Digital assessment of tertiary lymphoid structures and therapeutic responses in gastric cancer: A multi-centric retrospective study.

BACKGROUND: Tertiary lymphoid structures (TLSs) are associated with favorable prognosis and enhanced response to anti-cancer therapy. A digital assessment of TLSs could provide an objective alternative that mitigates variability inherent in manual evaluation. This study aimed to develop and validate a digital gene panel based on biological prior knowledge for assessment of TLSs, and further investigate its associations with survival and multiple anti-cancer therapies. MATERIALS AND METHODS: The present study involved 1,704 patients with gastric cancer from seven cancer centers. TLSs were identified morphologically through hematoxylin-and-eosin staining. We further developed a digital score based on targeted gene expression profiling to assess TLSs status, recorded as gene signature of tertiary lymphoid structures (gsTLS). For enhanced interpretability, we employed the SHapley Additive exPlanation (SHAP) analysis to elucidate its contribution to the prediction. We next evaluated the signature's associations with prognosis, and investigated its predictive accuracy for multiple anti-cancer therapies, including adjuvant chemotherapy and immunotherapy. RESULTS: The gsTLS panel with nine gene features achieved high accuracies in predicting TLSs status in the training, internal and external validation cohorts (area under the curve, range: 0.729-0.791). In multivariable analysis, gsTLS remained an independent predictor of disease-free and overall survival (hazard ratio, range: 0.346-0.743, all P < 0.05) after adjusting for other clinicopathological variables. SHAP analysis highlighted gsTLS as the strongest predictor of TLSs status compared with clinical features. Importantly, patients with high gsTLS (but not those with low gsTLS) exhibited substantial benefits from adjuvant chemotherapy (P < 0.05). Furthermore, we found that the objective response rate to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy was significantly higher in the high-gsTLS group (40.7%) versus the low-gsTLS group (5.6%, P = 0.036), and the diagnosis was independent from Epstein-Barr virus (EBV), tumor mutation burden (TMB), and programmed cell death-ligand 1 (PD-L1) expression. CONCLUSION: The gsTLS digital panel enables accurate assessment of TLSs status, and provides information regarding prognosis and responses to multiple therapies for gastric cancer.

Angioembolization for splenic injuries: does it help? Retrospective evaluation of grade III-V splenic injuries at two level I trauma centers.

Background: Splenic angioembolization (SAE) has increased in utilization for blunt splenic injuries. We hypothesized lower SAE usage would not correlate with higher rates of additional intervention or mortality when choosing initial non-operative management (NOM) or surgery. Study design: Trauma registries from two level I trauma centers from 2010 to 2020 were used to identify patients aged >18 years with grade III-V blunt splenic injuries. Results were compared with the National Trauma Data Bank (NTDB) for 2018 for level I and II centers. Additional intervention or failure was defined as any subsequent SAE or surgery. Mortality was defined as death during admission. Results: There were 266 vs 5943 patients who met inclusion/exclusion criteria at Stanford/Santa Clara Valley Medical Center (SCVMC) versus the NTDB. Initial intervention differed significantly between cohorts with the use of SAE (6% vs 17%, p=0.000). Failure differed significantly between cohorts (1.5% vs 6.5%, p=0.005). On multivariate analysis, failure in NOM was significantly associated with NTDB cohort status, age 65+ years, more than one comorbidity, mechanism of injury, grade V spleen injury, and Injury Severity Score (ISS) 25+. On multivariate analysis, failure in SAE was significantly associated with Shock Index >0.9 and 10+ units blood in 24 hours. On multivariate analysis, a higher risk of mortality was significantly associated with NTDB cohort status, age 65+ years, no private insurance, more than one comorbidity, mechanism of injury, ISS 25+, 10+ units blood in 24 hours, NOM, more than one hospital complications, anticoagulant use, other Abbreviated Injury Scale ≥3 abdominal injuries. Conclusions: Compared with national data, our cohort had less SAE, lower rates of additional intervention, and had lower risk-adjusted mortality. Shock Index >0.9, grade V splenic injuries, and increased transfusion requirements in the first 24 hours may signal a need for surgical intervention rather than SAE or NOM and may reduce mortality in appropriately selected patients. Level of evidence: Level II/III.

