Survival Outcomes In Patients Research Articles

Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy

Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. Invivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).

Abstract P41: Ex vivo Drug Testing Identifies a Novel Drug Pair in Targeting STS

Abstract Soft tissue sarcomas (STS) are a highly heterogeneous collection of tumors that arise from primitive mesenchymal cells. Due to a reliance on cytotoxic chemotherapy as standard of care, survival outcomes for advanced STS patients remain poor. While efforts to understand sarcomagenesis have revealed potential biomarkers, the diversity of STS subtypes and interpatient tumour heterogeneity has led to the lack of effective molecular targeted therapies available. Given the uniquely individualized nature of STS, we hypothesize that the application of an experimental-analytics method, Quadratic Phenotypic Optimization Platform (QPOP), towards primary STS patient samples can improve identification of patient-specific drug combinations. Across a total of 45 patient samples collected, QPOP identified a novel drug pair as most frequently top-ranked, outperforming standard of care ifosfamide and doxorubicin. Interestingly, analysis of QPOP ranking trends revealed this combination to be broadly effective, implying common targetable pathways independent of STS subtype. Single-drug and combination dose-response assays performed in a panel of established patient lines supported its synergistic interaction, accompanied by increased PARP and caspase-3 cleavage with immunoblotting, and increased apoptotic response with Annexin V assay. Mechanistically, this synergy results in cell cycle arrest and induction of programmed cell death pathways, as revealed by molecular profiling on representative patient and cell lines. We further showed that co-treatment synergistically repressed oncogenic MYC and activated the p27kip1 tumor suppressor. Finally, this combination was more effective at impairing tumor progression than single agents alone in an STS xenograft mouse model. Overall, work here provides preliminary clinical evidence for the prioritization of a novel drug pair in addressing STS beyond known clinicopathologic parameters. Citation Format: Sharon Pei Yi Chan, Wai Yee Wong, Nur Nadiah Ismail, Baiwen Luo, Benjamin Jieming Chen, Brandon Xuan Ming Phua, Xing Yi Woo, Tan Boon Toh, Edward Kai-Hua Chow, Valerie Shiwen Yang. Ex vivo Drug Testing Identifies a Novel Drug Pair in Targeting STS [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P41.

ScRNA-seq characterizing the heterogeneity of fibroblasts in breast cancer reveals a novel subtype SFRP4+ CAF that inhibits migration and predicts prognosis

IntroductionCancer-associated fibroblasts (CAFs) are a diverse group of cells that significantly impact the tumor microenvironment and therapeutic responses in breast cancer (BC). Despite their importance, the comprehensive profile of CAFs in BC remains to be fully elucidated.MethodsTo address this gap, we utilized single-cell RNA sequencing (scRNA-seq) to delineate the CAF landscape within 14 BC normal-tumor paired samples. We further corroborated our findings by analyzing several public datasets, thereby validating the newly identified CAF subtype. Additionally, we conducted coculture experiments with BC cells to assess the functional implications of this CAF subtype.ResultsOur scRNA-seq analysis unveiled eight distinct CAF subtypes across five tumor and six adjacent normal tissue samples. Notably, we discovered a novel subtype, designated as SFRP4+ CAFs, which was predominantly observed in normal tissues. The presence of SFRP4+ CAFs was substantiated by two independent scRNA-seq datasets and a spatial transcriptomics dataset. Functionally, SFRP4+ CAFs were found to impede BC cell migration and the epithelial-mesenchymal transition (EMT) process by secreting SFRP4, thereby modulating the WNT signaling pathway. Furthermore, we established that elevated expression levels of SFRP4+ CAF markers correlate with improved survival outcomes in BC patients, yet paradoxically, they predict a diminished response to neoadjuvant chemotherapy in cases of triple-negative breast cancer.ConclusionThis investigation sheds light on the heterogeneity of CAFs in BC and introduces a novel SFRP4+ CAF subtype that hinders BC cell migration. This discovery holds promise as a potential biomarker for refined prognostic assessment and therapeutic intervention in BC.

Survival outcome after surgery in patients with thymoma distant recurrence.

