Disappearing Signet Ring Cell Adenocarcinoma in Gastric Cancer Patients.

BACKGROUND: The incidence of diffuse-type gastric cancer is increasing steadily in the United States, Europe, and Asia. This subtype is known for aggressive clinical characteristics and transmural invasion. However, T1a diffuse-type cancers have been observed to have a better 5-year, disease-specific mortality than stage-matched intestinal tumors, supporting a clinical difference in these early-stage cancers. METHODS: Data on all living patients with T1a gastric adenocarcinoma with a finding of signet ring cell morphology on pathology and ≥1 year of follow-up from 2013 to 2023 at Memorial Sloan Kettering Cancer Center (MSK) was collected from a prospectively maintained database. Patients with known CDH1 or CTNNA1 mutations were excluded. RESULTS: In 7 of 30 patients, sporadic pathologically confirmed T1a signet ring cell (diffuse) cancer identified on initial biopsy was no longer detectable upon subsequent biopsy or resection with mean follow-up of 50 months. CONCLUSIONS: These cases allude to the distinct pathways of carcinogenesis in T1a signet ring cell cancers. Potential factors that may underlie the spontaneous regression of these T1a cancers include complete removal at initial biopsy, immune clearance, and lack of survival advantage conferred by signet ring cell genetic alterations in these cases. Given their more indolent behavior at an earlier stage, we suggest that these lesions can be closely followed by endoscopy in select circumstances with thorough disease assessment and an experienced care team.

Feasibility and Efficacy of Sentinel Lymph Node Mapping in Gastric Cancer.

BACKGROUND: Lymph node metastasis is a critical prognostic factor for patients with gastric carcinoma (GC). Sentinel lymph node (SLN) mapping has the potential to identify the initial site of draining lymph node metastasis and reduce the extent of surgical lymphadenectomy. This study aimed to evaluate the diagnostic accuracy of SLN mapping in GC. METHODS: The study enrolled 129 GC patients undergoing total or partial gastrectomy with D2 lymphadenectomy and indocyanine green fluorescence-guided SLN mapping. The primary outcomes were the negative predictive value (NPV) and sensitivity of SLN mapping. The secondary outcomes were clinicopathologic factors associated with SLN mapping accuracy and successful SLN mapping. RESULTS: The SLN detection rate in this study was 86.8 %. The study had an overall NPV of 83.1 % and an overall sensitivity of 65.8 %. The NPV was found to be significantly higher in the patients with no lymphovascular invasion (LVI) than in those with LVI (96.0 % vs 59.3 %; p < 0.001) and in the patients whose pathologic T (pT) stage lower than 3 than in those whose T stage was 3 or higher (92.0 % vs 66.7 %; p = 0.009). The sensitivity of SLN mapping was 50 % in the patients with no LVI and 33 % in the patients with a pT stage lower than 3. CONCLUSION: The study results showed that for patients with early-stage GC with no LVI, negative SLN findings may represent a potential additive predictor indicating the absence of regional LN metastasis. However, given the low sensitivity rates noted, further research is needed to identify specific patient populations that may benefit from SLN mapping in GC.

Morphologic Heterogeneity of Carcinoma with Signet Ring Cell Features at Different Primary Sites.

INTRODUCTION: Signet ring cells (SRCs) may be observed in carcinomas from multiple primary sites. Elucidating unknown primaries from metastases with SRCs represents a diagnostic challenge. This study examined morphologic characteristics of adenocarcinomas with SRCs from stablished primary sites and described objective features, which can aid in identifying the site of origin. METHODS: The series encompasses 257 cases of adenocarcinomas with SRCs from gastroesophageal junction (GEJ, n = 38), stomach (n = 48), pancreatobiliary system (n = 16), colorectum (n = 40), appendix (n = 32), breast (n = 41), and lung (n = 42). H&E sections were examined and scored using architectural and cytologic criteria. Morphometric analysis was performed using QuPath software. RESULTS: Extracellular mucin was more abundant in GEJ, colorectal, and appendiceal carcinomas. Poorly cohesive morphology was the most frequent pattern in gastric and breast carcinomas. The cytoplasmic mucin/vacuole was predominantly clear and targetoid in breast carcinomas. Breast and gastric carcinomas showed the highest nuclear to cytoplasmic (N/C) ratio, whereas appendiceal carcinoma the lowest. CONCLUSION: Morphological evaluation (extracellular mucin, architectural patterns, and the nature of cytoplasmic mucin/vacuole) represents an important step to determine the cancer site of origin in adenocarcinomas with SRCs and guides further ancillary studies. Cytological morphometry may help further refine morphological criteria and facilitate the construction of digital-pathology algorithms.

