Limited Survival Research Articles

Targeting Fatty Acid Synthase to Halt Tumor Progression and Enhance Radiosensitivity in Breast Cancer Cells

PurposeBreast cancer, the most prevalent cancer among women, is closely linked to abnormal glucose and lipid metabolism, leading to radioresistance by upregulating survival-signaling pathways. Overexpression of fatty acid synthase (FASN), a key enzyme in lipogenesis, results in excessive lipid synthesis in breast cancer. This study evaluated whether FASN inhibition enhanced the radiosensitivity of breast cancer cells and inhibited their progression, potentially uncovering mechanisms for new therapeutic strategies.MethodsMCF-7 breast cancer cells were treated with the FASN inhibitors orlistat and TVB-3166, and cytotoxicity was assessed using the MTT assay. Protein expression changes, migratory ability, and responses to radiotherapy were analyzed by the Western blotting, Transwell, and MTT assays, respectively. To confirm FASN dependence, MCF-7 cells were infected with shFASN lentivirus to verify the specificity of the observed effects to FASN inhibition.ResultsBoth orlistat and TVB-3166 treatments induced significant cell death. Reduced FASN, HKII, pERK, and pAKT expression levels, along with an increased BAX/p-BCL2 ratio, indicate that FASN inhibition disrupted cell proliferation and promoted apoptosis by altering tumor metabolism. Furthermore, decreased MMP9 expression correlated with reduced cell migration after FASN inhibition. Importantly, FASN inhibition significantly and dose-dependently enhanced the radiosensitivity of MCF-7 cells. These findings were validated using shFASN lentivirus, confirming that the observed effects were FASN-dependent.ConclusionFASN inhibition limited survival and migration and enhanced radiosensitivity in MCF-7 cells. These findings indicate the potential efficacy of FASN inhibitors as standalone therapies or as adjuncts to radiotherapy for breast cancer.

Role of Immunotherapy in the Management of Primary Melanoma of the Vagina: A National Analysis of a Rare Aggressive Malignancy

Background and ObjectivesPrimary melanoma of the vagina (PMV) is a rare, aggressive gynecological malignancy that presents significant challenges to women’s health. Despite advancements in immunotherapy (IO), the impact of IO on PMV remains unknown. This study aims to investigate prognostic factors associated with long-term survival in patients with PMV. MethodsThe National Cancer Database was queried from 2004-2019 to identify patients with PMV. Demographics, tumor characteristics, and treatment type were evaluated. The Kaplan Meier method was used to estimate overall survival (OS). Multivariate Cox regression analysis was performed to determine predictors of survival. ResultsOur cohort included 884 women with PMV; 16.0% were treated with IO. There were no differences in 5-year overall survival based on pathological characteristics or receipt of IO. Surgical resection was associated with improved 5-year OS (24.4% vs. 8.6%, p<0.001). Five-year OS was higher in patients who underwent lymphadenectomy (31.0% vs. 19.4%, p=0.003) and who had negative surgical margins (28.0% vs. 21.0%, p=0.04). Among patients who did not undergo surgery, those who received IO had nearly 2-fold higher 5-year OS, but this did not reach significance (13.7% vs. 7.7%, p=0.066). On multivariable analysis, older age, nodal metastasis, and higher comorbidity were independent predictors of poor OS, while receipt of IO was not. Surgical resection was the strongest independent predictor of improved OS. ConclusionsSurgical intervention with lymphadenectomy and negative margins was associated with prolonged survival in patients with PMV, while IO was not. Further investigation is needed to identify optimal treatment strategies for PMV. SynopsisIn this retrospective study of patients diagnosed with primary melanoma of the vagina, immunotherapy offered limited survival benefit, regardless of curative-intent surgery. Surgical intervention with lymphadenectomy and negative margins remained the most robust predictors of improved overall survival.

Comparative Study of Two Thoracic External Beam Radiotherapy Regimen 30Gy in 10 Fractions Versus 20Gy in 5 Fractions for Palliation of Symptoms in Non-Small Cell Lung Cancer

