percent (5/85) of tested patients in 2022 had pathogenic findings, consistent with historical incidence rates. The main provider barriers were time and testing logistics. Conclusions: Our data shows an improvement in the rates of genetic counseling referrals, the rates of genetic counseling attendance, and the rates of germline screening completion. This modest improvement is primarily related to increased awareness by our providers. We acknowledge the need for further improvements and are developing a prospective clinical trial to better educate and empower patients to understand the need and results of germline testing.
Emergency treatment for primary intracranial germ cell tumours (PICGCTs).
Authors: Murphy Ravindhi , Russell Jodie , Talbot Thomas , Lythgoe Mark , Sherpa Gina , Xing Eunice Yun , Khanna Sanjay , Li Ling , Tin Terry , Kalam Sabrina , Singh-Curry Victoria , Ghorani Ehsan , Caldwell Reece , Sarwar Naveed , Seckl Michael , Gonzalez Michael
Published: July 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: Singh Paramveer , Kaur Jasmeet , Mir Tanveer , Qureshi Waqas
Published: July 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 (>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 >45 annual cases, and small volume hospitals (SVH) were defined <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 < 0.01), had more proportion with private insurance (p =0.003). Patients treated at SVH experienced significantly higher rates of pneumonia (p < 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 < 0.01). In adjusted analysis, significant predictors for mortality included liver disease (OR: 6.12, (95% CI: 4.1 to 266); p < 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 < 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]
The role of TROP-2 in the progression and target therapy in penile squamous cell carcinoma.
Authors: Tang Yi , Tan Xingliang , Liu Zhicheng , Zhou Qianghua , Wei Wensu , Yuan Gangjun , Yao Kai
Published: July 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.
Impact of treatment approaches in patients with advance penile cancer: An analysis from a nationwide study.
Authors: Ganiyani Mohammad Arfat , Khosla Atulya Aman , Ahmad Shahzaib , Jatwani Karan , Rubens Muni , Roy Mukesh , Bastos Bruno R. , Ozambela Manuel , Eldefrawy Ahmed , Manoharan Murugesan , Garje Rohan
Published: July 2024

e17024

Background: Advance penile cancer (APC) is a rare and aggressive malignancy, characterized by the presence of metastases to lymph nodes and/or distant organs. The rarity of patients with APC poses challenges in conducting comprehensive studies, with most existing evidence being small-scale, retrospective analyses from single institutions. Additionally, the absence of large clinical trials limits the evidence to compare the survival rates with different treatment approaches in patients with APC. Methods: Our study utilized the national cancer database (NCDB) from 2004 to 2021. Our primary analytic cohort included patients diagnosed with advance penile cancer based on the AJCC 8 th classification (T4 or N3 or M1). Treatment modalities comprised perioperative systemic therapy combined with definitive surgery (PST), concurrent chemoradiation (CCR), surgery only (S), and systemic therapy only (ST). We used Kaplan-Meier analysis and the cox proportional regression to evaluate the impact of these treatment modalities on survival outcomes. Results: We identified 1342 patients with advance penile cancer. The median overall survival (OS) was 22.24 months (CI: 15.87-27.86, P <0.001) for patients who received PST, 16.99 months (CI: 13.86-27.4) for those who underwent CCR, 11.99 months (CI: 9.2-15.01) for patients managed with surgery only, and 10.94 months (CI: 9.95-14.09) for those who received only ST. Our multivariate analysis revealed combining PST with surgery was associated with 27% reduction in the risk of death (HR: 0.73, P = 0.037) compared to systemic therapy after adjusting for age, race, tumor grade, comorbidities, distant metastasis and socioeconomic factors. Conclusions: Treatment approach with systemic therapy along with definitive penile surgery is associated with improved survival in patients with advanced penile cancer compared to other treatment modalities. Whenever feasible, this treatment approach should be considered as a management strategy in patients with APC. Further prospective studies are needed to validate our observations. [Table: see text]
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: Shore Neal D. , Williams Jack , Clouthier Derek L. , Swift Stephanie L. , Tatman Sophie , Lang Shona , Hettle Robert
Published: July 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]
Association of baseline characteristics with adverse events (AEs) in the PROpel trial of olaparib (ola) plus abiraterone (abi) as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Armstrong Andrew J. , Saad Fred , Oya Mototsugu , Shore Neal D. , Procopio Giuseppe , Vianna Karina , Mehra Niven , Özgüroğlu Mustafa , Gedye Craig , Brown Emma , Schlürmann Friederike , Lee Ji Youl , Joung Jae Young , Sugimoto Mikio , Emmenegger Urban , Oscroft Emma , Shaw Bob , Winter Maria , Hosius Christian , Clarke Noel
Published: July 2024

