Anaplastic Large Cell Lymphoma of the Spine: Report of a Rare Case.

This abstract discusses a rare case of anaplastic large cell lymphoma (ALCL) involving the cervical and dorsal spine in a 17-year-old female. ALCL is a distinct subtype of lymphoma characterized by abnormal proliferation of lymphocytes and is divided into ALK-positive and ALK-negative subtypes. Spinal involvement in ALCL is uncommon, particularly in the cervical and dorsal regions. The patient presented with persistent fever, weakness, and delayed onset of severe neck pain. Diagnosis involved imaging, bone marrow biopsy, and lymph node biopsy. Treatment strategies for ALCL typically involve a multimodal approach, including chemotherapy, radiotherapy, and targeted therapy. However, due to the rarity of spinal involvement, treatment decisions are based on extrapolation from other ALCL cases. Prognosis is influenced by disease stage and ALK status, but specific outcomes for spinal involvement remain poorly established. This case emphasizes the need for considering lymphoma in patients with unexplained symptoms and abnormal imaging findings. It highlights the importance of further research to improve the understanding and management of ALCL with spinal involvement.

SASAN: ground truth for the effective segmentation and classification of skin cancer using biopsy images.

OBJECTIVES: Early skin cancer diagnosis can save lives; however, traditional methods rely on expert knowledge and can be time-consuming. This calls for automated systems using machine learning and deep learning. However, existing datasets often focus on flat skin surfaces, neglecting more complex cases on organs or with nearby lesions. METHODS: This work addresses this gap by proposing a skin cancer diagnosis methodology using a dataset named ASAN that covers diverse skin cancer cases but suffers from noisy features. To overcome the noisy feature problem, a segmentation dataset named SASAN is introduced, focusing on Region of Interest (ROI) extraction-based classification. This allows models to concentrate on critical areas within the images while ignoring learning the noisy features. RESULTS: Various deep learning segmentation models such as UNet, LinkNet, PSPNet, and FPN were trained on the SASAN dataset to perform segmentation-based ROI extraction. Classification was then performed using the dataset with and without ROI extraction. The results demonstrate that ROI extraction significantly improves the performance of these models in classification. This implies that SASAN is effective in evaluating performance metrics for complex skin cancer cases. CONCLUSIONS: This study highlights the importance of expanding datasets to include challenging scenarios and developing better segmentation methods to enhance automated skin cancer diagnosis. The SASAN dataset serves as a valuable tool for researchers aiming to improve such systems and ultimately contribute to better diagnostic outcomes.

Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

PROTAC-Mediated Dual Degradation of BCL-xL and BCL-2 Is a Highly Effective Therapeutic Strategy in Small-Cell Lung Cancer.

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future.

PROTAC-mediated dual degradation of BCL-xL and BCL-2 is a highly effective therapeutic strategy in small-cell lung cancer.

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216+venetoclax to reduce the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b leads to significant tumor growth delay similar to the DT2216+venetoclax combination in H146 xenografts by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. 753b at this dosage was well tolerated in mice without induction of severe thrombocytopenia as seen with navitoclax nor induced significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients warranting clinical trials in future.

Precision Oncology in Gastrointestinal and Colorectal Cancer Surgery.

Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.

Immunotherapy utilization in stage IIIA melanoma: less may be more.