ObjectiveAim of this study is to describe characteristics and survival outcome of patients who underwent surgical treatment for distant thymoma relapse according to the International Thymic Malignancy Interest Group definition(ITMIG). MethodsData of patients affected by thymoma recurrence from 4 different Institution were collected and retrospectively reviewed.Patients with loco-regional metastases, who underwent non-surgical therapies and with incomplete data on follow-up were excluded.According to the ITMIG distant recurrence definition,patients with recurrence due to hematogenic localization were included. Clinical and pathological characteristics were described using descriptive statistics while survival outcome was calculated using Kaplan-Meier curves and Cox regression analysis. ResultsThe analysis was conducted on 40 patients.A single localization was present in 13 patients,the relapse was intrathoracic in 28(70%),involving the lung in 26cases. Liver was operated in 7 cases, while other kind of abdominal involvement was detected in 8 cases.Adjuvant treatment was administered in 22cases(55%).Five and 10 year OS resulted 67% and30%. Univariable analysis identified as significant favorable factor a low-grade histology(A,B1, B2):5YOS 92.3% vs53.3% in high-grade (B3-C)(p=0.035). Site of recurrence and number of localization did not influence the prognosis, while in patients with adjuvant therapy administration there were a survival advantage also if not statistically significant:5YOS 84.8%vs54.5% in patients without adjuvant therapy(p=0.101).Multivariable analysis confirmed as independent prognostic factor low grade histology:HR=0.176,95% CI 0.042-0.744,p=0.018. ConclusionsOur study showed a good survival outcome in patients who underwent surgery for distant thymoma recurrence,independently from the number and site of the relapse localization. Patients with A,B1,B2 histology presented a significantly better survival than patients with B3-C.

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

Significance of preoperative exercise oxygen desaturation in lung cancer with interstitial lung disease.

Evaluating the diffusing capacity for carbon monoxide (DLco) is crucial for patients with lung cancer and interstitial lung disease. However, the clinical significance of assessing exercise oxygen desaturation (EOD) remains unclear. We retrospectively analyzed 186 consecutive patients with interstitial lung disease who underwent lobectomy for non-small cell lung cancer. EOD was assessed using two-flight test (TFT), with TFT positivity defined as ≥ 5% SpO2 reduction. We investigated the impact of EOD and predicted postoperative (ppo) %DLco on postoperative complications and prognosis. A total of 106 (57%) patients were identified as TFT-positive, and 58 (31%) patients had ppo% DLco < 30%. Pulmonary complications were significantly more prevalent in TFT-positive patients than in TFT-negative patients (52% vs 19%, P < 0.001), and multivariable analysis revealed that TFT-positivity was an independent risk factor (odds ratio 3.46, 95% confidence interval 1.70-7.07, P < 0.001), while ppo%DLco was not (P = 0.09). In terms of long-term outcomes, both TFT positivity and ppo%DLco < 30% independently predicted overall survival. We divided the patients into four groups based on TFT positivity and ppo%DLco status. TFT-positive patients with ppo%DLco < 30% exhibited the significantly lowest 5-year overall survival among four groups: ppo%DLco ≥ 30% and TFT-negative, 54.2%; ppo%DLco < 30% and TFT-negative, 68.8%; ppo%DLco ≥ 30% and TFT-positive, 38.1%; and ppo%DLco < 30% and TFT-positive, 16.7% (P = 0.001). Incorporating EOD evaluation was useful for predicting postoperative complications and survival outcomes in patients with lung cancer and interstitial lung disease.

Blood groups and Rhesus status as potential predictors of outcomes in patients with cardiac resynchronisation therapy

Cardiac resynchronisation therapy (CRT) improves prognosis in patients with heart failure (HF) however the role of ABO blood groups and Rhesus factor are poorly understood. We hypothesise that blood groups may influence clinical and survival outcomes in HF patients undergoing CRT. A total of 499 patients with HF who fulfilled the criteria for CRT implantation were included. Primary outcome of all-cause mortality and/or heart transplant/left ventricular assist device was assessed over a median follow-up of 4.6 years (IQR 2.3–7.5). Online repositories were searched to provide biological context to the identified associations. Patients were divided into blood (O, A, B, and AB) and Rhesus factor (Rh-positive and Rh-negative) groups. Mean patient age was 66.4 ± 12.8 years with a left ventricular ejection fraction of 29 ± 11%. There were no baseline differences in age, gender, and cardioprotective medication. In a Cox proportional hazard multivariate model, only Rh-negative blood group was associated with a significant survival benefit (HR 0.68 [0.47–0.98], p = 0.040). No association was observed for the ABO blood group (HR 0.97 [0.76–1.23], p = 0.778). No significant interaction was observed with prevention, disease aetiology, and presence of defibrillator. Rhesus-related genes were associated with erythrocyte and platelet function, and cholesterol and glycated haemoglobin levels. Four drugs under development targeting RHD were identified (Rozrolimupab, Roledumab, Atorolimumab, and Morolimumab). Rhesus blood type was associated with better survival in HF patients with CRT. Further research into Rhesus-associated pathways and related drugs, namely whether there is a cardiac signal, is required.