Metastatic non-small cell lung cancer (NSCLC) frequently manifests with symptoms from the primary tumor within the chest, such as shortness of breath, chest pain, coughing, and hemoptysis. Thoracic palliative radiotherapy is a viable option for alleviating symptoms in these patients, who typically have a poor prognosis and are not candidates for curative treatment. Given their limited survival, a shorter treatment period that achieves adequate palliation is often preferred. Hypofractionated thoracic radiotherapy may meet this criterion. This quasi-experimental study, conducted at the Department of Radiotherapy, Rajshahi Medical College Hospital from January to December 2020, aimed to compare the response and acute toxicity of two thoracic external beam radiotherapy (EBRT) regimens—30 Gy in 10 fractions versus 20 Gy in 5 fractions—in the palliation of symptoms in NSCLC patients. Seventy-two diagnosed NSCLC patients with chest tumor-related symptoms (cough, dyspnea, hemoptysis, chest pain) unsuitable for radical treatment were enrolled and allocated into two groups by a non-randomized technique. Arm-A received 30 Gy in 10 fractions, while Arm-B received 20 Gy in 5 fractions. Patients were assessed before radiotherapy, at the end of treatment, and at 4 and 8 weeks post-treatment. The study found that both Arm-A and Arm-B showed highly significant improvement in all symptoms compared to pre-treatment status (p &amp;lt; 0.001), with no significant difference between the two arms (p &amp;gt; 0.05). In Arm-A, 22.22% of patients achieved complete symptomatic response and 44.44% showed improvement, while in Arm-B, 19.44% of patients achieved complete symptomatic response and 50% showed improvement. No statistically significant difference was observed between the two arms regarding clinical symptomatic response (p &amp;gt; 0.05) or treatment-related toxicities (p &amp;gt; 0.05), all of which were manageable. In conclusion, both treatment regimens were equally effective in symptom palliation and had comparable toxicity profiles, supporting the use of either regimen depending on patient needs and resource availability.

Prognostic value of the cholesterol-dependent nutritional prognostic index in patients receiving adjuvant chemotherapy after radical esophageal cancer treatment

BackgroundEsophageal cancer is the 6th most common cancer in terms of incidence and the 4th most common cause of mortality in China. Given the limited survival outcomes observed in patients with locally advanced disease managed exclusively with surgical intervention, postoperative treatment is critically important. This study sought to assess the prognostic value of total cholesterol (TC) levels and the prognostic nutritional index (PNI) in patients undergoing postoperative chemotherapy for esophageal cancer.MethodsA total of 101 patients who underwent postoesophagectomy chemotherapy were included in this retrospective analysis. PNI values for prechemotherapy were calculated for each patient [PNI = albumin + 5 × lymphocyte count] and TC. The optimal cutoff values for these indices were calculated from the receiver operating characteristic (ROC) curve. Patients were stratified into three groups on the basis of their PNI and TC levels. A novel nutritional prognostic index, termed the cholesterol-dependent nutritional prognostic index (CPNI), was developed on the basis of the PNI and TC. Univariate and multivariate Cox analyses were employed to determine the associations between each indicator and clinical outcomes.ResultsThe prechemotherapy PNI, TC level, and TNM stage became independent risk factors for OS (p < 0.05). Patients in the high PNI-high TC group had significantly improved DFS and OS compared with those in the low PNI-low TC group (p < 0.001) and had a lower early recurrence rate (P = 0.008). In contrast, patients with a high CPNI had a higher mortality rate.ConclusionThe prechemotherapy PNI combined with TC is an accurate and useful predictor of patient prognosis.

RTID-02. PERSONALIZED PEPTIDE VACCINATION AMONG 173 PATIENTS WITH GLIOBLASTOMA

Abstract Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. GBM tumors from 173 patients were analyzed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoepitopes. In agreement with their treating physician, patients added a personalized peptide vaccine to their treatment as an individual healing attempt. Patients were monitored from October 2015 until August 2023. We retrospectively evaluated their clinical courses and the results of their immune monitoring data. Among all patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis was 31.9 months (95% CI: 25.0-36.5). Adverse events were infrequent and were predominantly grade 1 or 2. An immune response to at least one of the vaccinated peptides was detected in blood samples of 87 of 97 (90%) monitored patients. T-cell responses to vaccinated neoepitope peptides were durable in most patients. Significantly prolonged survival was observed for patients with multiple vaccine-induced immune responses (53 months) compared to those with no/low induced responses (27 months; P=0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients. This is the largest real-world observation involving GBM patients safely treated with a personalized peptide vaccine to date. This real-world observation will be translated into a clinical trial to evaluate the specific contribution of the neoantigen vaccine.

Postoperative Karnofsky performance status prediction in patients with IDH wild-type glioblastoma: A multimodal approach integrating clinical and deep imaging features.