e17030

Background: The PROpel trial (NCT03732820) met its primary endpoint and showed a statistically significant radiographic progression-free survival benefit (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.0001) with ola + abi vs placebo + abi in 1L mCRPC; whilst not statistically significant, overall survival (OS) was numerically prolonged (median 42.1 vs 34.7 months; HR 0.81, 95% CI 0.67–1.00; P=0.0544). To further inform clinical decision making, we provide exploratory post hoc analysis investigating the relationship between selected patient baseline characteristics and AEs for ola + abi. Methods: Anemia and venous thromboembolism events (VTEs) were identified as the only grade (Gr) ≥3 AEs or AEs of special interest reported in >20 (>5.0%) patients (pts) in the ola + abi arm (data cutoff 12 Oct 2022). Baseline characteristics were correlated with AEs using Cox regression by backwards elimination and analysis with AEs as dependent variables. Baseline characteristics assessed included: age (<70 or ≥70 y), time since diagnosis (20), Gleason score (<9 or 9–10), homologous recombination repair mutation status (HRRm, non-HRRm or unknown), race (white or non-white), prior docetaxel at metastatic hormone-sensitive prostate cancer (yes or no), pain (symptomatic or asymptomatic/mildly symptomatic), type of progression (prostate-specific antigen [PSA], radiographic or both), prior radiotherapy (yes or no) and albumin, creatinine, lactate dehydrogenase, alkaline phosphatase (ALP), hemoglobin (10<12 or ≥12) and log PSA levels. Results: 398 pts received ola + abi. 64 (16.1%) had Gr ≥3 anemia and 34 (8.5%) a VTE. Baseline characteristics correlated significantly with increased risk of these AEs as shown (Table); characteristics not shown were not associated with AEs. Conclusions: These results provide insight into which baseline characteristics correlate with the risk of Gr ≥3 anemia. Pts with abnormal ALP, pre-existing anemia, ECOG PS 1 or age ≥70 years could be at higher risk and the development of Gr ≥3 anemia during treatment with ola + abi should be monitored. Clinical trial information: NCT03732820 . [Table: see text]
Dosimetry of lutetium-177 PSMA-targeted radiopharmaceutical therapies for prostate cancer patients: A comparative systematic review and meta-analysis.
Authors: Ells Zachary , Dahlbom Magnus , Czernin Johannes , Grogan Tristan , Calais Jeremie
Published: July 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&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&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&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&T (p=<0.01). Average tumor doses tended to be higher for Lu177-PSMA-617 than for Lu177-PSMA-I&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&T has yet to be determined. Data for Lu177-PSMA-J591 are thus far too limited to draw firm conclusions.
Prevalence of HER-2 expression and correlation with clinicopathological features in gynecological cancer: A single-center retrospective study in China.
Authors: Chen Rui , Dong Juanhui , Li Guangxin , Peng Yi , Lei Haike , Yuan Li , Long Xingtao , Zhou Qi
Published: July 2024