Bispecific antibodies for the treatment of relapsed/refractory multiple myeloma: updates and future perspectives

Patients with relapsed/refractory multiple myeloma (RRMM) that are refractory to the five most active anti-MM drugs, so-called penta-refractory MM, have historically had dismal outcomes with subsequent therapies. Progressive immune dysfunction, particularly of the T-cell repertoire, is implicated in the development of disease progression and refractory disease. However, the advent of novel immunotherapies such as bispecific antibodies are rapidly changing the treatment landscape and improving the survival outcomes of patients with RRMM. Bispecific antibodies are antibodies that are engineered to simultaneously engage cytotoxic immune effector cells (T cells or NK cells) and malignant plasma cells via binding to immune effector cell antigens and extracellular plasma cell antigens leading to immune effector cell activation and malignant plasma cell destruction. Currently, bispecific antibodies that bind CD3 on T cells and plasma cell epitopes such as B-cell maturation antigen (BCMA), G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5) are the most advanced in clinical development and are showing unprecedented response rates in patients with RRMM, including patients with penta-refractory disease. In this review article, we explore the available clinical data of bispecific antibodies in RRMM and summarize the efficacy, safety, toxicity, clinical outcomes, mechanisms of resistance, and future directions of these therapies in patients with RRMM.

The Expression and Amplification of HER2 Has a Significant Impact on the Prognosis of Endometrial Carcinoma in Korean Patients

Objective: The purpose of this study was to analyze the protein overexpression and gene amplification of HER2 in endometrial carcinoma (EC) and to evaluate its role as a prognostic factor in Korean women. Methods: A tissue microarray (TMA) was constructed from samples from 191 patients with diverse histologic types of EC. HER2 protein expression and gene amplification status were analyzed using immunohistochemistry (IHC) and silver in situ hybridization (SISH), respectively. All patients were treated and followed up at a single tertiary medical center in Seoul, Korea, between July 2009 and October 2020. Results: In terms of histological type, among the 191 EC patients, 157 had endometrioid carcinoma, nine had uterine serous papillary carcinoma (USPC), one had clear cell carcinoma, one had squamous cell carcinoma, eight had mixed carcinoma, and 15 had uterine carcinosarcoma (UC). HER2 protein overexpression was observed in eight of the 191 (4.2%) EC patients; of these patients, five had IHC scores of 2+, and three had IHC scores of 3+. The HER2 overexpression rates of USPC, UC, and endometrioid carcinomas were 33.3%, 26.6%, and 0.6%, respectively. HER2 protein overexpression was significant in USPC and UC tissues (p &lt; 0.000) and was associated with poor overall survival (OS) (p &lt; 0.001). HER2 gene amplification was confirmed in seven of 184 patients (3.8%), including three patients with USPC and four patients with UC. OS was significantly shorter in patients who had HER2 amplification (p &lt; 0.001). On multivariate analysis, HER2 expression and HER2 amplification were statistically significantly associated with worse OS (p = 0.006). However, HER2 expression without amplification was not statistically associated with OS (p = 0.993). Conclusions: HER2 protein overexpression and gene amplification are significantly correlated with shorter OS in Korean women. HER2 can be considered an important predictor of survival outcomes in EC patients.