Glioblastoma is a highly aggressive brain tumor with limited survival that poses challenges in predicting patient outcomes. The Karnofsky Performance Status (KPS) score is a valuable tool for assessing patient functionality and contributes to the stratification of patients with poor prognoses. This study aimed to develop a 6-month postoperative KPS prediction model by combining clinical data with deep learning-based image features from pre- and postoperative MRI scans, offering enhanced personalized care for glioblastoma patients. Using 1,476 MRI datasets from the Brain Tumor Segmentation Challenge 2020 public database, we pretrained two variational autoencoders (VAEs). Imaging features from the latent spaces of the VAEs were used for KPS prediction. Neural network-based KPS prediction models were developed to predict scores below 70 at 6 months postoperatively. In this retrospective single-center analysis, we incorporated clinical parameters and pre- and postoperative MRI images from 150 newly diagnosed IDH wild-type glioblastoma, divided into training (100 patients) and test (50 patients) sets. In training set, the performance of these models was evaluated using the area under the curve (AUC), calculated through fivefold cross-validation repeated 10 times. The final evaluation of the developed models assessed in the test set. Among the 150 patients, 61 had 6-month postoperative KPS scores below 70 and 89 scored 70 or higher. We developed three models: a clinical-based model, an MRI-based model, and a multimodal model that incorporated both clinical parameters and MRI features. In the training set, the mean AUC was 0.785±0.051 for the multimodal model, which was significantly higher than the AUCs of the clinical-based model (0.716±0.059, P = 0.038) using only clinical parameters and the MRI-based model (0.651±0.028, P<0.001) using only MRI features. In the test set, the multimodal model achieved an AUC of 0.810, outperforming the clinical-based (0.670) and MRI-based (0.650) models. The integration of MRI features extracted from VAEs with clinical parameters in the multimodal model substantially enhanced KPS prediction performance. This approach has the potential to improve prognostic prediction, paving the way for more personalized and effective treatments for patients with glioblastoma.

NCMP-18. A CASE OF METASTATIC GLIOBLASTOMA MULTIFORME

Abstract Glioblastoma multiforme (GBM) is the most common primary brain tumor and rarely causes metastasis. We present a case of a 43-year-old female who developed tingling and heaviness in her right lower extremity in March 2023. This sensation progressed to involve her entire right hemi-body over the next two months. She presented to the emergency department where an MRI show a large left frontal parietal mass measuring 5.2x3.7x3.7cm with significant mass effect. She underwent surgical resection and surgical pathology showed IDH1-mutant R132H, retained ATRX, MGMT promoter mutation, and ki-67 of 80%. She received 6 weeks chemoradiation and then started maintenance temozolomide at 150mg/m2. Temozolomide was increased to 200mg/m2 for cycle 3 maintenance. In March 2024, she presented to the hospital with pain radiating down her legs and saddle anesthesia. MRI lumbar spine showed infiltrating osseous mass at S1 and S2 and bilateral sacral ala with anterior and posterior extraosseous invasion, invading the spinal canal resulting in moderate to severe spinal canal narrowing and compression of the sacral nerve roots. She underwent biopsy of the lesion which showed IDH wildtype metastatic GBM. She also underwent lumbar puncture and cerebrospinal fluid cytology was negative. She experienced pancytopenia limiting chemotherapy options. In April 2024, she underwent PET scan which showed hypermetabolic epidural soft tissue in spinal canal at L5-S1 level, widespread hypermetabolic skeletal lesions, tiny left cervical level 4 lymph node, small hypermetabolic right hilar, aortocaval, left retroperitoneal nodes and a tiny left common iliac node. The incidence of extracranial metastasis is 0.4-2.0% with less than 25 reported cases of bone marrow spread. This is thought to be rare due to the absence of lymphatics within the brain and the limited survival associated with GBM. This metastasis may occur through vascular invasion, perineural spread, lymphatics, direct invasion, or iatrogenic spread into soft tissues.