Patient metabolic profile defined by liver and muscle 18F-FDG PET avidity is independently associated with overall survival in gastric cancer.

BACKGROUND: PET-CT-based patient metabolic profiling is a novel concept to incorporate patient-specific metabolism into gastric cancer care. METHODS: Staging PET-CTs, demographics, and clinicopathologic variables of gastric cancer patients were obtained from a prospectively maintained institutional database. PET-CT avidity was measured in tumor, liver, spleen, four paired muscles, and two paired fat areas in each patient. The liver to rectus femoris (LRF) ratio was defined as the ratio of SUVmean of liver to the average SUVmean of the bilateral rectus femoris muscles. Kaplan-Meier and Cox-proportional hazards models were used to identify the impact of LRF ratio on OS. RESULTS: Two hundred and one patients with distal gastroesophageal (48%) or gastric (52%) adenocarcinoma were included. Median age was 65 years, and 146 (73%) were male. On univariate analysis, rectus femoris PET-CT avidity and LRF ratio were significantly associated with overall survival (p < 0.05). LRF ratio was significantly higher in males, early-stage cancer, patients with an ECOG 0 or 1 performance status, patients with albumin > 3.5 mg/dL, and those with moderately differentiated tumor histology. In multivariable regression, gastric cancer stage, albumin, and LRF ratio were significant independent predictors of overall survival (LRF ratio HR = 0.73 (0.56-0.96); p = 0.024). Survival curves showed that the prognostic impact of LRF was associated with metastatic gastric cancer (p = 0.009). CONCLUSIONS: Elevated LRF ratio, a patient-specific PET-CT-based metabolic parameter, was independently associated with an improvement in OS in patients with metastatic gastric cancer. With prospective validation, LRF ratio may be a useful, host-specific metabolic parameter for prognostication in gastric cancer.

First-line regorafenib with nivolumab and chemotherapy in advanced oesophageal, gastric, or gastro-oesophageal junction cancer in the USA: a single-arm, single-centre, phase 2 trial.

BACKGROUND: The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. FINDINGS: Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. INTERPRETATION: Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. FUNDING: Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.

Risk of Lymph Node Metastasis in T1b Gastric Cancer: An International Comprehensive Analysis from the Global Gastric Group (G3) Alliance.

OBJECTIVE: We sought to define criteria associated with low lymph node metastasis risk in patients with submucosal (pT1b) gastric cancer from 3 Western and 3 Eastern countries. SUMMARY BACKGROUND DATA: Accurate prediction of lymph node metastasis risk is essential when determining the need for gastrectomy with lymph node dissection following endoscopic resection. Under present guidelines, endoscopic resection is considered definitive treatment if submucosal invasion is only superficial, but this is not routinely assessed. METHODS: Lymph node metastasis rates were determined for patient groups defined according to tumor pathological characteristics. Clinicopathological predictors of lymph node metastasis were determined by multivariable logistic regression and used to develop a nomogram in a randomly selected subset that was validated in the remainder. Overall survival was compared between Eastern and Western countries. RESULTS: Lymph node metastasis was found in 701 of 3166 (22.1%) Eastern and 153 of 560 (27.3%) Western patients. Independent predictors of lymph node metastasis were female sex, tumor size, distal stomach location, lymphovascular invasion, and moderate or poor differentiation. Patients fulfilling the National Comprehensive Cancer Network guideline criteria, excluding the requirement that invasion not extend beyond the superficial submucosa, had a lymph node metastasis rate of 8.9% (53/594). Excluding moderately differentiated tumors lowered the rate to 3.4% (10/296). The nomogram's area under the curve was 0.690. Regardless of lymph node status, overall survival was better in Eastern patients. CONCLUSIONS: The lymph node metastasis rate was lowest in patients with well differentiated tumors that were ≤3 cm and lacked lymphovascular invasion. These criteria may be useful in decisions regarding endoscopic resection as definitive treatment for pT1b gastric cancer.