Pembrolizumab-based first-line treatment for PD-L1-positive, recurrent or metastatic head and neck squamous cell carcinoma: a retrospective analysis

BackgroundThe KEYNOTE-048 trial showed that pembrolizumab-based first-line treatment for R/M HNSCC led to improved OS in the PD-L1 CPS ≥ 1 population when compared to the EXTREME regimen. However, the R/M HNSCC real-world population is generally frailer, often presenting with multiple comorbidities, worse performance status and older age than the population included in phase III clinical trials.MethodsThis is a retrospective, single-centre analysis of patients with R/M HNSCC treated with pembrolizumab-based first-line treatment.ResultsFrom February 2021 to March 2023, 92 patients were treated with pembrolizumab-based first-line treatment. Patients treated with pembrolizumab-based chemoimmunotherapy had better ECOG PS and younger age than those treated with pembrolizumab monotherapy. Median PFS and OS were 4 months and 8 months, respectively. PFS was similar among patients treated with pembrolizumab-based chemoimmunotherapy and pembrolizumab monotherapy, while patients treated with pembrolizumab monotherapy had worse OS (log-rank p =.001, HR 2.7). PFS and OS were improved in patients with PD-L1 CPS > = 20 (PFS: log-rank p =.005, HR 0.50; OS: log-rank p =.04, HR 0.57). Patients with higher ECOG PS scores had worse PFS and OS (PFS, log-rank p =.004; OS, log-rank p = 6e-04). In multivariable analysis, ECOG PS2 was associated with worse PFS and OS.ConclusionsPFS in our real-world cohort was similar to the KEYNOTE-048 reference while OS was numerically inferior. A deeper understanding of clinical variables that might affect survival outcomes of patients with R/M HNSCC beyond ECOG PS and PD-L1 CPS is urgently needed.

Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC

Background and aimsSorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC.Materials and methodsA clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array.ResultsCRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC.ConclusionOur study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

Impact of gene expression profiling on diagnosis and survival after metastasis in patients with uveal melanoma.

Surveillance frequency for metastasis is guided by gene expression profiling (GEP). This study evaluated the effect of GEP on time to diagnosis of metastasis, subsequent treatment and survival. A retrospective study was conducted of 110 uveal melanoma patients with GEP (DecisionDx-UM, Castle Biosciences, Friendswood, Texas, USA) and 110 American Joint Committee on Cancer-matched controls. Surveillance testing and treatment for metastasis were compared between the two groups and by GEP class. Rates of metastasis, overall survival and melanoma-related mortality were calculated using Kaplan-Meier estimates. Baseline characteristics and follow-up time were balanced in the two groups. Patients' GEP classification was 1A in 41%, 1B in 25.5% and 2 in 33.6%. Metastasis was diagnosed in 26.4% (n = 29) in the GEP group and 23.6% (n = 26) in the no GEP group (P = 0.75). Median time to metastasis was 30.5 and 22.3 months in the GEP and no GEP groups, respectively (P = 0.44). Median months to metastasis were 34.7, 75.8 and 26.1 in class 1A, 1B and 2 patients, respectively (P = 0.28). Disease-specific 5-year survival rates were 89.4% [95% confidence interval (CI): 81.0-94.2%] and 84.1% (95% CI: 74.9-90.1%) in the GEP and no GEP groups respectively (P = 0.49). Median time to death from metastasis was 10.1 months in the GEP group and 8.5 months in the no GEP group (P = 0.40). There were no significant differences in time to metastasis diagnosis and survival outcomes in patients with and without GEP. To realize the full benefit of GEP, more sensitive techniques for detection of metastasis and adjuvant therapies are required.

Supplemental tube feeding: qualitative study of patient perspectives in advanced pancreatic cancer

ObjectivesMalnutrition is associated with poor quality of life and survival outcomes for patients with cancer, but is challenging to prevent or treat in pancreatic cancer due to the multifactorial drivers...

HSR24-159: Relationship Between Durable Transfusion Independence (TI) and Survival Outcomes in Patients (Pts) With Lower-Risk Myelodysplastic Syndrome (LR-MDS): An Analysis From US Health Insurance Claims Data.

HSR24-159: Relationship Between Durable Transfusion Independence (TI) and Survival Outcomes in Patients (Pts) With Lower-Risk Myelodysplastic Syndrome (LR-MDS): An Analysis From US Health Insurance Claims Data.

Systematic analysis of cuproptosis abnormalities and functional significance in cancer.