e17500

Background: Targeted therapy for human epidermal growth factor receptor 2 (HER2) has become a standard of care in several HER2-expressing solid tumors. Nonetheless, there remains an unmet need for effective treatment, for instance, anti-HER2 antibody-drug conjugates (ADCs), in advanced stage gynecological cancer. In this context, we presented a retrospective study on the incidence of HER2 expression in primary gynecological cancer based on a single-center data from southwestern China. Methods: Paraffin-embedded tumor tissue blocks, clinicopathological, and survival data of gynecological cancer patients were collected from Chongqing University Cancer Hospital. HER2 IHC scoring was carried out according to the updated ASCO/CAP guidelines for breast and gastroesophageal adenocarcinoma by two pathologists independently. Data analysis was performed using SPSS v.24. Results: A total of 104 cases of cervical cancer, 102 cases of endometrial cancer and 103 cases of ovarian cancer were included between 2019 and 2023. HER2 expression was detected in 31.7% samples, with scores of 1+, 2+, and 3+ in 23.9% (74/309: 36/104, 16/102, 22/103), 5.8% (18/309: 7/104, 7/102, 4/103), and 1.9% (6/309: 2/104, 1/102, 3/103) of patients, respectively. Notably, ultra-low HER2 expression with incomplete and faint staining in ≤10% of tumor cells was observed in 41.1% (127/309: 37/104, 53/102, 37/103) of patients. Metastasis and lymphovascular invasion were associated with elevated HER2 expression in endometrial cancer (p=0.037, 0.040, respectively), while a larger tumor size was associated with elevated HER2 expression in cervical cancer (p=0.004). However, no positive association between HER2 status and overall survival (OS) was found in cervical, endometrial or ovarian cancer. In our cohort, metastasis was the only risk factor related to reduced OS of gynecological cancer patients by COX regression analysis (HR=14.00, 95%CI=1.32-148.21, p=0.028). Conclusions: Our data revealed a considerable number of patients with HER2-low and ultra-low gynecological cancer. It might represent a significant portion in real-world scenarios and warrant more consideration in selecting candidates for HER2-targeted ADCs, especially for those with relapsed or refractory conditions. Given the inherent challenge in interpretation, the study highlights the necessity for a consensus on evaluating HER2 immuno-staining results in gynecological cancer. Clinical trial information: MR-50-23-019676 . [Table: see text]
Clinical and analytical validation for HRD status using targeted panel sequencing.
Authors: Bao Hua , Liu Rui , Tang Haimeng , Wu Xuxiaochen , Chen Xiaoxi , Wu Yong , Wu Xue , Shao Yang
Published: July 2024