Background: Immunotherapy agents are approved for adjuvant treatment of stage III melanoma; however, evidence for survival benefit in early stage III disease is lacking. Current guidelines for adjuvant immunotherapy utilization in stage IIIA rely on clinician judgment, creating an opportunity for significant variation in prescribing patterns. This study aimed to characterize current immunotherapy practice variations and to compare patient outcomes for different prescribing practices in stage IIIA melanoma. Study design: Patients with melanoma diagnosed from 2015-2019 that met American Joint Committee on Cancer 8th edition criteria for stage IIIA and underwent resection were identified in the National Cancer Database. Multiple imputation by chained equations replaced missing values. Factors associated with receipt of adjuvant immunotherapy were identified. Multivariable Cox proportional hazards regression compared overall survival across groups. Results: Of 4,432 patients included in the study, 34% received adjuvant immunotherapy. Patients had lower risk-adjusted odds of receiving immunotherapy if they were treated at an academic center (OR=0.48, 95%CI=0.33-0.72, p<0.001 vs. community facility) or at a high-volume center (OR=0.69, 0.56-0.84, p<0.001 vs. low-volume). Immunotherapy receipt was not associated with risk-adjusted survival (p=0.095). Moreover, patients treated at high-volume centers experienced longer overall risk-adjusted survival than those treated at low-volume centers (HR=0.52, 0.29-0.93, p=0.030). Risk-adjusted survival trended toward being longer at academic centers than at community centers, but the difference was not statistically significant. Conclusion: Academic and high-volume centers utilize significantly less adjuvant immunotherapy in stage IIIA melanoma than community and low-volume centers without compromise in overall survival. These findings suggest that this population may benefit from more judicious immunotherapy utilization.

Immunotherapy Initiation at the End of Life in Patients With Metastatic Cancer in the US.

Importance: While immunotherapy is being used in an expanding range of clinical scenarios, the incidence of immunotherapy initiation at the end of life (EOL) is unknown. Objective: To describe patient characteristics, practice patterns, and risk factors concerning EOL-initiated (EOL-I) immunotherapy over time. Design, Setting, and Participants: Retrospective cohort study using a US national clinical database of patients with metastatic melanoma, non-small cell lung cancer (NSCLC), or kidney cell carcinoma (KCC) diagnosed after US Food and Drug Administration approval of immune checkpoint inhibitors for the treatment of each disease through December 2019. Mean follow-up was 13.7 months. Data analysis was performed from December 2022 to May 2023. Exposures: Age, sex, race and ethnicity, insurance, location, facility type, hospital volume, Charlson-Deyo Comorbidity Index, and location of metastases. Main Outcomes and Measures: Main outcomes were EOL-I immunotherapy, defined as immunotherapy initiated within 1 month of death, and characteristics of the cohort receiving EOL-I immunotherapy and factors associated with its use. Results: Overall, data for 242 371 patients were analyzed. The study included 20 415 patients with stage IV melanoma, 197 331 patients with stage IV NSCLC, and 24 625 patients with stage IV KCC. Mean (SD) age was 67.9 (11.4) years, 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. The percentage of patients who received EOL-I immunotherapy increased over time for all cancers. More than 1 in 14 immunotherapy treatments in 2019 were initiated within 1 month of death. Risk-adjusted patients with 3 or more organs involved in metastatic disease were 3.8-fold more likely (95% CI, 3.1-4.7; P < .001) to die within 1 month of immunotherapy initiation than those with lymph node involvement only. Treatment at an academic or high-volume center rather than a nonacademic or very low-volume center was associated with a 31% (odds ratio, 0.69; 95% CI, 0.65-0.74; P < .001) and 30% (odds ratio, 0.70; 95% CI, 0.65-0.76; P < .001) decrease in odds of death within a month of initiating immunotherapy, respectively. Conclusions and Relevance: Findings of this cohort study show that the initiation of immunotherapy at the EOL is increasing over time. Patients with higher metastatic burden and who were treated at nonacademic or low-volume facilities had higher odds of receiving EOL-I immunotherapy. Tracking EOL-I immunotherapy can offer insights into national prescribing patterns and serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.

Cell surface RNAs control neutrophil recruitment.

RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions.

Identifying novel inhibitors targeting Exportin-1 for the potential treatment of COVID-19.

The nuclear export protein 1 (XPO1) mediates the nucleocytoplasmic transport of proteins and ribonucleic acids (RNAs) and plays a prominent role in maintaining cellular homeostasis. XPO1 has emerged as a promising therapeutic approach to interfere with the lifecycle of many viruses. In our earlier study, we proved the inhibition of XPO1 as a therapeutic strategy for managing SARS-COV-2 and its variants. In this study, we have utilized pharmacophore-assisted computational methods to identify prominent XPO1 inhibitors. After several layers of screening, a few molecules were shortlisted for further experimental validation on the in vitro SARS-CoV-2 cell infection model. It was observed that these compounds reduced spike positivity, suggesting inhibition of SARS-COV-2 infection. The outcome of this study could be considered further for developing novel antiviral therapeutic strategies against SARS-CoV-2.

