BACKGROUND:Metastatic cancer patients receiving systemic chemotherapy face increased risks for venous thromboembolism (VTE). Benefit has been shown for prophylactic anticoagulants in risk-stratified populations. Ovarian cancer (OC) is commonly advanced at diagnosis and treated with chemotherapy. Despite high VTE rates among OC patients, predictors of risk in this population are not well studied, and information on the benefit of oral anticoagulants is lacking. OBJECTIVE:A quality improvement (QI) intervention to improve appropriate anticoagulation in risk-selected OC patients receiving first-line chemotherapy was implemented, prospectively assessing VTE risk reduction. METHODS:Patients receiving first-line chemotherapy for OC at Sheba Medical Center 2020-2025 were included. A QI program (launched 07/2023) included staff education, EMR-incorporated Khorana scoring, integrated apixaban prescriptions and targeted chemo-suite questionnaires. Data was extracted from the EMR using MDClone® software with Natural Language Processing to identify VTE events in imaging reports. Descriptive statistics were used to compare patients treated before and after program implementation. Predictors of VTE were evaluated with logistic regression. RESULTS:Patient characteristics were comparable before and after program implementation. VTE rates were high at 16.9% before, and 12.5% following roll-out. No increase in bleeding events or blood products consumption was appreciated. Program implementation was found to be a significant protective factor on multivariable analysis, adjusting for other risk factors (aOR = 0.39 (0.17-0.81), p = 0.015). CONCLUSION:The implementation of an oral anticoagulation QI program successfully decreased VTE events during first-line chemotherapy for OC with no appreciable increase in risk. Future work will focus on improved risk stratification and selection for thromboprophylaxis.

INTRODUCTION:We hypothesized that pneumonitis during Pacific protocol (PDP) contributes to poor outcomes in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with chemoradiation (ChRT) and durvalumab. METHODS:We analysed cases with LANSCLC extracted from a single academic institution database to identify patient, tumour, and treatment characteristics predicting for development of PDP and its effect on oncologic outcomes. RESULTS:Our database review identified 119 patients with LANSCLC that were treated with ChRT and durvalumab. Sixty-five percent were male and had a mean age of 66 years (SD 8); 58% stage IIB-IIIA, and 51% adenocarcinoma. PDP occurred in 35 (29.4%) cases, at a mean 2.6 months from durvalumab initiation (range 0.3-11 months), and was mostly low grade: G1-12, G2-18, G3-3, G4-1, G5-1. PDP resulted in treatment interruption in 24 cases (20%) with treatment discontinuation in 17 cases (14.3%). Multivariate analysis (MVA) showed all-grades PDP correlated with tumour stage, ipsilateral lung V5 ≥ 70%, and mean heart dose (MHD) ≥ 6 Gy. Grades 2-5 PDP correlated with total lungs V20 ≥ 27% and MHD ≥ 6 Gy. PDP did not correlate with a history of prior radiation pneumonitis (RP) (9/119). PDP was associated with decreased 3-year local control (LC) and progression-free survival (PFS); LC 53% vs 75.5% (HR 2.15, P = 0.031); PFS 35.5% vs 56.5% (HR 1.8, P = 0.04); and a trend for shorter overall survival (OS; 66% vs 77.5%, HR 1.5, P = 0.27). CONCLUSION:PDP correlated with ipsilateral lung V5 ≥ 70%, lungs V20 ≥ 27% and MHD ≥ 6 Gy. PDP was associated with inferior LC and PFS and trended for shorter OS. ADVANCES IN KNOWLEDGE:PDP occurred in a third of patients resulting in treatment discontinuation in 14.3%. PDP grades 2-5 correlated with radiation dose to lungs V20 ≥ 27% and MHD ≥ 6 Gy. PDP was associated with inferior LC and PFS and trended for shorter OS.