e17501

Background: In cancer therapy, understanding homologous recombination deficiency (HRD) is paramount, particularly due to its positive association with sensitivity to PARP inhibitor (PARPi) therapy. We propose using a targeted sequencing approach as a cost-effective and efficient alternative to the current standard of whole genome sequencing (WGS). In this study, we determine the sensitivity and clinical applications of a panel of 437 genes and over 12000 heterozygous SNP loci for evaluating HRD. Methods: HRD positivity for this assay was set at an HRD score of ≥38. To determine the limit of detection (LOD), we diluted 19 samples (4 tiers, 20 repeats each) with known HRD status. Accuracy of the assay was determined by comparing HRD status calls of 40 samples with those obtained through whole genome sequencing. Reproducibility of the assay was tested by measuring variance of HRD status for 30 samples between experimental conditions (2 operators* 3 repeats). Samples were obtained from 85 ovarian cancer (OC) patients undergoing platinum-based (Pt) chemotherapy and were profiled using our targeted sequencing assay. Results: The LOD for BRAC1/2 copy number deletions was established at a tumor purity (TP) of 30%. On the level of individual mutations, LODs range between 1.74% to 5.85% AF with a median of 2.26% AF. Repeatability analysis yields high concordance (APA= 97.83%, 95%CI= 95.34% - 99.00%; ANA= 97.73%, 95%CI= 95.13% - 98.95%), which emphasizes the precision of the assay. Comparisons against WGS based HRD scores reveal strong correlations, with Pearson coefficients of 0.975 for single sample (tumor sample only) and 0.987 for paired sample (tumor + normal sample) HRD score analysis. Through tumor profiling, we identified novel gene mutations associated with resistance to PARPi therapy in the HRD-positive population of our cohort. In the clinical setting, HRD-positive OC patients were found to experience longer progression free survival than their HRD-negative counterparts (median PFS = 18.3 vs 11.4 months, p<0.05). Upon further investigation, we observed that HRD-positive patients who did not carry pathogenic alterations on BRCA1/2 gene showed significantly longer PFS than HRD-negative patients without pathogenic BRCA1/2 alterations (median PFS = 18.5 vs 11.6 months, p<0.05). Conclusions: In summary, this targeted panel offers enhanced sensitivity, reliability, and precision in the assessment of HRD status for informed cancer therapy decisions. In practice, we showed that the targeted sequencing approach is a viable solution for determining HRD status of OC patients and can potentially serve as a predictive biomarker for treatment response. We believe that out assay emerges as a cornerstone in the advancement of personalized cancer care, and offers a sensitive, reliable, and precise approach to HRD assessment for improving patient outcomes.
White blood cell kinetics in patients with gynecologic cancer receiving mecapegfilgrastim prophylaxis: A multicenter real-world study.
Authors: Chen Yong , Chen Liang , Li Gang , Zuo Li , Cheng Gang , Xu Nong , Mao Chenyu , Shen Peng , Chen Minbin , Wang Yanhong , Wang Zhanggui , Zhao Rusen , Bie Jun , Zheng Weie , Yan Haijiao , Zhang Guifang , Yang Zhe , Zhang Ningling , Xu Rui-Hua , Huang Xin
Published: July 2024

e17502

Background: Some studies have indicated that using granulocyte-colony stimulating factor (G-CSF) following chemotherapy in patients with solid tumors may increase the risk of excessive white blood cell (WBC) elevation. In this real-world study, we aimed to assess the changes in WBC counts after prophylactic administration of 6 mg mecapegfilgrastim (a long-acting G-CSF) in multiple chemotherapy cycles among Chinese gynecological cancer patients, with a particular focus on those with low body weight (≤50 kg). Methods: A multicenter prospective cohort study was conducted involving gynecological cancer patients who received at least two consecutive chemotherapy cycles with mecapegfilgrastim 6 mg (administered 24 hours post-chemotherapy) between October 2019 and November 2021. Absolute WBC and absolute neutrophil counts (ANC) were recorded at baseline and on the 7th and 14th days of each cycle. Results: A total of 256 gynecological cancer patients completing 2-4 treatment cycles, including 86 with cervical cancer, 136 with ovarian cancer, and 34 with endometrial cancer, were analyzed. Of them, 58 had a pre-chemotherapy body weight of ≤50 kg, and 198 had a body weight of >50 kg. The majority of patients received taxane-based chemotherapy regimens with a cycle duration of ≥14 days. For day 7 post-chemotherapy WBC counts, data were collected from 535 cycles, including 125 cycles in the ≤50 kg group and 410 cycles in the >50 kg group. Elevated WBC counts (>10.0×10^9/L) were observed in 56 cycles (44.8%) in the ≤50 kg group and 177 cycles (43.2%) in the >50 kg group. On day 14 post-chemotherapy, data from 505 cycles, comprising 115 cycles in the ≤50 kg group and 390 cycles in the >50 kg group, indicated elevated WBC counts in 27 cycles (23.5%) in the ≤50 kg group and 63 cycles (16.2%) in the >50 kg group. In the ≤50 kg group, 3 cases (5.2%) experienced an ANC <0.5×10^9 /L, with no febrile neutropenia observed. In the >50 kg group, 11 cases (5.6%) experienced an ANC <0.5×10^9 /L, with 1 patient (0.51%) experiencing febrile neutropenia. Conclusions: In patients with low body weight (≤50 kg), the administration of 6 mg mecapegfilgrastim effectively stabilizes WBC elevation, exhibiting a favorable safety and efficacy profile. This regimen ensures the timely and appropriate progression of patients to subsequent cycles of chemotherapy. WBC counts in patients. [Table: see text]
CRS-HIPEC following neo-adjuvant pressurized intraperitoneal aerosol chemotherapy (PIPAC) with systemic chemotherapy in primarily advanced inoperable epithelial ovarian cancer: An ISPSM collaborative study.
Authors: Somashekhar S.P. , Chandrashekar Rohit Kumar C. , Rajgopal Ashwin K. , Fernandes Aaron Marian , Shanbhag Esha , Rakshit Susmita , Ahuja Vijay Kumar
Published: July 2024