Perfluorooctanesulfonic Acid and Perfluorooctanoic Acid Promote Migration of Three-Dimensional Colorectal Cancer Spheroids.

Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are persistent environmental contaminants that are of increasing public concern worldwide. However, their relationship with colorectal cancer (CRC) is poorly understood. This study aims to comprehensively investigate the effect of PFOS and PFOA on the development and progression of CRC in vitro using a series of biological techniques and metabolic profiling. Herein, the migration of three-dimensional (3D) spheroids of two CRC cell lines, SW48 KRAS wide-type (WT) and SW48 KRAS G12A, were observed after exposure to PFOS and PFOA at 2 µM and 10 µM for 7 days. The time and dose-dependent migration phenotype induced by 10 µM PFOS and PFOA was further confirmed by wound healing and trans-well migration assays. To investigate the mechanism of action, derivatization-mass spectrometry-based metabolic profiles were examined from 3D spheroids of SW48 cell lines exposed to PFOS and PFOA (2 µM and 10 µM). Our findings revealed this exposure altered epithelial-mesenchymal transition related metabolic pathways, including fatty acid ß-oxidation and synthesis of proteins, nucleotides, and lipids. Furthermore, this phenotype was confirmed by the downregulation of E-cadherin and upregulation of N-cadherin and vimentin. These findings show novel insight into the relationship between PFOS, PFOA, and CRC.

Role of colectomy in the management of appendiceal tumors: a retrospective cohort study.

BACKGROUND: Appendiceal tumors represent a range of histologies that vary in behavior. Recommendations for treatment with appendectomy versus right hemicolectomy (RHC) for different tumor types are evolving and sometimes conflicting. This study sought to characterize variation in the United States around surgical treatment of major appendiceal tumor types over time and describe differences in outcomes based on procedure. METHODS: Patients diagnosed with appendiceal goblet cell adenocarcinoma (GCA), mucinous adenocarcinoma, neuroendocrine neoplasm (NEN), or non-mucinous adenocarcinoma from 2004-2017 were identified in the National Cancer Database. Trends in RHC over time and predictors of RHC were identified. Surgical outcomes for each histologic type and stage were compared. RESULTS: Of 18,216 patients, 11% had GCAs, 34% mucinous adenocarcinoma, 31% NENs, and 24% non-mucinous adenocarcinoma. Rate of RHC for NEN decreased from 68% in 2004 to 40% in 2017 (p = 0.008) but remained constant around 60-75% for other tumor types. Higher stage was associated with increased odds of RHC for all tumor types. RHC was associated with higher rate of unplanned readmission (5% vs. 3%, p < 0.001) and longer postoperative hospital stay (median 5 days vs. 3 days, p < 0.001). On risk-adjusted analysis, RHC was significantly associated with increased survival versus appendectomy for stage 2 disease of all tumor types (HRs 0.43 to 0.63) and for stage 1 non-mucinous adenocarcinoma (HR = 0.56). CONCLUSIONS: Most patients with appendiceal tumors undergo RHC, which is associated with increased readmission, longer length of stay, and improved survival for stage 2 disease of all types. RHC should be offered selectively for appendiceal tumors.

Tobramycin-loaded nanoparticles of thiolated chitosan for ocular drug delivery: Preparation, mucoadhesion and pharmacokinetic evaluation.