DDDR-18. TARGETTING GLIOBLASTOMA MULTIFORME USING A MULTIACTION ANTICANCER ANTI-INFLAMMATORY THERAPEUTIC STRATEGY

Abstract Glioblastoma multiforme (GBM) represents a significant challenge in adult brain tumor management, characterized by its aggressive nature and poor prognosis despite multimodal therapies. Current standard chemotherapy, Temozolomide (TMZ), offers limited survival benefits. In a recent breakthrough, the cyclic peptide cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) acetate (c2), initially developed for prostate cancer, demonstrates remarkable promise against GBM. By selectively inhibiting the inflammatory phospholipase enzyme sPLA2IIA, c2 significantly impedes GBM cell proliferation, surpassing TMZ efficacy in multiple resistant cell lines. Moreover, c2 exhibits potential to inhibit tumor growth and metastasis, confirmed in 3D tumoroid and wound healing assays. Mechanistic insights reveal modulation of crucial cellular pathways, including viral entry, cytoskeletal structure, and signaling cascades. Preclinical investigations demonstrate c2’s ability to penetrate the blood-brain barrier and attenuate tumor progression markers. At multiple levels, c2 is shown to target inhibition of ERBB2 and EGFR signalling and also have impacts on HIF1-NF-kB axis. This study proposes c2 as a potent anti-GBM candidate, warranting evaluations for its pharmacological profile, safety, and efficacy. With its potential to address the urgent need for effective GBM therapies, c2 holds promise as a significant advancement in GBM treatment, offering hope for improved patient outcomes.

TMIC-81. AN IMMUNOSUPPRESSIVE MACROPHAGE NICHE MAY DRIVE T CELL DYSFUNCTION AND IMMUNOTHERAPY RESISTANCE IN MELANOMA BRAIN METASTASES

Abstract Nearly half of metastatic melanoma patients develop brain metastases (MBM). Local therapies like surgery and radiotherapy provide limited survival benefit. While targeted therapies and immune checkpoint inhibitors (ICI) improved outcomes in patients with asymptomatic MBM, the prognosis is still grim for the majority of patients. To decipher resistance mechanism to immunotherapy in MBM, we integrated datasets from both single-cell RNAseq (scRNAseq) and spatial transcriptomics (Visium). Our scRNAseq analysis of 25 MBM patients (7 treated pre-surgery with ICI) showed that lymphoid cells increased by 8.1-fold post-ICI (p=0.006). Notably, 34% of these were CXCL13+CXCR6+ putative tumor-reactive T cells (TR-T), known for their critical role as tumor-killing effectors. This led us to investigate why, despite their prevalence, TR-T don’t translate to effective immunotherapy in MBM. Our scRNAseq interactome analysis revealed that ICI intensified IFN-II interactions between TR-T and interferon-stimulated macrophage/microglia (Mφ.ISG). However, it also boosted immunosuppressive interactions, like the TIGIT-NECTIN2 interaction, which increased 20 fold, potentially diminishing TR-T’s effectiveness. To overcome the lack of spatial context in scRNAseq, we applied spatial transcriptomics on 27 MBM sections, including 12 post-ICI treatments. Remarkably, TR-T were primarily found (63%) in proximity with Mφ.ISG cells—not with tumor cells. These TR-T-Mφ.ISG niches were 1.7 times more prevalent in ICI-treated samples; these niches are rich in chemokine receptors like CCR1 and immunosuppressive molecules like NECTIN2. This suggests that Mφ.ISG cells are chemotactically attracted to TR-T, forming a barrier that impedes TR-T’s tumor interaction and impairs their functionality. Our current efforts focus on pinpointing key pathways enriched within TR-T-Mφ.ISG niches, particularly in ICI-treated MBM. We are also assessing the clinical impact of these niches in relation to patient survival. Our goal is to elucidate how specific immunosuppressive subsets and molecules within the MBM microenvironment restrict TR-T effectiveness, with the ultimate objective of enhancing ICI efficacy for these patients.

BIOM-74. IDENTIFICATION OF EMP2 AS A TARGETABLE BIOMARKER IN GLIOBLASTOMA TUMORS RESISTANT TO ANTI-ANGIOGENIC THERAPIES

Abstract BACKGROUND The role of Epithelial Membrane Protein-2 (EMP2) in mediating resistance to current anti-angiogenic drugs in the treatment of glioblastoma (GBM) is an intriguing hypothesis that may provide insights into improving the limited survival benefits observed in current therapies. Investigating the interaction between EMP2 and anti-angiogenic drugs such as bevacizumab or Aflibercept could lead to a better understanding of the mechanisms underlying resistance, potentially opening up new avenues for more effective treatment strategies. OBJECTIVE To use EMP2 as a targetable biomarker for anti-VEGF resistance and test combination therapy with anti-VEGF (Aflibercept or bevacizumab), and a novel anti-EMP2 mAb in SB28 and GL261 GBM mouse models. METHODS Tumor tissue was collected prospectively from patients undergoing surgery for suspected glioblastoma and stained for EMP2 and HIF-2a using standard immunohistochemistry. Patients had banked tumor tissue both before and after bevacizumab treatment with 3 months of clinical and radiologic follow-up available. To establish syngeneic models, 10-week-old mice were subcutaneously implanted with murine SB28 or GL261 GBM cells. RESULTS Immunohistochemistry conducted on pre- and post-bevacizumab-treated patient samples revealed an increase in EMP2 and HIF-2a protein expression post-treatment. This increase in EMP2 expression correlated with reduced survival time. Similarly, the in vivo models showed a significant upregulation in both markers in the Aflibercept-treated cohort compared to the control. Treatment with either polyclonal sera to VEGF or Aflibercept failed to reduce tumor load or provide a therapeutic benefit. However, combination therapy with Aflibercept and anti-EMP2 mAb was found to significantly reduce tumor volume and weight in both SB28 and GL261 tumors. These findings highlight the potential effectiveness of combination therapies targeting EMP2 and VEGF in reducing tumor load in GBM. CONCLUSION Our results suggest that EMP2 can be a promising new therapeutic target that can be combined with anti-VEGF treatment to potentially increase overall survival in GBM patients.

