Independent Stage Classification for Gastroesophageal Junction Adenocarcinoma.

In gastroesophageal junction (GEJ) adenocarcinoma cases, a prognosis based on ypTNM staging could be affected by preoperative therapy. Patients with esophageal adenocarcinoma and gastric adenocarcinoma who underwent preoperative therapy followed by surgical resection from 2006 through 2017 were identified in the National Cancer Database. To enable stage-by-stage OS comparisons, tumors were classified into four gross ypTNM groups: ypT1/2, N-negative; ypT1/2, N-positive; ypT3/4, N-negative; and ypT3/4, N-positive. Prognostic factors were examined, and an OS prediction nomogram was developed for patients with abdominal/lower esophageal and gastric cardia adenocarcinoma, representing GEJ cancers. We examined 25,463 patient records. When compared by gross ypTNM group, the abdominal/lower esophageal and gastric cardia adenocarcinoma groups had similar OS rates, differing from those of other esophageal or gastric cancers. Cox regression analysis of patients with GEJ cancers showed that preoperative chemoradiotherapy was associated with shorter OS than preoperative chemotherapy after adjustment for the ypTNM group (hazard ratio 1.31, 95% CI 1.24-1.39, p < 0.001), likely owing to downstaging effects. The nomogram had a concordance index of 0.833 and a time-dependent area under the curve of 0.669. OS prediction in GEJ adenocarcinoma cases should include preoperative therapy regimens. Our OS prediction nomogram provided reasonable OS prediction for patients with GEJ adenocarcinoma, and future validation is needed.

Feasibility and value of genomic profiling in cancer of unknown primary: real-world evidence from prospective profiling study.

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. The most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging because of paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies.

Clinical Impact of Positive Surgical Margins in Gastric Adenocarcinoma in the Era of Preoperative Therapy.

BACKGROUND: Microscopically positive (R1) surgical margins after gastrectomy increase gastric cancer recurrence risk, but optimal management after R1 gastrectomy is controversial. We sought to identify the impact of R1 margins on recurrence patterns and survival in the era of preoperative therapy for gastric cancer. METHODS: Patients who underwent gastrectomy for adenocarcinoma during 1998-2017 at a major cancer center were enrolled. Clinicopathologic factors associated with positive margins were examined, and incidence, sites, and timing of recurrence and survival outcomes were compared between patients with positive and negative margins. RESULTS: Of 688 patients, 432 (63%) received preoperative therapy. Thirty-four patients (5%) had R1 margins. Compared with patients with negative margins, patients with R1 margins more frequently had aggressive clinicopathologic features, such as linitis plastica (odds ratio [OR] 7.79, p < 0.001) and failure to achieve cT downstaging with preoperative treatment (OR 5.20, p = 0.005). The 5 year overall survival (OS) rate was lower in patients with R1 margins (6% vs 60%; p < 0.001), and R1 margins independently predicted worse OS (hazard ratio 2.37, 95% CI 1.51-3.75, p < 0.001). Most patients with R1 margins (58%) experienced peritoneal recurrence, and locoregional recurrence was relatively rare in this group (14%). Median time to recurrence was 8.5 months for peritoneal dissemination and 15.7 months for locoregional recurrence. CONCLUSION: R1 margins after gastrectomy were associated with aggressive tumor biology, high incidence of peritoneal recurrence after a short interval, and poor OS. In patients with R1 margins, re-resection to achieve microscopically negative margins has to be considered with caution.

Neoadjuvant chemotherapy for high-risk intrahepatic cholangiocarcinoma - does pathologic response mean better outcomes?

BACKGROUND: The role of neoadjuvant chemotherapy (NAC) in the management of intrahepatic cholangiocarcinoma (ICC) remains unknown. We sought to evaluate our experience treating high-risk ICC with NAC and to determine the prognostic significance of pathologic response. METHODS: Patients with ICC treated with NAC and surgery were analyzed using a prospectively maintained database. Pathologic response was graded by a blinded pathologist. Clinicopathologic/treatment variables were evaluated for associations with survival. RESULTS: Among 45 patients who received NAC followed by hepatectomy for high-risk ICC, 32(71%) were considered stage III, and 6(13%) were considered stage IV at time of diagnosis. Major response was identified in 39% of cases, including 2 with pathologic complete response. Patients with major response had a longer median NAC duration than patients with minor response (6 vs 4cycles, P=0.02). Regimen (gemcitabine/cisplatin vs gemcitabine/cisplatin/nab-paclitaxel) was not associated with response rate. Median recurrence-free (RFS) and overall survival (OS) were 11 and 45 months. Pathologic response was not associated with improved survival. CONCLUSION: Pathologic response to NAC was not associated with survival in this highly selected cohort. Nonetheless, the extended OS experienced by these high-risk patients is encouraging and suggests that NAC may help select patients who stand to benefit from aggressive resection.