e17504

Background: PIPAC has shown improved objective response rate with improved quality of life in combination with IV chemotherapy when compared to IV chemotherapy alone in salvage situations. Methods: All patients with primarily inoperable advanced epithelial ovarian cancer not been able to receive optimal IV chemotherapy or not responding to first line of chemotherapy who could not undergo CRS-HIPEC were challenged with PIPAC & IV chemotherapy as a salvage situation after discussion in MDT. Patients who subsequently underwent CRS-HIPEC were analysed to study their clinical characteristics, extent of disease and peri-operative outcomes. PIPAC was given with Cisplatin 15mg/m2 and doxorubicin 3mg/m2. Intravenous chemotherapy was given within one week of PIPAC. Each cycle was repeated once in 4-5 weeks. Patients who underwent subsequently CC0 cytoreduction got HIPEC with Injection cisplatin 100mg/m2. All outcomes were prospectively entered in the registry and analysed retrospectively. Results: 120 PIPAC applications were done in 45 patients. 30 patients received 3 cycles of PIPAC with IV chemotherapy given within one week of PIPAC. Mean PCI initially was 25±5 with nearly 55% of them having ECOG 2 performance status and mean ascities volume of 500±55 ml . Out of 45 patients 28 underwent CRS-HIPEC subsequently. Mean age 54.5±10.74, PCI 15±5, duration of surgery 9.6±1.2 hrs. The mean drop in PCI who completed 3 PIPAC with IV chemotherapy was 10±3. Out of 45 patients nearly 60% showed PRGS 1, 25% PRGS 2 and 15% PRGS 3. 30.4% had total peritonectomy, 12.7% had multivisceral resection, 30% required diaphgramatic resections, 25%required mesentric stripping, 45.8% had one bowel resections and stoma rate was 4.5%. Overall G3-G5 morbidity was 25.4% with major ones being post-operative intra-abdominal collection (21.8%), electrolyte imbalance (16.4%), pulmonary (16.4%) followed by hematological (12.7%). The 30 day mortality was 3.8%. During PIPAC + IV chemotherapy no significant grade 3-4 morbidity was seen. Conclusions: Neo-adjuvant PIPAC with Intravenous chemotherapy might be a promising combination for inducing good response rates in advanced epithelial ovarian carcinoma. CRS-HIPEC following neo-adjuvant PIPAC + IV chemotherapy is safe, feasible and tolerable. PIPAC repeated every 4-5 weeks along with systemic chemotherapy provides a ideal scenario to monitor & assess response to loco regional and systemic chemotherapy.
Anlotinib combined with penpulimab as first-line treatment for persistent, recurrent, or metastatic cervical cancer: Preliminary results from ALTER-GO-020, a single-arm, open-label, multi-cohort, multi-center phase II clinical study.
Authors: Wang Dengfeng , Liu Hong , Chen Lihong , He Mian , Zhao Weidong , Xiang Yang , Zhang Guonan
Published: July 2024