INTRODUCTION:Chemo-immunotherapy (IO) is the preferred first-line treatment for stage IVB or recurrent cervical cancer. However, limited data exist on the efficacy and safety of using IO-alone as a de-escalation strategy. We report outcomes from a case series of selected patients treated with IO-alone and review the feasibility of de-escalating first-line treatment. METHODS:The authors conducted a literature review using Google Scholar and PubMed to identify reports using IO-alone as a de-escalation strategy across malignancies published between 1999 and December 2024 and also reviewed a cervical cancer database from a tertiary academic to identify patients with stage IVB or recurrent disease treated with IO-alone. The authors used the Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS). RESULTS:Among 582 patients treated between 2015 and 2021, 18 met the inclusion criteria. The median age was 43 years (range 28-84); 67% had squamous cell carcinoma, 11% adenocarcinoma, and 80% expressed PD-L1. CPS scores were <1 in 20%, 1--10 in 33%, and >10 in 47%. Most patients had oligo-metastatic disease (83%). Treatment with IO-alone began a median of 7 months after platinum-based chemotherapy. Indications included prior adjuvant (44%) or neoadjuvant (22%) chemotherapy, clinical trial participation (11%), or patient preference (22%). Median PFS and OS were 27 months and 82 months, respectively. CONCLUSIONS:These findings support the need for clinical trials evaluating IO-alone as a first-line treatment option for de-escalation in stage IVB or recurrent cervical cancer. Biomarker development is needed to better identify candidates for personalized therapy.

5581 Background: Ovarian cancer (OC) is characterized by a high recurrence rate following primary surgical and systemic therapy with decreasing efficacy of subsequent treatment lines and accumulating toxicity. Immunotherapy had shown limited efficacy in recurrent OC with 8% response rate in a notable cohort study (Keynote 100).The combination of Pembrolizumab (P) with Lenvatinib (L) was evaluated in a small cohort of platinum resistant OC (LEEP 005) with a 32% response rate. This study assessed the P+L combination’s effectiveness in the platinum sensitive recurrence setting. Methods: In this investigator initiated phase 2 study (NCT04519151), we enrolled patients with platinum sensitive recurrent OC. Inclusion criteria were high grade serous or endometrioid histology, maximum of two previous treatment lines, measurable disease per RECIST 1.1, reserved organ function, and ECOG of 0 or 1. Patients received P (200mg every three weeks) and L (20mg daily) until disease progression or unacceptable toxicity or up to 35 cycles of P. L treatment could be maintained beyond 35 courses of P per investigator decision. Study's primary end point is response rate (RR), and secondary end points encompass progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and quality of life. Correlative study explored archival/fresh tumor tissue and blood biomarkers for response as well as fecal and vaginal microbiome. Results: Between May 2021 and July 2023 24 patients were treated. Median age was 65 years (range 43-77). 11(46%) received 1 prior treatment line and 11(46%) received prior bevacizumab. At a median follow up of 30 months, 12/24 (50%) had RECIST 1.1 response, 2 (8%) with CR and 10 (42%) with PR. Median PFS was 8 months. Median OS and DOR were not reached. At 6 and 12 months, response persisted in 10 and 3 patients, respectively. Treatment-related adverse events were noted in all patients, predominantly hypertension and fatigue. Dose reduction of L occurred in 19 (79%) patients mainly due to hypertension 8(33%), fatigue in 7(30%) and arthralgia in 5(21%). Discontinuation due to adverse event occurred in three patients (hepatitis, nephrotic range proteinuria, diabetic keto-acidosis). There was no treatment-related death. Data on the QOL analysis and biomarker study will be presented later. Conclusions: L+P combination showed meaningful responses and manageable toxicity in platinum sensitive recurrent OC patients thus potentially provides a non chemotherapy alternative. Effect on survival and response to subsequent therapies is yet to be evaluated. Further research is essential to pinpoint the patient subset that can benefit the most from this combination. Clinical trial information: NCT04519151 .