Cuproptosis is a recently discovered type of cell death, but the role and behavior of cuproptosis-related genes (CuRGs) in cancers remain unclear. This paper aims to address these issues by analyzing the multi-omics characteristics of cancer-related genes (CuRGs) across various types of cancer. To investigate the impact of somatic copy number alterations (SCNA) and DNA methylation on CRG expression, we will analyze the correlation between these factors. We developed a cuproptosis index (CPI) model to measure the level of cuproptosis and investigate its functional roles. Using this model, we assessed the clinical prognosis of colorectal cancer patients and analyzed genetic changes and immune infiltration features in different CPI levels. The study's findings indicate that the majority of cancer-related genes (CuRGs) were suppressed in tumors and had a positive correlation with somatic copy number alterations (SCNA), while having a negative correlation with DNA methylation. This suggests that both SCNA and DNA methylation have an impact on the expression of CuRGs. The CPI model is a reliable predictor of survival outcomes in patients with colorectal cancer and can serve as an independent prognostic factor. Patients with a higher CPI have a worse prognosis. We conducted a deeper analysis of the genetic alterations and immune infiltration patterns in both CPI positive and negative groups. Our findings revealed significant differences, indicating that CuRGs may play a crucial role in tumor immunity mechanisms. Additionally, we have noticed a positive correlation between CuRGs and various crucial pathways that are linked to the occurrence, progression, and metastasis of tumors. Overall, our study systematically analyzes cuproptosis and its regulatory genes, emphasizing the potential of using cuproptosis as a basis for cancer therapy.

Real-world Outcomes in Newly Diagnosed Multiple Myeloma Based on Interphase Fluorescent In situ Hybridization: A Retrospective Analysis

Introduction: Limited data exist on interphase fluorescent in situ hybridization (iFISH)-based survival outcomes in newly diagnosed multiple myeloma (NDMM) from India. Objectives: To study the demographics and iFISH-based survival outcomes in NDMM patients treated with proteasome inhibitors from a community-based cancer setup. Materials and Methods: We reviewed the records of 25 patients treated with proteasome inhibitors between June 2017 and April 2023 using five high-risk (HR) iFISH markers based on mSMART 3.0. Results: The median age was 60 years (range 34–87). HR iFISH was detected in 12 (48%) patients. With a median follow-up of 27 months, the overall response at the last follow-up was 80% (very good partial response - 52%, complete remission - 20%, and partial response - 8%), with 8 (32%) relapses. Twenty (80%) patients remain alive, with five deaths in HR (sepsis [ n = 3]). The 2.5-year overall survival in HR and standard risk was 55.6% ± 15.2% and 100% ( P = 0.01), and event-free survival was 32.4% ± 16.5% and 77.8% ± 13.8% ( P = 0.02), respectively. Conclusions: Using limited iFISH HR markers helps in the early and effective stratification of NDMM in the real world. Sepsis remains an important cause of mortality in an Indian setup.

Sequencing Treatments in Patients with Advanced Well-Differentiated Pancreatic Neuroendocrine Tumor (pNET): Results from a Large Multicenter Italian Cohort.

Background: The optimal treatment sequencing for advanced, well-differentiated pancreatic neuroendocrine tumors (pNETs) is unknown. We performed a multicenter, retrospective study to evaluate the best treatment sequence in terms of progression-free survival to first-line (PFS1) and to second-line (PFS2), and overall survival among patients with advanced, well-differentiated pNETs. Methods: This multicenter study retrospectively analyzed the prospectively collected data of patients with sporadic well-differentiated pNETs who received at least two consecutive therapeutic lines, with evidence of radiological disease progression before change of treatment lines. Results: Among 201 patients, 40 (19.9%) had a grade 1 and 149 (74.1%) a grade 2 pNET. Primary tumor resection was performed in 98 patients (48.8%). First-line therapy was performed in 128 patients with somatostatin analogs (SSA), 35 received SSA + radioligand therapy (RLT), 21 temozolomide-based chemotherapy, and 17 SSA + targeted therapy. PFS was significantly longer in patients with grade 1 pNETs compared to those with grade 2, in patients who received primary tumor surgery, and in patients treated with RLT compared to other treatments. At multivariate analysis, the use of upfront RLT was independently associated with improved PFS compared to SSA. Second-line therapy was performed in 94 patients with SSA + targeted therapy, 35 received chemotherapy, 45 SSA + RLT, and 27 nonconventional-dose SSA or SSA switch. PFS was significantly longer in patients treated with RLT compared to other treatments. At multivariate analysis, the type of second-line therapy was independently associated with the risk for progression. OS was significantly longer in patients who received primary tumor surgery, with Ki67 < 10%, without extrahepatic disease, and in patients who received SSA-RLT sequence compared to other sequences. Conclusions: In this large, multicenter study, RLT was associated with better PFS compared to other treatments, and the SSA-RLT sequence was associated with the best survival outcomes in patients with pNETs with Ki67 < 10%. Primary tumor surgery was also associated with improved survival.