Context matters - Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas.

Genome sequencing has revealed the importance of epigenetic regulators in tumorigenesis. The genes encoding the chromatin remodeling complex DAXX:ATRX are frequently mutated in pancreatic neuroendocrine tumors; however, the underlying mechanisms of how mutations contribute to tumorigenesis are only partially understood, in part because of the lack of relevant preclinical models. Here, we used genetically engineered mouse models combined with environmental stress to evaluate the tumor suppressor functions of Daxx and Atrx in the mouse pancreas. Daxx or Atrx loss, alone or in combination with Men1 loss, did not drive or accelerate pancreatic neuroendocrine tumorigenesis. Moreover, Daxx loss did not cooperate with environmental stresses (ionizing radiation or pancreatitis) or with the loss of other tumor suppressors (Pten or p53) to promote pancreatic neuroendocrine tumorigenesis. However, owing to promiscuity of the Cre promoter used, hepatocellular carcinomas and osteosarcomas were observed in some instances. Overall, our findings suggest that Daxx and Atrx are not robust tumor suppressors in the endocrine pancreas of mice and indicate that the context of a human genome is essential for tumorigenesis. This article has an associated First Person interview with the first author of the paper.

Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial.

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing. Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. Design, Setting, and Participants: This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. Interventions: Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. Main Outcomes and Measures: The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. Results: Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. Conclusions and Relevance: In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies. Trial Registration: ClinicalTrials.gov Identifier: NCT03074513.

Navigating Nodal Metrics for Node-Positive Gastric Cancer in the United States: An NCDB-Based Study and Validation of AJCC Guidelines.

BACKGROUND: The optimal number of examined lymph nodes (ELNs) and the positive lymph node ratio (LNR) for potentially curable gastric cancer are not established. We sought to determine clinical benchmarks for these values using a large national database. METHODS: Demographic, clinicopathologic, and treatment-related data from patients treated using an R0, curative-intent gastrectomy registered in the National Cancer Database during 2004 to 2016 were evaluated. Patients with node-positive (pTxN+M0) disease were considered for analysis. RESULTS: A total of 22,018 patients met the inclusion criteria, with a median follow-up of 2.2 years. Mean age at diagnosis was 65.6 years, 66% were male, 68% were White, 33% of tumors were located near the gastroesophageal junction, and 29% of patients had undergone preoperative therapy. Most primary tumors (62%) were category pT3-4, 67% had a poor or anaplastic grade, and 19% had signet features. Clinical nodal staging was inaccurate compared with staging at final pathology. The mean [SD] number of nodes examined was 19 [11]. On multivariable analysis, the pN category, ELNs, and LNR were independently associated with survival (all P<.0001). Using receiver operating characteristic (ROC) analysis, an optimal ELN threshold of ≥30 was established for patients with pN3b disease and was applied to the entire cohort. Node positivity and LNR had minimal change beyond 30 examined nodes. Stage-specific LNR thresholds calculated by ROC analysis were 11% for pN1, 28% for pN2, 58% for pN3a, 64% for pN3b, 30% for total combined. By using an ELN threshold of ≥30, prognostically advantageous stage-specific LNR values could be determined for 96% of evaluated patients. CONCLUSIONS: Using a large national cancer registry, we determined that an ELN threshold of ≥30 allowed for prognostically advantageous LNRs to be achieved in 96% of patients. Therefore, ≥30 examined nodes should be considered a clinical benchmark for practice in the United States.

Influence of Baseline Positron Emission Tomography in Metastatic Gastroesophageal Cancer on Survival and Response to Therapy.