Amputation-Free Survival, WIfI Stage, and GLASS Classifications in Distal Crural or Pedal Bypass for Chronic Limb-Threatening Ischemia.

Background: Chronic limb-threatening ischemia (CLTI) is a severe condition with high risks of amputation and mortality, especially in patients with distal crural or pedal artery disease. Despite advances in endovascular techniques, bypass surgery remains crucial for patients with CLTI. This study aimed to investigate amputation-free survival, Wound, Ischemia, and foot Infection (WIfI) staging, and Global Limb Anatomic Staging System (GLASS) classifications in patients undergoing distal crural or pedal bypass for CLTI. Methods: This retrospective study analyzed all patients who underwent distal crural or pedal bypass for CLTI in a tertiary vascular centre from January 2010 to December 2019. The data were collected from hospital records and preoperative imaging. WIfI stages and GLASS classifications were determined for each patient, and the primary endpoint was amputation-free survival. Secondary outcomes included bypass patency, 30-day morbidity, and mortality. Results: We identified 31 bypasses performed on 29 patients with a median age of 67 years (79% male). Preoperatively, 94% of limbs were staged GLASS III and 55% were classified WIfI stage 4. Failed endovascular revascularization preceded bypass surgery in 65% of the cases. Thirty-day mortality was 3% (n = 1) and 30-day major amputation rate was 10%. Primary patency was 87%, and secondary patency was 94% at 30 days. Median duration of follow-up for survival was 59 months with a mean follow-up index (FUI) of 0.99 ± 0.05, and for major amputation and bypass patency 54 months (mean FUI 0.9 ± 0.19 and 0.85 ± 0.28, respectively). At one year, amputation-free survival was 58%, decreasing to 45% at two years, 39% at three years, and 32% at five years. Most major amputations occurred in WIfI stage 4 patients, but 53% of WIfI stage 4 and 80% of WIfI stage 3 patients were alive without major amputation after one year. Conclusions: Distal crural and pedal bypasses are essential for limb salvage in high-risk CLTI patients, particularly those with failed prior revascularization. However, the procedure is associated with limited long-term amputation-free survival. WIfI and GLASS classifications are useful for stratifying risk and guiding treatment, but outcomes suggest the need for individualized care strategies. Further research into perioperative management and alternative interventions is warranted to improve long-term outcomes in this population.

The impact of progression-directed therapy on survival in metastatic castration-refractory prostate cancer: MEDCARE phase 3 trial.

Metastatic castration-refractory prostate cancer (mCRPC) presents a therapeutic challenge despite advancements in treatment. Once mCRPC is attained, patients face limited survival prospects. Next-line systemic treatment (NEST) is the standard of care for progressive mCRPC, encompassing various therapeutic options with associated toxicity and costs. In patients with oligoprogressive mCRPC, data suggest that progression-directed therapy (PDT), such as metastasectomy or stereotactic body radiotherapy, delays the initiation of NEST. The MEDCARE phase III trial aims to assess the impact of PDT on overall survival (OS) in oligoprogressive mCRPC. In this multicentric, randomised, prospective trial, we aim to randomise 246 patients in 1:1 allocation ratio between the standard-of-care therapy (surveillance or NEST) or PDT while continuing the current systemic treatment. Patients will be stratified based on number of progressive lesions (one vs ≥one), location of progressive lesions (local recurrence, N or M1a vs M1b or M1c) and previous systemic therapy (palliative androgen-deprivation therapy [pADT] vs pADT + androgen receptor-targeted agent or patients who received docetaxel in the past). The primary endpoint is OS, and the secondary endpoints include quality of life, radiographic progression-free survival (PFS), modified PFS, prostate cancer-specific survival and PDT-induced toxicity. This is the first randomised phase 3 trial in the setting of PDT in patients with oligoprogressive mCRPC with OS as the primary endpoint.