BACKGROUND:Poly (ADP-ribose) polymerase inhibitors (PARPi) play a pivotal role in ovarian cancer management. With medical cannabis emerging as a novel component of supportive care, this study investigated the impact of medical cannabis use on oncological outcomes in patients with ovarian cancer undergoing PARPi therapy. METHODS:The study included patients from a single institution database treated for ovarian cancer between January 2014 and January 2020 who received PARPi maintenance therapy in a first-line or recurrent disease setting after a confirmed response to platinum-based treatment. The study categorized patients as cannabis users and cannabis-naïve. Univariate and multivariate Cox regression analysis and the Kaplan-Meier method were used to assess the effects of medical cannabis use on the duration of PARPi therapy, progression-free survival, and overall survival. RESULTS:Among the eligible patients (n=93), most were cannabis-naïve (69%, n=64) while the rest used medical cannabis (31%, n=29). Medical cannabis use rates were comparable for patients receiving PARPi therapy post-primary treatment or for recurrence (42%, n=9, vs 27%, n=20; p=0.1). Both groups exhibited similar median duration for PARPi therapy (12.1 vs 9.5 months; p=0.89) and progression-free survival (20 vs 21 months; p=0.83). Kaplan-Meier analysis detected no differences in progression-free survival associated with cannabis use. Although cannabis users had an extended overall survival compared with the cannabis-naïve group (129.3 vs 99 months; p=0.03), cannabis use was insignificant for overall survival on multivariate analysis (p=0.10). Multivariate analysis showed stage IV at diagnosis (p=0.02) to be the sole factor associated with progression-free survival (p=0.02). CONCLUSION:Medical cannabis usage in patients receiving PARPi treatment showed no association with duration of PARPi therapy, progression-free survival, or overall survival.

Renal development is a complex process in which two major processes, tubular branching and nephron development, regulate each other reciprocally. Our previous findings have indicated that collagen XVIII (ColXVIII), an extracellular matrix protein, affects the renal branching morphogenesis. We investigate here the role of ColXVIII in nephron formation and the behavior of nephron progenitor cells (NPCs) using isoform-specific ColXVIII knockout mice. The results show that the short ColXVIII isoform predominates in the early epithelialized nephron structures whereas the two longer isoforms are expressed only in the later phases of glomerular formation. Meanwhile, electron microscopy showed that the ColXVIII mutant embryonic kidneys have ultrastructural defects at least from embryonic day 16.5 onwards. Similar structural defects had previously been observed in adult ColXVIII-deficient mice, indicating a congenital origin. The lack of ColXVIII led to a reduced NPC population in which changes in NPC proliferation and maintenance and in macrophage influx were perceived to play a role. The changes in NPC behavior in turn led to notably reduced overall nephron formation. In conclusion, the results show that ColXVIII has multiple roles in renal development, both in ureteric branching and in NPC behavior.

Abstract Background Borderline resectable stage III non-small cell lung cancer (NSCLC) poses significant clinical challenges. This study evaluated the outcomes of patients receiving neoadjuvant chemoradiation (NA-CRT), durvalumab, and surgery. Materials and Methods A retrospective analysis of an institutional database identified patients with borderline resectable stage III NSCLC treated with NA-CRT, durvalumab, and completion surgery. The data collected included radiographic and pathologic responses, surgical and clinical outcomes, and adverse events (AEs). Results Between 2017 and2021, 11 patients received NA-CRT, durvalumab, and completion surgery. Patients received a median number of 6 durvalumab treatments. Preoperative imaging revealed partial response (n = 5) or stable disease (n = 6). Surgical procedures included lobectomy (n = 10) or pneumonectomy (n = 1), resulting in R0 resection in all patients. Eight patients (73%) had a pathologic complete response (pCR), and 9 (82%) had a major pathologic response (MPR). At a median follow-up of 27 months, two cases of metastatic recurrence occurred. The median, 1-year, and 2-year estimates of progression-free survival (PFS) and overall survival (OS) were: 23 months and 25 months, 82% and 100%, and 72% and 80% respectively. Univariate analysis revealed no factors associated with pCR, MPR, PFS, or OS. Six patients had immune-related AEs (irAEs), 6 had postoperative AEs, and none were grade 4 or 5. Conclusion This integrated approach of NA-CRT + durvalumab exhibited promising outcomes and tolerability in patients with borderline resectable stage III NSCLC. These results suggest a rationale for including radiation therapy in future trials examining neoadjuvant strategies for resectable NSCLC patients.