A Prospective Clinical Trial to Evaluate Mesothelin as a Biomarker for the Clinical Management of Patients With Esophageal Adenocarcinoma.

OBJECTIVE: To investigate the utility of serum soluble mesothelin-related peptide (SMRP) and tumor mesothelin expression in the management of esophageal adenocarcinoma (ADC). BACKGROUND: Clinical management of esophageal ADC is limited by a lack of accurate evaluation of tumor burden, treatment response, and disease recurrence. Our retrospective data showed that tumor mesothelin and its serum correlate, SMRP, are overexpressed and associated with poor outcomes in patients with esophageal ADC. METHODS: Serum SMRP and tumoral mesothelin expression from 101 patients with locally advanced esophageal ADC were analyzed before induction chemoradiation (pretreatment) and at the time of resection (posttreatment), as a biomarker for treatment response, disease recurrence, and overall survival (OS). RESULTS: Pre and posttreatment serum SMRP was ≥1 nM in 49% and 53%, and pre and post-treatment tumor mesothelin expression was >25% in 35% and 46% of patients, respectively. Pretreatment serum SMRP was not significantly associated with tumor stage ( P = 0.9), treatment response (radiologic response, P = 0.4; pathologic response, P = 0.7), or recurrence ( P =0.229). Pretreatment tumor mesothelin expression was associated with OS (hazard ratio: 2.08; 95% CI: 1.14-3.79; P = 0.017) but had no statistically significant association with recurrence ( P = 0.9). Three-year OS of patients with pretreatment tumor mesothelin expression of ≤25% was 78% (95% CI: 68%-89%), compared with 49% (95% CI: 35%-70%) among those with >25%. CONCLUSIONS: Pretreatment tumor mesothelin expression is prognostic of OS for patients with locally advanced esophageal ADC, whereas serum SMRP is not a reliable biomarker for monitoring treatment response or recurrence.

Distinct Differences in Gastroesophageal Junction and Gastric Adenocarcinoma in 2194 Patients: In Memory of Rebecca A. Carr, February 24, 1988-January 19, 2021.

OBJECTIVE: We sought to compare gastroesophageal junction (GEJ) cancer and gastric cancer (GC) and identify clinicopathological and oncological differences. SUMMARY BACKGROUND DATA: GEJ cancer and GC are frequently studied together. Although the treatment approach for each often differs, clinico-pathological and oncological differences between the 2 have not been fully evaluated. METHODS: We retrospectively identified patients with GEJ cancer or GC who underwent R0 resection at our center between January 2000 and December 2016. Clinicopathological characteristics, disease-specific survival (DSS), and site of first recurrence were compared. RESULTS: In total, 2194 patients were analyzed: 1060 (48.3%) with GEJ cancer and 1134 (51.7%) with GC. Patients with GEJ cancer were younger (64 vs 66 years; P < 0.001), more often received neoadjuvant treatment (70.9% vs 30.2%; P < 0.001), and had lower pathological T and N status. Five-year DSS was 62.2% in patients with GEJ cancer and 74.6% in patients with GC ( P < 0.001). After adjustment for clinicopathological factors, DSS remained worse in patients with GEJ cancer (hazard ratio, 1.78; 95% confidence interval, 1.40-2.26; P < 0.001). The cumulative incidence of recurrence was approximately 10% higher in patients with GEJ cancer ( P < 0.001). The site of first recurrence was more likely to be hematogenous in patients with GEJ cancer (60.1% vs 31.4%; P < 0.001) and peritoneal in patients with GC (52.9% vs 12.5%; P < 0.001). CONCLUSIONS: GEJ adenocarcinoma is more aggressive, with a higher incidence of recurrence and worse DSS, compared with gastric adenocarcinoma. Distinct differences between GEJ cancer and GC, especially in patterns of recurrence, may affect evaluation of optimal treatment strategies.