e17506

Background: The BEATcc trial demonstrated the combination of atezolizumab plus bevacizumab and platinum regimen as first-line treatment for recurrent, or metastatic cervical cancer significantly improves progression-free survival (PFS) and overall survival (OS) regardless of PD-L1 status. ALTER-GO-020 is an ongoing open-label, single-arm, multi-cohort phase II study evaluating the combination of anlotinib (a multitarget anti-angiogenic TKI) and penpulimab (anti-PD-1 antibody) as a chemotherapy-free regimen for patients (pts) with recurrent or metastatic gynecological cancer. Here, we report the preliminary results of the cohort of patients with recurrent or metastatic cervical cancer from ALTER-GO-020. Methods: Eligible pts were histologically confirmed persistent, recurrent, or metastatic cervical cancer (including adenocarcinoma, adenosquamous carcinoma, or squamous-cell carcinoma), not amenable to curative treatment, and had no prior systemic treatment for metastatic, persistent, or recurrent disease. Pts were treated with anlotinib (12mg, po qd, d1-14, q3w) plus penpulimab (200mg, IV, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included PFS, duration of response (DOR), disease control rate (DCR), OS and safety. Results: From May 2022 to Nov 2023, 17 pts were enrolled. The median age was 52 years (range, 31-70), 65% of pts were squamous-cell carcinoma, 88% received previous chemoradiotherapy with or without surgery, and 71% had previously received neoadjuvant/adjuvant platinum-containing chemotherapy. As of date cutoff (Dec, 2023), the median follow-up time was 6.8 months (range, 1.4-18.3 months). In the efficacy analysis (n=17), the preliminary ORR was 58.8% (95% CI: 32.9%-81.6%), DCR was 88.2% (95% CI: 63.6%-98.5%). The mPFS was 11.0 months (95% CI: 5.4-16.7 months). The mOS was not reached. Treatment-related adverse events (TRAEs) of any grade occurred in all 17 pts, in which 8 (47.1%) were grade ≥3. The most common grade ≥3 TRAEs were hypertension (29.4%), hand foot syndrome (11.8%), fatigue (11.8%), and diarrhea (5.9%). TRAEs led to dose reduction and interruption were 29.4%, and 35.3% of pts, respectively. No TRAEs leading to death. Conclusions: The preliminary results demonstrated that anlotinib plus penpulimab as a first-line therapy for persistent, recurrent, or metastatic cervical cancer showed promising antitumor efficacy and manageable safety profile. Clinical trial information: NCT05028504 .
Zimberelimab combined with concurrent chemoradiotherapy for patients with locally advanced cervical cancer: Early results of efficacy and safety.
Authors: Lin Genlai , Ma Guifen , Wang Sitong , Xiao Chunli , Shi Tingyan , Xiang Libing , Jiang Li , Du Shisuo , Zeng Zhaochong
Published: July 2024

e17507

Background: To assess the efficacy and safety of zimberelimab combined with concurrent chemoradiotherapy (CCRT) for locally advanced cervical cancer (LACC) patients (pts). Methods: This a single arm, open label, prospective phase II study. participants aged 18-75 years of FIGO 2018 IIB-IVA LACC, with histologically confirmed adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma untreated with radiotherapy or immunotherapy for cervical cancer were included. Nineteen enrolled pts received zimberelimab (240 mg, IV, Q2W) for up to one year starting from the first week of radiotherapy, combined with CCRT, including cisplatin (25-40 mg/m2), paclitaxel (35 mg/m2), once a week for up to 5 cycles, intensity modulated radiation therapy (IMRT, 45-50 Gy/25-28 f), with a simultaneous integrated boost of 10-15 Gy to involved metastatic lymph nodes, followed by brachytherapy (30-40 Gy, 5-6 Gy/f, biw). All radiotherapy was completed within 8 weeks. The primary endpoint was objective response rate (ORR) assessed by investigators per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), 3-year overall survival (OS) rate and safety. Results: The median age was 57 years (range, 32 to 71), with 6 pts in stage IIB, 2 pts in stage IIIB, 8 pts in stage IIIC, and 3 pts in stage IVA. All pts completed CCRT successfully, with 18 pts completed 5 cycles of chemotherapy, while only 1 pts received 4 cycles of chemotherapy. The median cycles with zimberelimab treatment was 15 (range, 6 to 26). Grade (G) 3 and higher treatment related adverse events (TRAEs) were observed in 13 pts (13/19, 68.4%), 1 pts had G4 lymphopenia (1/19, 5.3%). The most frequent ≥G3 TRAEs was lymphopenia (11/19, 57.9%), followed by leukopenia (7/19, 36.8%). The ORR was 100%, with complete responses in 18 pts (18/19, 94.7%) and partial responses in 1 pts (1/19, 5.3%). At data cutoff (October 31, 2023), 2 pts had disease progression (2/19, 10.5%), 17 pts have been remaining in disease remission (17/19, 89.5%). Conclusions: Zimberelimab combined with CCRT achieved promising anti-tumor effects and manageable toxicities in LACC pts. Further follow-up results are expected. Trial registration: ClinicalTrials.gov Identifier: NCT05437692. Clinical trial information: NCT05437692 . [Table: see text]
Immunotherapy-based neoadjuvant therapy followed by concurrent chemoradiotherapy in locally advanced and advanced cervical cancer: A real-world study.
Authors: Wei Qianxue , Qu Hui , Gong Tingting , Gao Song , Tian Nan , Li Xiuqin
Published: July 2024