BACKGROUND: The value of baseline fluorodeoxyglucose-positron emission tomography-computed tomography (PET-CT) remains uncertain once gastroesophageal cancer is metastatic. We hypothesized that assessment of detailed PET-CT parameters (maximum standardized uptake value [SUVmax] and/or total lesion glycolysis [TLG]), and the extent of metastatic burden could aid prediction of probability of response or prognosticate. METHODS: We retrospectively analyzed treatment-naive patients with stage 4 gastroesophageal cancer (December 2002-August 2017) who had initial PET-CT for cancer staging at MD Anderson Cancer Center. SUVmax and TLG were compared with treatment outcomes for the full cohort and subgroups based on metastatic burden (≤2 or >2 metastatic sites). RESULTS: We identified 129 patients with metastatic gastroesophageal cancer who underwent PET-CT before first-line therapy. The median follow-up time was 61 months. The median overall survival (OS) was 18.5 months; the first progression-free survival (PFS) was 5.5 months. SUVmax or TLG of the primary tumor or of all metastases combined had no influence on OS or PFS, whether the number of metastases was ≤2 or >2. Overall response rates (ORRs) to first-line therapy were 48% and 45% for patients with ≤2 and >2 metastases, respectively (nonsignificant). ORR did not differ based on low or high values of SUVmax or TLG. CONCLUSIONS: This is the first assessment of a unique set of PET-CT data and its association with outcomes in metastatic gastroesophageal cancer. In our large cohort of patients, detailed analyses of PET-CT (by SUVmax and/or TLG) did not discriminate any parameters examined. Thus, baseline PET-CT in untreated metastatic gastroesophageal cancer patients has limited or no utility.

Benchmarks for nodal yield and ratio for node-positive gastric cancer.

BACKGROUND: We aimed to elucidate prognostic markers of node-positive gastric cancers with a focus on examined lymph nodes and lymph node ratio. METHODS: Patients treated with curative-intent gastrectomy at The University of Texas MD Anderson Cancer Center from 1995-2019 were evaluated. Patients with non-metastatic, node-positive gastric cancers were considered for analysis. RESULTS: Of 775 patients, 281 met the inclusion criteria. The mean age was 58 years, 61% were male, 51% were White, 65% received preoperative therapy, and 71% of tumors were located in the gastric body. The median overall survival was 3.6 years, and 1-, 5-, and 10-year overall survival rates were 91%, 41%, and 29%, respectively. pN3 category was associated with worse overall survival (hazard ratio 1.79, P = .001) and recurrence-free survival (hazard ratio 1.92, P = .004). Nodal burden was associated with aggressive biologic traits in primary tumors, including higher rates of lymphovascular and perineural invasion and lower preoperative therapy response rates. By receiver-operative characteristic analysis, threshold values of ≥30 examined lymph nodes and <30% lymph node ratio were most discriminant for overall survival. On adjusted analysis, positive margins, additional organ resection, <30 examined lymph nodes, and ≥30% lymph node ratio were associated with worse recurrence-free survival and overall survival. Among patients with high node burden (pN3), <30 examined lymph nodes remained significant on adjusted survival analysis. CONCLUSION: Greater than or equal to 30 examined lymph nodes and <30% lymph node ratio were significantly associated with longer recurrence-free survival and overall survival, independent of lymphadenectomy type. These prognostic benchmarks should be considered in the surgical management of gastric cancer in the United States.

Development and Validation of a Novel Nomogram for Individualized Prediction of Survival in Cancer of Unknown Primary.

PURPOSE: Prognostic uncertainty is a major challenge for cancer of unknown primary (CUP). Current models limit a meaningful patient-provider dialogue. We aimed to establish a nomogram for predicting overall survival (OS) in CUP based on robust clinicopathologic prognostic factors. EXPERIMENTAL DESIGN: We evaluated 521 patients with CUP at MD Anderson Cancer Center (MDACC; Houston, TX; 2012-2016). Baseline variables were analyzed using Cox regression and nomogram developed using significant predictors. Predictive accuracy and discriminatory performance were assessed by calibration curves, concordance probability estimate (CPE ± SE), and concordance statistic (C-index). The model was subjected to bootstrapping and multi-institutional external validations using two independent CUP cohorts: V1 [MDACC (2017), N = 103] and V2 (BC Cancer, Vancouver, Canada and Sarah Cannon Cancer Center/Tennessee Oncology, Nashville, TN; N = 302). RESULTS: Baseline characteristics of entire cohort (N = 926) included: median age (63 years), women (51%), Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 (64%), adenocarcinomas (52%), ≥3 sites of metastases (30%), and median follow-up duration and OS of 40.1 and 14.7 months, respectively. Five independent prognostic factors were identified: gender, ECOG PS, histology, number of metastatic sites, and neutrophil-lymphocyte ratio. The resulting model predicted OS with CPE of 0.69 [SE: ± 0.01; C-index: 0.71 (95% confidence interval: 0.68-0.74)] outperforming Culine/Seve prognostic models (CPE: 0.59 ± 0.01). CPE for external validation cohorts V1 and V2 were 0.67 (± 0.02) and 0.70 (± 0.01), respectively. Calibration curves for 1-year OS showed strong agreement between nomogram prediction and actual observations in all cohorts. CONCLUSIONS: Our user-friendly CUP nomogram integrating commonly available baseline factors provides robust personalized prognostication which can aid clinical decision making and selection/stratification for clinical trials.