Objective We hypothesized that driver mutations in epidermal growth factor receptor (EGFR) are associated with decreased pathologic response to neoadjuvant chemoradiation (NA-ChRT) in locally advanced non-small cell lung cancer (LA-NSCLC).Methods Patients with Stage IIB-IIIA NSCLC treated with NA-ChRT, completion surgery, and underwent molecular profile testing were identified in a lung cancer database. Pathologic response was quantified using: (i) major pathologic response (MPR), (ii) complete pathologic response (pCR), and (iii) mean residual viable tumor cells (MRTC). Two groups were formed based on the presence or absence of driver mutations. Clinical and pathological correlations between the groups were studied.Results Forty-seven patients underwent tumor molecular profile testing, NA-ChRT, and completion surgery. Compared to the no-driver mutation group, the driver mutation group had lower MPR (23% vs 71%, p = 0.003), pCR (0% vs 26%, p = 0.02), and higher MRTC (43.4% vs 15.8%, p = 0.009). Univariate analysis showed an increased MPR rate for smokers, squamous cell histology, ChRT-surgery interval >65 days, and no-driver mutations. Multivariate analysis showed that only no-driver mutations (OR 0.39, p = 0.02) remained significant for MPR. PD-L1 status did not affect MPR. At 2 years, the driver mutation group had lower rates of local control (Hazard ration [HR] 0.67, p = 0.17) and disease-free survival (HR 0.5, p = 0.001). Overall survival was similar for both groups (HR = 1.04, p = 0.86).Conclusion Following 60 Gray NA-ChRT, tumors with a driver mutation had lower MPR and pCR rates than tumors without a driver mutation. PD-L1 was not associated with tumor regression.Advances in knowledge Patients with resectable LA-NSCLC and an EGFR driver mutation treated with neoadjuvant-ChRT and completion surgery have reduced pathologic regression, lower local control rates, and shorter disease-free survival than patients without a driver mutation. Evaluation of molecular testing should be introduced in LA-NSCLC intended for prognostication and treatment decisions.

OBJECTIVE:The use of chemoradiation in patients with stage IVB cancer of the cervix was evaluated to determine if definitive treatment offers benefit. METHODS:A database of 546 patients with cancer of the cervix treated between January 2005 and May 2021 at a tertiary academic medical center was reviewed retrospectively to identify patients with stage IVB disease. Log rank test, regression analysis, and the Kaplan-Meier method were used to identify and compare variables and estimate progression free survival and overall survival. RESULTS:Thirty-three patients with stage IVB cervical cancer were identified. Median age was 53 years (range 28-78). Pathology subtypes were squamous cell (n=22, 67%), adenocarcinoma (n=8, 24%), and clear cell (n=3, 9%). Metastases were classified as lymphatic (n=14, 42%) or hematogenous (n=19, 58%). Following treatment to all sites with chemoradiotherapy and selected use of surgery (n=23), six patients (26%, lymphatic n=4, hematogenous n=2) remained disease free for a median duration of 4 years (range 3-17 years). Recurrences in the remaining patients were distant (n=13) or local (n=4). All patients in the chemotherapy group (n=10, 100%) progressed. Kaplan-Meier analysis showed that median progression free survival was longer for patients treated at all disease sites than for patients treated with chemotherapy alone (19 vs 11 months, p=0.01). However, this was not the case for overall survival (49 vs 33 months, p=0.15). Patients with metastases limited to lymph nodes also had longer median progression free survival (22 vs 11 months, p=0.04) but not overall survival (p=0.68). CONCLUSIONS:Patients with stage IVB cancer of the cervix may benefit from treatment to all sites of disease, if feasible and safe, as demonstrated by improved progression free survival.