e17509

Background: Locally advanced and advanced cervical cancer (CC), characterized by extensive local invasion and potential distant metastasis, present substantial clinical challenges. Although concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced CC, a considerable proportion (23%-34%) of treated pts experienced recurrence or subsequent metastasis. Recently, neoadjuvant therapy (NAT) has been proposed to increase the radiosensitivity and decreases the fraction of hypoxic cells. Particularly, immunotherapy (IO)-based NAT has shown high activity in treating CC. Moreover, IO plus CRT has shown promise in enhancing both local control and systemic response. Hence, we analyzed the efficacy and safety of IO-based NAT followed by CCRT for locally advanced and advanced CC in a real-world setting. Methods: This study retrospectively analyzed data from pts with locally advanced and advanced CC who underwent IO-based NAT followed by CCRT at Shengjing Hospital of China Medical University from January 2022 to January 2024. Outcome measures included complete response (CR), partial response (PR), objective response rate (ORR), progression free survival (PFS), and safety. Tumor responses after neoadjuvant or CCRT therapy were evaluated using RECIST v1.1 and PFS was analyzed with the Kaplan-Meir method. Safety was assessed by adverse events (AEs) referring to CTCAEs v 5.0. Results: A total of 20 pts (median age 57 years, range, 39-72) were included in this analysis, with 15% at stage IIIB, 60% at IIIC, 10% at IVA, and 15% at IVB. Eight (40%) pts received 1 cycle of neoadjuvant IO, 8 (40%) received 1-4 cycles of neoadjuvant IO + chemotherapy, and 4 (20%) received 2 cycles of neoadjuvant IO + bevacizumab (Bev) + chemotherapy. After NAT, all 20 pts received CCRT. In the overall population, ORR after NAT was 55% (11/20), with 5% CR and 50% PR. Regarding different IO-based NAT regimens, objective responses were achieved in 1 of 8 (12.5%) pts receiving neoadjuvant IO, 6 of 8 (75%) pts receiving neoadjuvant IO + chemotherapy, and 4 of 4 (100%) pts receiving neoadjuvant IO + Bev + chemotherapy. After CCRT, 6 (30%) pts had a CR and 7 (35%) pts had a PR, resulting in an ORR of 65.0%. At a median follow-up of 14.9 months, the median PFS was not reached, with a 12-month and 24-month PFS rates of 68% and 56%, respectively. The most common treatment-related AEs during NAT were white blood cell count decreased (50%) and neutrophil count decreased. Conclusions: IO-based NAT followed by CCRT were effective and well-tolerated for pts with locally advanced and advanced CC. This treatment modalities may provide a potential therapeutic strategy for locally advanced and advanced CC.