Survival of Locally Advanced MSI-high Gastric Cancer Patients Treated With Perioperative Chemotherapy: A Retrospective Cohort Study.

OBJECTIVE: To evaluate the efficacy of chemotherapy in patients with microsatellite instability (MSI)-high gastric cancer. BACKGROUND: Although MSI-high gastric cancer is associated with a superior prognosis, recent studies question the benefit of perioperative chemotherapy in this population. METHODS: Locally advanced gastric adenocarcinoma patients who either underwent surgery alone or also received neoadjuvant, perioperative, or adjuvant chemotherapy between 2000 and 2018 were eligible. MSI status, determined by next-generation sequencing or mismatch repair protein immunohistochemistry, was determined in 535 patients. Associations among MSI status, chemotherapy administration, overall survival (OS), disease-specific survival, and disease-free survival were assessed. RESULTS: In 535 patients, 82 (15.3%) had an MSI-high tumor and ∼20% better OS, disease-specific survival, and disease-free survival. Grade 1 (90%-100%) pathological response to neoadjuvant chemotherapy was found in 0 of 40 (0%) MSI-high tumors versus 43 of 274 (16%) MSS. In the MSI-high group, the 3-year OS rate was 79% with chemotherapy versus 88% with surgery alone ( P =0.48). In the MSS group, this was 61% versus 59%, respectively ( P =0.96). After multivariable interaction analyses, patients with MSI-high tumors had superior survival compared with patients with MSS tumors whether given chemotherapy (hazard ratio=0.53, 95% confidence interval: 0.28-0.99) or treated with surgery alone (hazard ratio=0.15, 95% confidence interval: 0.02-1.17). CONCLUSIONS: MSI-high locally advanced gastric cancer was associated with superior survival compared with MSS overall, despite worse pathological chemotherapy response. In patients with MSI-high gastric cancer who received chemotherapy, the survival rate was ∼9% worse compared with surgery alone, but chemotherapy was not significantly associated with survival.

Durvalumab and PET-Directed Chemoradiation in Locally Advanced Esophageal Adenocarcinoma: A Phase Ib/II Study.

OBJECTIVE: To determine the safety and efficacy of adding the anti-PD-L1 antibody durvalumab to induction FOLFOX and preoperative chemotherapy in locally advanced esophageal adenocarcinoma. BACKGROUND: Neoadjuvant induction FOLFOX followed by positron emission tomography (PET) directed chemoradiation has demonstrated improved survival for esophageal adenocarcinoma. There is clear benefit now for the addition of immune checkpoint inhibitors both in early and advanced stage disease. Given these results we investigated the safety and efficacy of adding durvalumab to induction FOLFOX and preoperative chemoradiotherapy. METHODS: Patients with locally advanced resectable esophageal/gastroesophageal junction adenocarcinoma received PET-directed chemoradiation with durvalumab before esophagectomy. Patients who had R0 resections received adjuvant durvalumab 1500 mg every 4 weeks for 6 treatments. The primary endpoint of the study was pathologic complete response. RESULTS: We enrolled 36 patients, 33 of whom completed all preoperative treatment and underwent surgery. Preoperative treatment was well tolerated, with no delays to surgery nor new safety signals. Pathologic complete response was identified in 8 [22% (1-sided 90% lower bound: 13.3%)] patients with major pathologic response in 22 [61% (1-sided 90% lower bound: 50%)] patients. Twelve and 24-month overall survival was 92% and 85%, respectively. CONCLUSIONS: The addition of durvalumab to induction FOLFOX and PET-directed chemoradiotherapy before surgery is safe, with a high rate of pathologic response, as well as encouraging survival data.

High Interobserver Variability Among Pathologists Using Combined Positive Score to Evaluate PD-L1 Expression in Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma.