Highly protective and functional strengthening strategies for 3D printed continuous carbon fiber reinforced polymer composites: Manufacturing and properties

Carbon fiber-reinforced polymer (CFRP) composites have gradually emerged as a crucial material in the aerospace industry. However, inadequate impact resistance and thermal stability limit survival in extreme environments. Inspired by the specific functions of multiple layers of tissue, from bird feathers to the musculoskeletal system. We propose low-cost composite strengthening strategies and efficient novel three-dimensional graphene aerogel manufacturing methods. A novel graphene aerogel/carbon fiber reinforced polymer (GAC) composite prepared by in-situ laser-induced graphene (LIG) layers on the surface of 3D-printed CFRP. GAC composites enhance CFRP's impact protection, thermal insulation, and electromagnetic shielding capabilities. For protection, GAC composites reduce low-velocity impact damage by 26.2 %. The graphene layer can increase the thermal buffering capacity of the material four times, and the long-term service temperature can be increased by 40 % compared to traditional CFRP. For functionality, the composites enable electromagnetic interference (EMI) shielding effectiveness of up to 50.2 dB. Furthermore, it can achieve surface heating above 400 °C and rapid de-icing through electrothermal effects. The simple and efficient processing method of GAC composites and tunable functionalities holds promise for the development of highly protective and intelligent aircraft skins.

Surprisingly wide climatic niche breadth of a relict mountain species raises hope for survival under climate change

AbstractAimsWe assessed the juvenile climatic niche breadth of a relict mountain species by comparing field observations and transplant experiments within and beyond the elevational limits of its distribution range.LocationLebanon – Near East – Mediterranean region.MethodsWe studied the survival and growth of the Cedar of Lebanon (Cedrus libani) to determine the lower and upper elevational range limits of its juvenile stage through an experimental setup with and without water supplementation and with potentially competing species as a control. The experiment included eight common gardens at elevations ranging from 110 to 2330 m, within and far beyond the warm and cold limits of Cedar distribution observed under natural conditions.ResultsWe observed unexpectedly high survival and growth rates of Cedar at elevations well below the range of its natural distribution in Lebanon. Below the observed warm limit, water stress at very low elevations and competition at low and medium elevations limited juvenile survival. In contrast, cold temperature and water stress limited survival at elevations slightly above the observed upper natural limit. The experimental setup demonstrated that the elevation range suitable for Cedar growth and survival was twice as wide as the range within which Cedar is observed under natural conditions.Main ConclusionsHigh survival rates experimentally observed beyond the warm limit of the natural distribution range of the Cedar of Lebanon raise hope for its resilience to ongoing climate warming. If this pattern were frequent among montane species, it would challenge predictions of massive extinction with climate change and pave the way for promoting adaptive actions such as competition management to improve their survival.

MSI-H Detection by ddPCR in Endoscopic Ultrasound Fine Needle Biopsy (EUS-FNB) from Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited survival. Curative opportunities are only available for patients with resectable cancer. Palliative chemotherapy is the current standard of care for unresectable tumors. Numerous efforts have been made to investigate new therapeutic strategies for PDAC. Immunotherapy has been found to be effective in treating tumors with high microsatellite instability (MSI-H), including PDAC. The ability of the Endoscopic Ultrasound Fine Needle Biopsy (EUS-FNB) to reliably collect tissue could enhance new personalized treatment by permitting genomic alterations analysis. The aim of this study was to investigate the feasibility of obtaining adequate DNA for molecular analysis from EUS-FNB formalin-fixed-paraffin-embedded (FFPE) specimens. For this purpose, FFPE-DNA obtained from 43 PDAC archival samples was evaluated to verify adequacy in terms of quantity and quality and was tested to evaluate MSI-H status by droplet digital PCR (ddPCR). All samples were suitable for ddPCR analysis. Unlike the 1–2% MSI-H frequency found with traditional techniques, ddPCR detected this phenotype in 16.28% of cases. This study suggests the ddPCR ability to identify MSI-H phenotype, with the possibility of improving the selection of patients who may benefit from immunotherapy and who would be excluded by performing traditional diagnostic methods.

Advance Care Planning: A Retrospective Audit in a National Referral Center for Interstitial Lung Diseases.