Objectives: The identification and targeting of actionable genomic alterations (AGA) have revolutionized the treatment of cancer in general and mostly for non-small cell lung cancer (NSCLC). We investigated whether in NSCLC patients PIK3CA mutations are actionable.Materials and Methods: Chart review was performed of advanced NSCLC patients. PIK3CA mutated patients were analyzed as two groups: Group A: without any non-PIK3CA established AGA; Group B: with coexisting AGA. Group A was compared to a cohort of non-PIK3CA patients (group C), using t-test and chi-square. To evaluate the impact of PIK3CA mutation on outcome, we compared Group A survival to age/sex/histology matched cohort of non-PIK3CA mutated patients (group D) by Kaplan-Meier method.A patient with a PIK3CA mutation was treated with a PI3Ka-isoform selective inhibitor BYL719 (Alpelisib).Results: Of a cohort of 1377 patients, 57 are PIK3CA mutated (4.1%). Group A: n-22, group B: n-35. Group A median age is 76 years, 16 (72.7%) men, 10 (45.5%) squamous, 4 (18.2%) never smokers. Two never-smoker female adenocarcinoma patients had solitary PIK3CA mutation. One of them was treated with a PI3Kaisoform selective inhibitor BYL719 (Alpelisib), with rapid clinical and partial radiological improvement. Group B, compared with Group A, included younger patients (p = 0.030), more females (p = 0.028) and more adenocarcinoma cases (p < 0.001). Compared to group C, group A patients were older (p = 0.030) and had more squamous histology (p = 0.011).Conclusion: In a small minority of NSCLC patients with PIK3CA mutation there are no additional AGA. PIK3CA mutations may be actionable in these cases.

To evaluate effects of Continuous Positive Airway Pressure (CPAP) on cardiac position, volume, and motion in a cohort of patients receiving thoracic radiation therapy (RT). Patients underwent 3-dimensional (3D) and 4D-computerized tomography (CT) imaging with free-breathing (FB) and CPAP for RT planning. All scans were co-registered on the treatment planning system for contouring, identification of the center of heart volume and comparative measurements of cardiac displacement, volume and motion. Heart volume (HV) was created from 3D-CT contours. Range of heart motion was estimated by creating an internal heart volume (IHV) from 4D-CT contours. Magnitude of cardiac motion (cardiac excursion) was recorded as the difference in volume between IHV and HV. Wilcoxon signed rank test and Spearmen's rank correlation coefficient were used to assess differences between variables and correlations between lung volume and heart parameters. Results from 9 patient data sets were available for this report. Compared to FB, CPAP use was associated with caudal displacement of the HV (1 cm, p < 0.008) and IHV (1.1 cm, p < 0.008). CPAP use decreased HV 6% (p < 0.008) and IHV 13% (p < 0.008). Cardiac excursion was 49% (p < 0.01) less with CPAP than with FB. CPAP use increased mean lung volume by 30% (p < 0.008) which correlated with caudal displacement of the HV (r = 0.83, p < 0.008) and IHV (r = 0.98, p < 0.001). The use of CPAP reduced cardiac motion and volume although the reduction in volume was minimal. The increase in lung volume correlated with caudal displacement of the heart. These results suggest the mechanism for achieving dosimetric benefit was obtained by cardiac displacement and decreased lung and heart motion rather than reduction of HV. Further evaluation of CPAP as a novel technique to reduce heart exposure when offering RT is warranted.