Reliable, reproducible methods to interpret programmed death ligand-1 (PD-L1) expression on tumor cells (TC) and immune cells (IC) are needed for pathologists to inform decisions associated with checkpoint inhibitor therapies. Our international study compared interpathologist agreement of PD-L1 expression using the combined positive score (CPS) under standardized conditions on samples from patients with gastric/gastroesophageal junction/esophageal adenocarcinoma. Tissue sections from 100 adenocarcinoma pretreatment biopsies were stained in a single laboratory using the PD-L1 immunohistochemistry 28-8 and 22C3 (Agilent) pharmDx immunohistochemical assays. PD-L1 CPS was evaluated by 12 pathologists on scanned whole slide images of these biopsies before and after a 2-hour CPS training session by Agilent. Additionally, pathologists determined PD-L1-positive TC, IC, and total viable TC on a single tissue fragment from 35 of 100 biopsy samples. Scoring agreement among pathologists was assessed using the intraclass correlation coefficient (ICC). Interobserver variability for CPS for 100 biopsies was high, with only fair agreement among pathologists both pre- (range, 0.45-0.55) and posttraining (range, 0.56-0.57) for both assays. For the 35 single biopsy samples, poor/fair agreement was also observed for the total number of viable TC (ICC, 0.09), number of PD-L1-positive IC (ICC, 0.19), number of PD-L1-positive TC (ICC, 0.54), and calculated CPS (ICC, 0.14), whereas calculated TC score (positive TC/total TC) showed excellent agreement (ICC, 0.82). Retrospective histologic review of samples with the poorest interpathologist agreement revealed the following as possible confounding factors: (1) ambiguous identification of positively staining stromal cells, (2) faint or variable intensity of staining, (3) difficulty in distinguishing membranous from cytoplasmic tumor staining, and (4) cautery and crush artifacts. These results emphasize the need for objective techniques to standardize the interpretation of PD-L1 expression when using the CPS methodology on gastric/gastroesophageal junction cancer biopsies to accurately identify patients most likely to benefit from immune checkpoint inhibitor therapy.

A More Extensive Lymphadenectomy Enhances Survival After Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Adenocarcinoma.

OBJECTIVE: We sought to determine the extent of lymphadenectomy that optimizes staging and survival in patients with locally advanced EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy. SUMMARY OF BACKGROUND DATA: Several studies have found that a more extensive lymphadenectomy leads to better disease-specific survival in patients treated with surgery alone. Few studies, however, have investigated whether this association exists for patients treated with neoadjuvant chemoradiotherapy. METHODS: We examined our prospective database and identified patients with EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy between 1995 and 2017. Overall survival (OS) and DFS were estimated using Kaplan-Meier methods, and a multivariable Cox proportional hazards model was used to identify independent predictors of OS and DFS. The relationship between the total number of nodes removed and 5-year OS or DFS was plotted using restricted cubic spline functions. RESULTS: In total, 778 patients met the inclusion criteria. The median number of excised nodes was 21 (interquartile range, 16-27). A lower number of excised lymph nodes was independently associated with worse OS and DFS (OS: hazard ratio, 0.98; confidence interval, 0.97-1.00; P = 0.013; DFS: hazard ratio, 0.99; confidence interval, 0.98-1.00; P = 0.028). Removing 25 to 30 lymph nodes was associated with a 10% risk of missing a positive lymph node. Both OS and DFS improved with up to 20 to 25 lymph nodes removed, regardless of treatment response. CONCLUSIONS: The optimal extent of lymphadenectomy to enhance both staging and survival after chemoradiotherapy, regardless of treatment response, is approximately 25 lymph nodes.

Survival After Trimodality Therapy in Patients With Locally Advanced Esophagogastric Adenocarcinoma: Does Only a Complete Pathologic Response Matter?