Comprehensive assessment of immune context and immunotherapy response via noninvasive imaging in gastric cancer.

BACKGROUNDThe tumor immune microenvironment can provide prognostic and therapeutic information. We aimed to develop noninvasive imaging biomarkers from computed tomography (CT) for comprehensive evaluation of immune context and investigate their associations with prognosis and immunotherapy response in gastric cancer (GC).METHODSThis study involved 2,600 patients with GC from 9 independent cohorts. We developed and validated 2 CT imaging biomarkers (lymphoid radiomics score [LRS] and myeloid radiomics score [MRS]) for evaluating the IHC-derived lymphoid and myeloid immune context respectively, and integrated them into a combined imaging biomarker [LRS/MRS: low(-) or high(+)] with 4 radiomics immune subtypes: 1 (-/-), 2 (+/-), 3 (-/+), and 4 (+/+). We further evaluated the imaging biomarkers' predictive values on prognosis and immunotherapy response.RESULTSThe developed imaging biomarkers (LRS and MRS) had a high accuracy in predicting lymphoid (AUC range: 0.765-0.773) and myeloid (AUC range: 0.736-0.750) immune context. Further, similar to the IHC-derived immune context, 2 imaging biomarkers (HR range: 0.240-0.761 for LRS; 1.301-4.012 for MRS) and the combined biomarker were independent predictors for disease-free and overall survival in the training and all validation cohorts (all P < 0.05). Additionally, patients with high LRS or low MRS may benefit more from immunotherapy (P < 0.001). Further, a highly heterogeneous outcome on objective response ​rate was observed in 4 imaging subtypes: 1 (-/-) with 27.3%, 2 (+/-) with 53.3%, 3 (-/+) with 10.2%, and 4 (+/+) with 30.0% (P < 0.0001).CONCLUSIONThe noninvasive imaging biomarkers could accurately evaluate the immune context and provide information regarding prognosis and immunotherapy for GC.

Biology-guided deep learning predicts prognosis and cancer immunotherapy response.

Substantial progress has been made in using deep learning for cancer detection and diagnosis in medical images. Yet, there is limited success on prediction of treatment response and outcomes, which has important implications for personalized treatment strategies. A significant hurdle for clinical translation of current data-driven deep learning models is lack of interpretability, often attributable to a disconnect from the underlying pathobiology. Here, we present a biology-guided deep learning approach that enables simultaneous prediction of the tumor immune and stromal microenvironment status as well as treatment outcomes from medical images. We validate the model for predicting prognosis of gastric cancer and the benefit from adjuvant chemotherapy in a multi-center international study. Further, the model predicts response to immune checkpoint inhibitors and complements clinically approved biomarkers. Importantly, our model identifies a subset of mismatch repair-deficient tumors that are non-responsive to immunotherapy and may inform the selection of patients for combination treatments.

Benchmarks and Geographic Differences in Gallbladder Cancer Surgery: An International Multicenter Study.

BACKGROUND: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population. PATIENTS AND METHODS: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group. RESULTS: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%. CONCLUSIONS: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery.

Neoadjuvant Treatment Strategies for Resectable Proximal Gastric, Gastroesophageal Junction and Distal Esophageal Cancer.

Neoadjuvant treatment strategies for resectable proximal gastric, gastroesophageal junction (GEJ), and distal esophageal cancer have evolved over several decades. Treatment recommendations differ based on histologic type-squamous cell carcinoma (SCC) versus adenocarcinoma (AC)-as well as the exact location of the tumor. Recent and older clinical trials in this area were critically reviewed. Neoadjuvant chemoradiation with concurrent taxane- or fluoropyrimidine-based chemotherapy has an established role for both AC and SCC of the distal esophagus and GEJ. The use of perioperative chemotherapy for gastric AC is based on the FLOT4 and MAGIC trials; however, the utility of neoadjuvant chemoradiation in this setting requires further evaluation. Additional clinical trials evaluating chemotherapy, targeted therapy, immunotherapy, and radiation that are currently in process are highlighted, given the need for further disease control.