Introduction/Background MAP kinase pathway alterations are prevalent in low grade serous ovarian cancer (LGSOC) in up to 60% of patients, of them, minority harbor BRAF V600E mutation. While MILO-ENGOT ov11 study showed 13% response to Binimetinib (a MEK inhibitor), irrespective of mutation status, the value of BRAF and MEK inhibition in BRAF mutant patients was not evaluated. Herein we report the results of 5 patients treated with Dabrafenib and Trametinib (D+T) for non-resectable LGSOC. Methodology We collected data from 5 patients who received D+T combination as compassionate use for BRAF V600E mutant LGSOC. All patients signed the Israeli informed consent for the use of off-label medications. Data on disease stage, prior lines of therapy, best response per RECIST, duration of response (DOR), survival and safety were collected. Results 5 patients were treated with the combination of D+T. The median age was 53.8 years. The stage of the disease varied from IIIC-IVB (2/3). Median prior systemic treatment lines was 2 (range 0–5). Overall 4 of 5 patients (80%) had documented response. 2 patients achieved CR, and 2 patients had PR as best response. 1 patient was not evaluated due to early clinical deterioration. PFS was 18 months for the first patient, other 3 have ongoing responses at 18, 5 and 5 months. All patients had major relief of symptoms. 1 patient had 2 re-inductions of treatment following subsequent chemotherapy with 6 months PFS in each re-induction. The most frequent side effects were fatigue G1 (5/5) and pyrexia (4/5). None required permanent discontinuation. 3 patients are still receiving treatment. Conclusion Targeting BRAF V600E mutation with combined BRAF and MEK inhibition in LGSOC yields high response rate with durable and meaningful improved disease control. These cases should emphasize the importance of performing the BRAF V600E mutation test for all patients with LGSOC.

Abstract Objective Compare outcomes in patients with stage III non–small cell lung cancer (NSCLC) treated with chemoradiation and adjuvant durvalumab to historical controls treated with chemoradiation alone. Methods The records of patients with stage III NSCLC treated with definitive chemoradiation ± adjuvant durvalumab were reviewed retrospectively. Primary endpoints were progression free survival (PFS), overall survival (OS), and adverse events (AE). Results Between September 2009 and September 2020, 215 patients were treated with concurrent chemoradiation (n = 144) or concurrent chemoradiation followed by adjuvant durvalumab (n = 71). Compared to historical controls, durvalumab use was associated with improved PFS: median (27 months vs. 10 months, p < 0.0001), 1‐year (83.1% vs. 43.8, p < 0.0001); and improved OS; median (not reached vs. 24 months, p < 0.0001), 1‐year (85.9% vs. 81.9%, p < 0.0001). Multivariate analysis showed adjuvant durvalumab was associated with increased OS (p = 0.005) and PFS (p = 0.001). Within the durvalumab group, only clinical stage IIIA versus IIIB/C was associated with improved OS (p = 0.049), but not PFS. There was no association between PFS or OS and Eastern Cooperative Oncology Group (ECOG) score, prior history of immune disease, programmed death‐ligand 1 (PD‐L1) receptor status, delay in starting durvalumab beyond 42 days, or development of an AE. During durvalumab treatment, 63 AE were reported in 52 patients with treatment discontinuation in 11. Pneumonitis was the most common AE reported (n = 35, 49%). Most AE were grade 1–2 (n = 57). Grade 3–4 AE were uncommon (n = 6) and none were grade 5. Conclusion Treatment with adjuvant durvalumab following chemoradiation was associated with improved PFS and OS compared to chemoradiation alone.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition ( MET ) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases ( n = 11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.

Collagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of homeostasis. We provide evidence that ColXVIII has a specific role in kidney ontogenesis by regulating the interaction between mesenchymal and epithelial tissues as observed in analyses of total and isoform-specific knockout embryos, mice, and ex vivo organ primordia. ColXVIII deficiency, both temporally and spatially, impacts the 3D pattern of ureteric tree branching morphogenesis via its specific isoforms. Proper development of ureteric tree depends on a tight control of the nephron progenitor cells (NPCs). ColXVIII-deficient NPCs are leaving the NPC pool faster than in controls. Moreover, the data suggests that ColXVIII mediates the kidney epithelial tree patterning via its N-terminal domains, and especially the Thrombospondin-1-like domain, and that this morphogenetic effect involves ureteric epithelial integrins. Altogether, the results propose a significant role for ColXVIII in a complex signalling network regulating renal progenitors and kidney development.