Real-world treatment patterns and clinical outcomes in patients with stage III NSCLC in Korea: The KINDLE study.

KINDLE-Korea is part of a real-world KINDLE study that aimed to characterize the treatment patterns and clinical outcomes of patients with stage III non-small cell lung cancer (NSCLC). The KINDLE was an international real-world study that explores patient and disease characteristics, treatment patterns, and survival outcomes. The KINDLE-Korea included stage III NSCLC patients diagnosed between January 2013 and December 2017. A total of 461 patients were enrolled. The median age was 66 years (range: 24-87). Most patients were men (75.7%) with a history of smoking (74.0%), stage IIIA NSCLC (69.2%), and unresectable disease (52.9%). A total of 24.3% had activating EGFR mutation and 62.2% were positive for PDL1 expression. Broadly categorized, 44.6% of the patients received chemoradiation (CRT)-based therapy, 35.1% underwent surgery, and 20.3% received palliative therapies as initial treatment. The most commonly adopted approaches for patients with stage IIIA and IIIB disease were surgery and CRT, respectively. The median PFS was 15.2 months and OS was 66.7 months. Age >65 years, adenocarcinoma histology, and surgery as the initial treatment were significantly associated with longer OS. This study revealed the heterogeneity of treatment patterns and survival outcomes in patients with stage III NSCLC before durvalumab consolidation came into clinical practice. There is an unmet need for patients who are not eligible for surgery as an initial therapy. Novel therapeutic approaches are highly warranted to improve clinical outcomes.

Management Modalities of Pancreatic Cancer and Surgical Outcomes of Braun's Anastomosis Addition in Whipple's Procedure: A Single-center Prospective Study

  Background: Pancreatic cancer is an aggressive malignancy with high mortality rate. Many morbidities associated with Whipple's procedure that endanger patients’ life which need updated surgical techniques to lower these morbidities. The aim of this study is to determine management modalities of pancreatic cancer and surgical outcomes of adding Braun's jejunojejunostomy to Whipple's procedure for reduction of postoperative risks in Sudanese patients to reach excellent surgical practice. Subjects and Methods: This is a prospective-cohort study conducted during the period between January 2022 and July 2023 at Ibn Sina specialized hospital, Khartoum, Sudan, on sixty-three patients diagnosed with resectable pancreatic cancer. Addition of Braun’s jejunojejunostomy to elective open Whipple’s surgery was performed. Results: Seventy-three percent of patients diagnosed with pancreatic cancer were males with the ratio (3:1). Patients’ distribution according to age ranged between 46 and 60 years representing (41.3%). The significant reported comorbidities that associated with PC were diabetes mellitus (30.2%) and businessmen (39.7%). Most of patients were lived in rural areas (57.1%). Abdominopelvic CT-scan revealed stage (II) of pancreatic cancer in (68.2%) of patients. The predominant morbidity after addition of Braun's jejunojejunostomy was wound infections noticed in (17.5%) of patients. Moreover, other complications were categorized as follows: pulmonary infections in (6.35 %) of cases, postoperative diabetes mellitus in (4.76 %) of cases, entero-cutaneous fistula in (4.76 %) of cases, delayed gastric emptying in (3.17%) of cases, biliary leak in (3.17%) of cases, (3.17%) of cases, pancreatic fistula in one case (1.58%), gastric outlet obstruction in one case (1.58%) and postoperative GIT bleeding in one case (1.58%). Postoperative hospital stay of patients were ranged between 8-15 days for (66.7%) of cases. The mortality rate was zero. Conclusions: To reduce the rate of lethal surgical morbidities of Whipple's procedure, we recommend addition of Braun's jejunojejunostomy as useful technique. Moreover, it will potentially help in improving the quality of surgical practice and survival outcomes of patients who diagnosed with pancreatic cancer.

Symptomatic brain metastases in melanoma.

Although clinical outcomes in metastatic melanoma have improved in recent years, the morbidity and mortality of symptomatic brain metastases remain challenging. Response rates and survival outcomes of patients with symptomatic melanoma brain metastases (MBM) are significantly inferior to patients with asymptomatic disease. This review focusses upon the specific challenges associated with the management of symptomatic MBM, discussing current treatment paradigms, obstacles to improving clinical outcomes and directions for future research.