The present work aimed to develop nanoparticles of tobramycin (TRM) using thiolated chitosan (TCS) in order to improve the mucoadhesion, antibacterial effect and pharmacokinetics. The nanoparticles were evaluated for their compatibility, thermal stability, particle size, zeta potential, mucoadhesion, drug release, kinetics of TRM release, corneal permeation, toxicity and ocular irritation. The thiolation of chitosan was confirmed by 1H NMR and FTIR, which showed peaks at 6.6 ppm and 1230 cm-1, respectively. The nanoparticles had a diameter of 73 nm, a negative zeta potential (-21 mV) and a polydispersity index of 0.15. The optimized formulation, NT8, exhibited the highest values of mucoadhesion (7.8 ± 0.541h), drug loading (87.45 ± 1.309%), entrapment efficiency (92.34 ± 2.671%), TRM release (>90%) and corneal permeation (85.56%). The release pattern of TRM from the developed formulations was fickian diffusion. TRM-loaded nanoparticles showed good antibacterial activity against Pseudomonas aeruginosa. The optimized formulation NT8 (0.1% TRM) greatly increased the AUC(0-∞) (1.5-fold) while significantly reducing the clearance (5-fold) compared to 0.3% TRM. Pharmacokinetic parameters indicated improved ocular retention and bioavailability of TRM loaded nanoparticles. Our study demonstrated that the TRM-loaded nanoparticles had improved mucoadhesion and pharmacokinetics and a suitable candidate for effective treatment of ocular bacterial infections.

Multi-omic analysis reveals metabolic pathways that characterize right-sided colon cancer liver metastasis.

There are well demonstrated differences in tumor cell metabolism between right sided (RCC) and left sided (LCC) colon cancer, which could underlie the robust differences observed in their clinical behavior, particularly in metastatic disease. As such, we utilized liquid chromatography-mass spectrometry to perform an untargeted metabolomics analysis comparing frozen liver metastasis (LM) biobank samples derived from patients with RCC (N = 32) and LCC (N = 58) to further elucidate the unique biology of each. We also performed an untargeted RNA-seq and subsequent network analysis on samples derived from an overlapping subset of patients (RCC: N = 10; LCC: N = 18). Our biobank redemonstrates the inferior survival of patients with RCC-derived LM (P = 0.04), a well-established finding. Our metabolomic results demonstrate increased reactive oxygen species associated metabolites and bile acids in RCC. Conversely, carnitines, indicators of fatty acid oxidation, are relatively increased in LCC. The transcriptomic analysis implicates increased MEK-ERK, PI3K-AKT and Transcription Growth Factor Beta signaling in RCC LM. Our multi-omic analysis reveals several key differences in cellular physiology which taken together may be relevant to clinical differences in tumor behavior between RCC and LCC liver metastasis.

The Representation of Surgery in Oncology Clinical Trials: 2001 to 2022.

BACKGROUND: Surgery is a mainstay of cancer care. Since the advancement of cancer treatment occurs through clinical trials, it is critical to investigate the degree and nature of representation of surgery in oncological clinical trials. METHODS: This observational analysis used publicly available data from clinicaltrials.gov to investigate non-industry-funded oncological clinical trials in the United States between 2012 and 2022. RESULTS: From 2012 to 2022, 1,861 (15.7%) of the 11,843 registered oncologic clinical trials were surgical. There was a 43.2% increase in proportional surgical trials and an 18.9% increase in oncology trials over the last two decades. Surgery+diagnostic-technique trials increased from 5.14 to 12.6% (P < 0.001, 95%CI [- 0.097, - 0.052]), surgery+radiation trials increased from 5.24 to 8.1% (P = 0.004, 95%CI [- 0.047, - 0.0088]), surgery+systemic-therapy trials decreased from 34.5 to 29.2% (P = 0.003, 95%CI [0.018, 0.088]), surgery+supportive-therapy trials increased from 8.0 to 11.3% (P = 0.004, 95%CI [- 0.056, - 0.01]) and 'surgery-as-the-variable' trials decreased from 12.0 to 3.5% (P < 0.001, 95%CI[0.065, 0.1]). Systemic therapy with biologics increased from 38.1 to 53.9% (P < 0.001, 95%CI [- 0.22, - 0.091]). Surgery-vs.-no-surgery trials increased from 16.8 to 37.3% (P = 0.001, 95%CI [- 0.32, - 0.078]). CONCLUSION: Surgical oncology trials increased by 43.2% over the last 10 years. The focus of clinical trials is changing to the encouragement of innovation in more diagnostic and less invasive techniques, and targeted therapies.

Impact of COVID-19 on the gastrointestinal surgical oncology patient population.