Objective: To examine whether patients with both breast cancer (BC) and endometrial cancer (EC) have different features of disease, and whether the sequence of appearance of these tumors is correlated with a more aggressive course. Methods: A retrospective, multi-center observational cohort study of patients treated in two tertiary medical centers between 2014 and 2020. Files of patients who had a co-diagnosis of BC and EC were reviewed and clinical, epidemiological, pathological and genetic characteristics were collected. Results: 67 patients with a co-diagnosis of both malignances were divided into two groups according to primary tumor diagnosis: BC first group (43/67, 64%) and EC first group (24/67, 36%). The time interval between diagnosis of malignancies was significantly longer in the BC first group (mean 144.5 months vs. 67 months, p < 0.05). BRCA mutations were found in higher numbers in the BC first group (27.5% vs. 9.5%, p = 0.18). A significantly higher number of patients in the BC first group had uterine serous carcinoma (USC) histology (44% vs. 12.5%, p < 0.05). This was independent of tamoxifen usage among patients (OR 0.65, 95% CI 0.17-2.49). Conclusions: In patients suffering from both BC and EC, the sequence of occurrence of malignancies has relevance: When EC presents as a second primary tumor, it tends to present in a more aggressive form, independent of previous tamoxifen use. The time interval between the diagnosis of malignancies was significantly longer in this group, offering an opportunity to improve preventive measures to decrease the likelihood of a subsequent lethal second cancer.

Purpose Both beta 1- and beta 2-adrenoceptor proteins were detected on the cell surface of pancreatic ductal adenocarcinoma. The current study evaluated the association between beta-blocker use and pancreatic cancer risk. Methods We conducted a nested case-control study in a large population representative database. Each pancreatic cancer case was matched with four controls based on age, sex, practice site, and duration of follow-up using incidence density sampling. Beta-blocker use was defined as any prescription prior to index date and was stratified into non-selective and selective beta(1)-blockers. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for pancreatic cancer risk associated with beta-blocker use was estimated using conditional logistic regression. Results The study included 4113 patients with pancreatic cancer and 16 072 matched controls. When compared to never users, there was no association between any beta-blocker use and pancreatic cancer risk (adjusted OR 1.06, 95% CI 0.97-1.16, P = .16). Analysis by receptor selectivity showed use of non-selective beta-blockers for more than 2 years was associated with a reduced pancreatic cancer risk (OR 0.75, 95% CI 0.57-1.00, P = .05). When compared to former users both users of selective beta 1-blockers and non-selective beta-blockers had a reduced pancreatic cancer risk (OR 0.78, 95% CI 0.67-0.90, P = .001) and (OR 0.67, 95% CI 0.49-0.92, P = .01), respectively. Conclusion Beta-blocker use was not associated with increased pancreatic cancer risk. However, long-term use of beta-blockers may be associated with decreased pancreatic cancer risk.

Lutetium-177-PSMA ([177Lu]-PSMA-617), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA), enabling targeted radiation therapy to metastatic prostate lesions. Our objective was to retrospectively analyze the activity of [177Lu]-PSMA-617 given off-trial to men with metastatic castration resistant prostate cancer (mCRPC) and identify clinical factors associated with PSA response. Electronic medical records of all men treated with [177Lu]-PSMA-617 were reviewed and analyzed. Overall survival was calculated using the Kaplan–Meier method. The association between potential variables and PSA response was analyzed by univariate analysis, using either logistic regression or χ2/Fisher’s exact test. Multivariable analysis was carried out using logistic regression on all categorical variables with a P-value of <0.1 on univariate analysis. Variables found to be statistically significant were then used to define a categorical score. A total of 52 patients received at least one cycle of [177Lu]-PSMA-617. Clinical benefit was observed in 28 patients (52%). PSA decline ≥20% and ≥50% was observed in 26 (50%) and 18 patients (35%), respectively. Achievement of any PSA decline at first measurement was significantly associated with survival. There was a negative association between the number of previous chemotherapy lines and PSA decline above 20%. Univariate analysis followed by multivariable analysis showed that older age and higher hemoglobin were significantly associated with a PSA decline >20%. A score combining these two parameters was significantly associated with PSA response. In summary, [177Lu]-PSMA-617 is active in the ‘real-life’ setting of heavily pretreated men with mCRPC.