Acute Colonic Pseudo-Obstruction After Posterior Spinal Fusion: A Case Report and Literature Review.

BACKGROUND: Acute colonic pseudo-obstruction (ACPO) or Ogilvie's syndrome occurs in 0.22%-7% of patients undergoing surgery, with a mortality of up to 46%. ACPO increased median hospital days versus control in spinal surgery (14 vs. 6 days; P < 0.001). If defined as postoperative ileus, the incidence was 7%-13.4%. Postoperative ileus is associated with 2.9 additional hospital days and an $80,000 increase in cost per patient. We present a case of ACPO in an adult patient undergoing spinal fusion for correction of scoliosis and review the available literature to outline clinical characteristics and surgical outcomes. CASE DESCRIPTION: The patient was a 31-year-old woman with untreated advanced scoliosis with no history of neurologic issues. T2-L3 spinal instrumentation and fusion was completed. Plain abdominal radiography showed of dilated cecum 11 cm and the department of general surgery was consulted. Neostigmine administration was planned after conservative treatment failure after transfer to the intensive care unit. The patient was discharged home with no recurrence >60 days. Thirty cases were found in our literature review using PubMed and Embase databases and summarized. CONCLUSIONS: Of 30 cases reviewed, only 3 cases of ACPO were specific to patients undergoing spinal fusion for scoliosis. According to the literature, 20% of patients had resolution with conservative treatment, 40% with neostigmine, and 30% with surgical intervention. Other noninvasive treatments may have similar efficacy in preventing complications leading to surgical invention. Sixty clinical trials and 9 systematic reviews were summarized with an updated management algorithm.

A Systematic Review of Opt-out Versus Opt-in Consent on Deceased Organ Donation and Transplantation (2006-2016).

BACKGROUND: Significant numbers of patients in the USA and UK die while waiting for solid organ transplant. Only 1-2% of deaths are eligible as donors with a fraction of the deceased donating organs. The form of consent to donation may affect the organs available. Forms of consent include: opt-in, mandated choice, opt-out, and organ conscription. Opt-in and opt-out are commonly practiced. A systematic review was conducted to determine the effect of opt-in versus opt-out consent on the deceased donation rate (DDR) and deceased transplantation rate (DTR). METHODS: Literature searches of PubMed and EMBASE between 2006 and 2016 were performed. Research studies were selected based on certain inclusion criteria which include USA, UK, and Spain; compare opt-in versus opt-out; primary data analysis; and reported DDR or DTR. Modeled effect on US transplant activity was conducted using public data from Organ Procurement and Transplantation Network and Centers for Disease Control WONDER from 2006 to 2015. RESULTS: A total of 2400 studies were screened and six studies were included. Four studies reported opt-out consent increases DDR by 21-76% over 5-14 years. These studies compared 13-25 opt-out countries versus 9-23 opt-in countries. Three studies reported opt-out consent increases DTR by 38-83% over 11-13 years. These studies compared 22-25 opt-out versus 22-28 opt-in countries. Modeled opt-out activity on the USA resulted in 4753-17,201 additional transplants annually. CONCLUSION: Opt-out consent increases DDR and DTR and may be useful in decreasing deaths on the waiting list in the USA and other countries. REGISTRATION NUMBER: PROSPERO CRD42019098759.

Clinical Activity of Nivolumab for Human Papilloma Virus-Related Juvenile-Onset Recurrent Respiratory Papillomatosis.

BACKGROUND: Juvenile-onset recurrent respiratory papillomatosis (JO-RRP) is a human papilloma virus-mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO-RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth. MATERIALS AND METHODS: We treated two patients with refractory JO-RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling. RESULTS: Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on-treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma. CONCLUSION: Nivolumab appears to have promising activity in JO-RRP, and further clinical investigation with more patients in clinical trials is warranted. IMPLICATIONS FOR PRACTICE: To the authors' knowledge, this article is the first report describing clinical activity with a programed cell death-1 (PD-1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD-1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.