OBJECTIVE: To evaluate whether pCR exclusively defines major pathologic response to treatment with improved survival. SUMMARY BACKGROUND DATA: pCR after trimodality therapy for EAC is infrequent but associated with improved prognosis. Yet most clinical trials and correlative studies designate pCR as the primary endpoint. METHODS: We analyzed our prospectively maintained database for patients who underwent trimodality therapy for locally advanced esophageal adeno-carcinoma between 1995 and 2017. Overall survival (OS) was examined by percentage TR in the primary tumor bed and pathologic nodal stage (ypN0) using Kaplan-Meier plots. Optimal thresholds of TR for differentiating patients in terms of OS were investigated with descriptive plots using restricted cubic spline functions; associations were quantified using Cox multivariable analysis. RESULTS: Among 788 patients, median follow-up was 37.5 months (range, 0.4210.6); median OS was 48.3 months (95% CI, 42.2-58.8). Absence of residual nodal disease was independently associated with improved survival ( P < 0.001). Survival curves for 90% to 99% TR and 100% TR were similar, and a change in probability of improved OS was observed at 90% TR. On multivariable analysis, combining 90% to 99% and 100% TR was independently associated with improved OS, compared with 50% to 89% and <50% TR. CONCLUSIONS: ypN0 status is the strongest indicator of major pathologic response to trimodality therapy, in addition to >90% TR in the primary tumor bed. These findings may allow the definition of major pathologic response to be expanded, from pCR to > 90% TR and ypN0. This has meaningful implications for future clinical trials and correlative studies.

PD-L1 expression and overall survival in Asian and western patients with gastric cancer.

Aim: Data are limited on PD-L1 expression and its association with overall survival (OS) in gastric cancer (GC) patients receiving routine care in different regions. Materials & methods: In a retrospective study, PD-L1 expression was assayed using the 22C3 pharmDx on GC tumor samples collected between 2003 and 2017 at South Korean and US cancer centers. PD-L1 positivity was defined as combined positive score (CPS) ≥1. The relationship between PD-L1 and OS was analyzed. Results: Of 574 GC tumor samples, 67.4% were CPS ≥1 (68.7% in Korean and 65.7% in US patients). PD-L1 expression was not associated with OS (adjusted hazard ratio: 0.94; 95% CI: 0.75-1.17). Conclusion: PD-L1 prevalence and its association with OS was similar between South Korean and US GC patients.

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix.

During the process of tumor progression, cancer cells can produce the requisite growth- and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg-Gly-Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.

Multi-institutional Development and External Validation of a Nomogram to Predict Recurrence After Curative Resection of Pancreatic Neuroendocrine Tumors.

OBJECTIVE: To develop a nomogram estimating the probability of recurrence free at 5 years after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs). BACKGROUND: Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up. METHOD: A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5 years after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve. RESULTS: The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51 months, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/ American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P = <0.001). On the external cohort of 328 patients, the nomogram c-index was 0.84 (95% confidence interval 0.79-0.88). CONCLUSION: Our externally validated nomogram predicts the probability of recurrence-free survival at 5 years after PanNETs curative resection, with improved accuracy over current staging systems. Estimating individual recurrence risk will guide the development of personalized surveillance programs after surgery.

Outcomes of Neoadjuvant Chemotherapy for Clinical Stages 2 and 3 Gastric Cancer Patients: Analysis of Timing and Site of Recurrence.

BACKGROUND: This study aimed to analyze timing and sites of recurrence for patients receiving neoadjuvant chemotherapy for gastric cancer. Neoadjuvant chemotherapy followed by surgical resection is the standard treatment for locally advanced gastric cancer in the West, but limited information exists as to timing and patterns of recurrence in this setting. METHODS: Patients with clinical stage 2 or 3 gastric cancer treated with neoadjuvant chemotherapy followed by curative-intent resection between January 2000 and December 2015 were analyzed for 5-year recurrence-free survival (RFS) as well as timing and site of recurrence. RESULTS: Among 312 identified patients, 121 (38.8%) experienced recurrence during a median follow-up period of 46 months. The overall 5-year RFS rate was 58.9%, with RFS rates of 95.8% for ypT0N0, 81% for ypStage 1, 77.4% for ypStage 2, and 22.9% for ypStage 3. The first site of recurrence was peritoneal for 49.6%, distant (not peritoneal) for 45.5%, and locoregional for 11.6% of the patients. The majority of the recurrences (84.3%) occurred within 2 years. Multivariate analysis showed that ypT4 status was an independent predictor for recurrence within 1 year after surgery (odds ratio, 2.58; 95% confidence interval, 1.10-6.08; p = 0.030). CONCLUSIONS: The majority of the recurrences for patients with clinical stage 2 or 3 gastric cancer who received neoadjuvant chemotherapy and underwent curative resection occurred within 2 years. After neoadjuvant chemotherapy, pathologic T stage was a useful risk predictor for early recurrence.