Background: The onset of the COVID-19 pandemic led to substantial alterations in healthcare delivery and access. In this study, we aimed to evaluate the impact of COVID-19 on the presentation and surgical care of patients with gastrointestinal (GI) cancers. Methods: All patients who underwent GI cancer surgery at a large, tertiary referral center between March 15, 2019 and March 15, 2021 were included. March 15, 2020 was considered the start of the COVID-19 pandemic. Changes in patient, tumor, and treatment characteristics before the pandemic compared to during the pandemic were evaluated. Results: Of 522 patients that met study criteria, 252 (48.3%) were treated before the COVID-19 pandemic. During the first COVID-19 wave, weekly volume of GI cancer cases was one-third lower than baseline (p = 0.041); during the second wave, case volume remained at baseline levels (p = 0.519). There were no demographic or tumor characteristic differences between patients receiving GI cancer surgery before versus during COVID-19 (p > 0.05 for all), and no difference in rate of emergency surgery (p > 0.9). Patients were more likely to receive preoperative chemotherapy during the first six months of the pandemic compared to the subsequent six months (35.6% vs. 15.5%, p < 0.001). Telemedicine was rapidly adopted at the start of the pandemic, rising from 0% to 47% of GI surgical oncology visits within two months. Conclusions: The COVID-19 pandemic caused an initial disruption to the surgical care of GI cancers, but did not compromise stage at presentation. Preoperative chemotherapy and telemedicine were utilized to mitigate the impact of a high COVID-19 burden on cancer care.

Surgical treatment of stage IV gastroenteropancreatic neuroendocrine carcinoma: Experience and outcomes in the United States.

BACKGROUND AND OBJECTIVES: Surgery for metastatic gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) has not been well-studied. This retrospective cohort study describes patients in the United States with stage IV GEP-NEC and their survival outcomes segregated by surgery. METHODS: Patients diagnosed with stage IV GEP-NEC from 2004 to 2017 in the National Cancer Database were categorized into three groups: no surgery, primary site or metastatic site ("single-site") surgery, and primary site and metastatic site ("multisite") surgery. Factors associated with surgical treatment were identified, and risk-adjusted overall survival of each group was compared. RESULTS: Of 4171 patients included, 958 (23.0%) underwent single-site surgery and 374 (9.0%) underwent multisite surgery. The strongest predictor of surgery was primary tumor type. Compared with no surgery, the risk-adjusted mortality reduction associated with single-site surgery ranged from 63% for small bowel (HR = 0.37, 0.23-0.58, p < 0.001) NEC to 30% for colon and appendix NEC (HR = 0.70, 0.61-0.80, p < 0.001), while the mortality reduction associated with multisite surgery ranged from 77% for pancreas NEC (HR = 0.23, 0.17-0.33, p < 0.001) to 48% for colon and appendix NEC (HR = 0.52, 0.44-0.63, p < 0.001). CONCLUSIONS: We observed an association between extent of surgical intervention and overall survival for patients with stage IV GEP-NEC. Surgical resection should be further investigated as a treatment option for highly-selected patients with this aggressive disease.

First-principle insight into the structural, electronic, elastic and optical properties of Cs-based double perovskites Cs2XCrCl6 (X = K, Na).

This study communicates the theoretical investigations on the cubic double perovskite compounds Cs2XCrCl6 (X = K or Na). Density functional theory (DFT) calculations were carried out using the TB-mBJ approximation. These compounds were found to be stable in the cubic perovskite structure having lattice constants in the range of 10.58-10.20. The stability of the investigated materials was assessed by the Gold-Schmidt tolerance method, which resulted in the tolerance factor values of 0.891 and 0.951 for Cs2KCrCl6 and Cs2NaCrCl6, respectively. The calculated values of the elastic constants C11, C12, and C44 of the cubic compounds studied by our research team confirm the elastic stability. The values of the formation energies were also calculated for both the compounds and were found in the range from -2.1 to -2.3. The electronic behavior of the presently investigated materials was examined by inspecting their band structures and the density of states. It was observed that both the materials have half-metallic nature. To check the suitability of the studied compounds in optical applications, we determined the real and imaginary parts of their respective dielectric functions, absorption coefficients, optical conductivities, refractive index, and reflectivity as a function of a wide range of incident photon energies up to 40 eV.