Idiopathic and progressive pulmonary fibrosis (IPF/PPF) of known cause are relatively rare lung diseases with a limited survival time after diagnosis. Conscious attention for palliative care is recommended. Optimal care requires collaboration to define goals and preferences for future medical treatment and care with the patient and their families, to inform (or enable) Advance Care Planning (ACP). To get insight into the frequency of key elements of ACP described after dialogues with patients with IPF/PPF. A retrospective audit included charts of patients with IPF/PPF who died between December 2017 and December 2020. A data extraction model was developed based on a guideline for patient federation and wider literature and finally consisted of fourteen key elements. Subsequently content analysis was performed. The medical charts of 60 patients showed that an element of ACP was recorded in 57(95%) of cases. No medical chart contained all fourteen key elements of ACP. Most frequently recorded ACP elements were: knowledge of illness, goals of treatment and care and fears and concerns. The lack of structural implementation of ACP in the care for patients with interstitial lung disease, results in only some elements of ACP being dialogued by health care professionals (HCP). These notes recorded are often superficial and reflect the view of the HCP. Implementation of ACP conversations and structured documentation is needed to gain better insight into the wishes and preferences of the patient.

Clinical Significance of a Prospective Large Genomic Screening for SCLC: The Genetic Classification and a Biomarker-Driven Phase 2 Trial of Gedatolisib

IntroductionSCLC has been treated as a single entity resulting in limited survival improvement. Developing effective tools for guiding appropriate therapeutic strategies is crucial. MethodsA total of 1035 SCLCs were prospectively analyzed by a genomic screening platform: LC-SCRUM-Asia. Fresh frozen tumor samples were subjected to a next-generation sequencing system enabling the integrative analysis of cancer-related genes. A phase 2 trial of gedatolisib for SCLC with PI3K/AKT/mTOR pathway mutations was conducted based on this screening. ResultsOn the basis of the treatment outcomes and therapeutic targets, the following five distinct genetic subgroups were identified in SCLC: NSCLC-subgroup (genetic alterations associated with NSCLC, 8.5%); Hotspot-subgroup (targetable hotspot mutations common in tumors, 3.0%); PI3K-subgroup (PI3K/AKT/mTOR pathway mutations, 7.4%); MYC-subgroup (MYC family amplifications, 13.0%); and HME-subgroup (mutations in the histone-modifying enzymes, 17.6%). The NSCLC-subgroup (hazard ratio = 1.57; 95% confidence interval: 1.22–2.03) and MYC-subgroup (hazard ratio = 1.56; 95% confidence interval: 1.26–1.93) had significantly shorter progression-free survivals after first-line platinum-based treatment. The Hotspot-subgroup and MYC-subgroup were candidates for novel targeted therapies. The HME-subgroup had a favorable survival in patients who received programmed cell death (ligand) 1 inhibitor-based therapies (p = 0.005, log-rank test) regardless of some overlap with other subgroups. There were 15 patients enrolled into the phase 2 trial of gedatolisib in the PI3K-subgroup, and the overall response rate and the disease control rate were 6.7% and 20%, respectively. The MYC-subgroup or NSCLC-subgroup was associated with unfavorable clinical outcomes in this trial. ConclusionsMolecular classification of SCLC by genetic approach is beneficial for predicting the treatment outcomes and effectively guiding the clinical choices.

Novel multifactor predictive model for postoperative survival in gallbladder cancer: a multi-center study

BackgroundGallbladder cancer (GBC) is a highly aggressive malignancy, with limited survival profiles after curative surgeries. This study aimed to develop a practical model for predicting the postoperative overall survival (OS) in GBC patients.MethodsPatients from three hospitals were included. Two centers (N = 102 and 100) were adopted for model development and internal validation, and the third center (N = 85) was used for external testing. Univariate and stepwise multivariate Cox regression were used for feature selection. A nomogram for 1-, 3-, and 5-year postoperative survival rates was constructed accordingly. Performance assessment included Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves. Kaplan-Meier curves were utilized to evaluate the risk stratification results of the nomogram. Decision curves were used to reflect the net benefit.ResultsEight factors, TNM stage, age-adjusted Charlson Comorbidity Index (aCCI), body mass index (BMI), R0 resection, blood platelet count, and serum levels of albumin, CA125, CA199 were incorporated in the nomogram. The time-dependent C-index consistently exceeded 0.70 from 6 months to 5 years, and time-dependent ROC revealed an area under the curve (AUC) of over 75% for 1-, 3-, and 5-year survival. The calibration curves, Kaplan-Meier curves and decision curves also indicated good prognostic performance and clinical benefit, surpassing traditional indicators TNM staging and CA199 levels. The reliability of results was further proved in the independent external testing set.ConclusionsThe novel nomogram exhibited good prognostic efficacy and robust generalizability in GBC patients, which might be a promising tool for aiding clinical decision-making.