Association of Obesity with Worse Operative and Oncologic Outcomes for Patients Undergoing Gastric Cancer Resection.

BACKGROUND: How obesity has an impact on operative and oncologic outcomes for gastric cancer patients is unclear, and the influence of obesity on response to neoadjuvant chemotherapy (NAC) has not been evaluated. METHODS: Patients who underwent curative gastrectomy for primary gastric cancer between 2000 and 2018 were retrospectively identified. After stratification for NAC, operative morbidity, mortality, overall survival (OS), and disease-specific survival (DSS) were compared among three body mass index (BMI) categories: normal BMI (< 25 kg/m2), mild obesity (25-35 kg/m2), and severe obesity (≥ 35 kg/m2). RESULTS: During the study period, 984 patients underwent upfront surgery, and 484 patients received NAC. Tumor stage did not differ among the BMI groups. However, the rates of pathologic response to NAC were significantly lower for the patients with severe obesity (10% vs 40%; p < 0.001). Overall complications were more frequent among the obese patients (44.3% for obese vs 24.9% for normal BMI, p < 0.001). Intraabdominal infections were also more frequent in obese patients (13.9% for obese vs 4.7% for normal BMI, p = 0.001). In the upfront surgery cohort, according to the BMI, OS and DSS did not differ, whereas in the NAC cohort, severe obesity was independently associated with worse OS [hazard ratio (HR) 1.87; 95% confidence interval (CI) 1.01-3.48; p = 0.047] and disease-specific survival (DSS) (HR 2.08; 95% CI 1.07-4.05; p = 0.031). CONCLUSION: For the gastric cancer patients undergoing curative gastrectomy, obesity was associated with significantly lower rates of pathologic response to NAC and more postoperative complications, as well as shorter OS and DSS for the patients receiving NAC.

A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations.

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are classified according to morphology as well-differentiated neuroendocrine tumours (NETs) G3 or poorly differentiated neuroendocrine carcinomas (NECs). Little data exist concerning which morphological criteria this subdivision should be based on. Uncertainty exists if the NEC group should be further subdivided according to proliferation rate. Clinical data on NET G3 and NEC with a lower Ki-67 range are limited. A total of 213 patients with high-grade GEP-NEN (Ki-67 >20%) were included from the Nordic NEC Registries. Four experienced NET pathologists re-evaluated the cases to develop the best morphological criteria to separate NET G3 from NEC, assuming longer survival in NET G3. Organoid growth pattern, capillary network in direct contact to tumour cells, and absence of desmoplastic stroma were found to best separate NET G3 from NEC. Of 196 patients with metastatic disease, NET G3 was found in 12.3%, NEC with a Ki-67 <55% (NEC < 55) in 29.6%, and NEC with a Ki-67 ≥55% (NEC ≥ 55) in 56.6%. Only in 1.5%, the morphology was ambiguous. Of 164 patients receiving first-line chemotherapy, 88% received platinum/etoposide treatment. Response rate was higher for NEC ≥ 55 (44%) than that of NEC < 55 (25%) and NET G3 (24%) (p = 0.025 and p = 0.026). Median progression-free survival was 5 months for all groups. Median overall survival was 33 months for NET G3 compared to 11 months for both NEC < 55 and NEC ≥ 55 (p = 0.004 and 0.003). Specific morphological criteria can separate NET G3 from NECs and show prognostic significance. High-grade GEP-NEN patients stratified by morphology and proliferation rate demonstrate significant differences in response to chemotherapy and survival.

Regorafenib in Combination with First-Line Chemotherapy for Metastatic Esophagogastric Cancer.

BACKGROUND: Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer. MATERIALS AND METHODS: Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS. RESULTS: Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy. CONCLUSION: Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control. IMPLICATIONS FOR PRACTICE: Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.