Health care contact days in older adults enrolled in SWOG cancer clinical trials.

64 Background: Health care contact days—days with health care contact outside the home—are a measure of how much of a patient’s life is consumed by health care. This number of contact days are especially relevant for older adults with advanced cancer facing limited survival. One concern is that patients with different sociodemographic and clinical backgrounds may be at particular risk of increased contact days. Thus, there is a critical need to understand factors associated with contact days. Methods: We linked data from 6 SWOG trials in advanced cancer to Medicare claims data. These trials encompassed a variety of primary cancer types [prostate (S9916, S0421), lung (S0003, S0124, S0819), and pancreas (S0205)]. Health care contact days (days with ambulatory, emergency department, inpatient, or facility-based care) in the first 12 months were calculated using Medicare database files. A day with &gt;1 source of contact counted as 1. We examined sociodemographic (age, race, ethnicity, sex, insurance status, rurality, area deprivation index) and clinical (prognostic risk, cancer type, performance status) predictors of contact days, using negative binomial regression, with a log link and clustering by study ID, including an offset variable for duration of observation. We examined predictors in univariate and multivariable analysis. We report relative risk (RRs) estimates and 95% CI. Results: We included 1,429 patients (median age, 71 years, 7.6% Black, 2.7% Hispanic, 21.4% female, and 23.5% rural residence). Of these, 741 (51.9%) patients died in the first year. The median number of contact days was 48, out of a median of 350 days of observation. At a trial level, median percentage of contact days ranged from 14% (prostate) to 27% (lung). The most common sources of contact days were ambulatory clinician visits (median=17), tests (median=12), and treatments (median=11). In multivariable regression, factors associated with increased contact days included increasing age (per year, RR=1.02 [1.01-1.02], p&lt;.001), insurance status (Medicare alone or with Private or Medicaid insurance, vs Military/VA, none, or other insurance, RR=2.47 [2.16-2.83], p&lt;.001), higher prognostic risk score (RR=1.14 [1.04-1.25], p=.004), and type of cancer (pancreas, RR=1.69 [1.51-1.89] and lung, RR=1.69 [1.54-1.85] vs prostate, p&lt;.001 for both). Conclusions: This novel linkage of trial and claims data to evaluate contact days and associated factors found that older trial participants spent up to one in four days with health care contact. Ambulatory appointments were the most common source of contact days. Encouragingly, rural residence and neighborhood deprivation were not associated with contact days, increasing confidence that participants from diverse geographic areas may receive equitable care in trials. These data highlight the frequency of contact days for trial participants, while identifying factors to consider when benchmarking contact days.

A Preliminary Phenomenological Exploration of Experiences of the Empty Pelvis Syndrome Derived From a Modified-Delphi: The Price of Survival Following Pelvic Exenteration for Advanced Pelvic Cancer.

The empty pelvis syndrome (EPS) is common after pelvic exenteration (PE), causing fluid collections, bowel obstruction, perineal sinuses, and fistulas. The best approach to fill the pelvis to mitigate this remains controversial, and the impact of EPS on health-related quality of life (HrQoL) is unknown. This study is the first to begin to explore lived-experiences of EPS complications. Unstructured EPS virtual focus group meetings were conducted with a convenience sample of patients who underwent PE, as an extension of a modified-Delphi study. Interpretative phenomenological analysis was conducted on verbatim transcripts to generate group experiential themes. Twelve patients (eight UK, one Dutch, and three Belgian) participated in four focus groups. Eight EPS complications were reported, (two pelvic collections, five chronic perineal sinuses, and one bowel obstruction). Group experiential themes were 'Out of Options', depicting patients forced to accept complications or limited survival; 'The New Normal', with EPS potentially delaying adaptation to post-PE HrQoL; 'Information Influencing Adaptation,' emphasising the significance of patients understanding EPS to cope with its effects; and 'Symptoms,' reporting manifestations of EPS, the resultant physical limitations, and an intangible feeling that patients lost part of themselves. EPS may influence patient decision-making, regret, adaptation, and information-seeking. It can cause a variety of unpleasant symptoms and physical limitations, which may include phantom phenomenon. This work supports ongoing purposeful HrQoL research to better define these themes.