Determinants of Survival for Patients with Neoadjuvant-Treated Node-Negative Gastric Cancer.

BACKGROUND: This study sought to determine prognostic markers for disease recurrence and survival in a cohort of neoadjuvant-treated, node-negative gastric cancer patients (ypT0-4N0M0). METHODS: Clinicopathologic data from patients treated with neoadjuvant therapy followed by curative-intent gastrectomy at the University of Texas MD Anderson Cancer Center from 1995 to 2017 were evaluated. Patients with AJCC TNM stage ypT0-4N0M0 were considered for analysis. RESULTS: The inclusion criteria were met by 212 patients with a mean age of 58.3 years. Of these patients, 60 % were male, 53 % were Caucasian, 87 % received chemoradiation, and 13 % received chemotherapy. The findings showed a median overall survival (OS) rate of 11.3 years, a 5-year survival rate of 72 %, and a 10-year survival rate of 57 %. During a median follow-up period of 5.5 years, 38.2 % of the patients died. In the multivariable analysis, ypT4-stage and nodal yield fewer than 16 were significantly associated with reduced OS. Cancer classified as ypT4 had more aggressive biologic traits, including lymphovascular and perineural invasion, and was treated more aggressively with total gastrectomy and additional organ resection despite frequent positive margins. Depth of invasion remained significantly associated with worse outcome after the analysis controlled for nodal yield and possible stage migration. Compared with ypT0-3 tumors, ypT4 cancers were associated with significantly more recurrences (13 % vs. 45 %; p < 0.05), and the primary modes of failure for ypT4 lesions were local recurrence and peritoneal metastases (88 % of recurrences). CONCLUSIONS: Depth of primary tumor invasion and nodal yield were significantly associated with OS among the patients with ypT0-4N0M0 gastric cancer. Serosal invasion (ypT4) was associated with a high rate of peritoneal recurrence, and trials of intraperitoneal therapy targeting these patients should be considered.

Cancer of Unknown Primary Presenting as Bone-Predominant or Lymph Node-Only Disease: A Clinicopathologic Portrait.

BACKGROUND: Cancer of unknown primary (CUP) presenting as bone-predominant (BCUP) or lymph node-only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the "one-treatment-fits-all" approach. MATERIALS AND METHODS: We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non-BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan-Meier method was used to estimate overall survival and compared using log-rank test. RESULTS: In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor-risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor-risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil-to-lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS. CONCLUSION: BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor-risk Culine group and high neutrophil-to-lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long-term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site-directed therapy. IMPLICATIONS FOR PRACTICE: Cancer of unknown primary (CUP) rarely presents as bone-predominant (BCUP) or lymph node-only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor-risk group and neutrophil-to-lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided.

Preoperatively Treated Diffuse-Type Gastric Adenocarcinoma: Glucose vs. Other Energy Sources Substantially Influence Prognosis and Therapy Response.

Diffuse type of gastric adenocarcinoma (dGAC) generally confers a poor prognosis compared to intestinal type. Some dGACs are not avid on fluorine-18 fluoro-2-deoxy-D-glucose PET (FDG-PET) while others seem to consume glucose avidly. We analyzed the outcomes based on the avidity (high with standardized uptake value (SUV) > 3.5 or low with SUV ≤ 3.5) of the primary on baseline FDG-PET. We retrospectively selected 111 localized dGAC patients who had baseline FDG-PET (all were treated with preoperative chemotherapy and chemoradiation). FDG-PET avidity was compared with overall survival (OS) and response to therapy. The mean age was 59.4 years and with many females (47.7%). The high-SUV group (58 (52.3%) patients) and the low-SUV group (53 (47.7%) patients) were equally divided. While the median OS for all patients was 49.5 months (95% CI: 38.5-98.8 months), it was 98.0 months (95% CI: 49.5-NE months) for the low-SUV group and 36.0 months for the high-SUV (p = 0.003). While the median DFS for all patients was 38.2 months (95%CI: 27.7-97.6 months), it was 98.0 (95% CI: 36.9-NE months) months for the low-SUV group was and only 27.0 months (95% CI: 15.2-63.2 months) for the high-SUV group (p = 0.005). Clinical responses before surgery were more common in the low-SUV group but overall we observed only 4 pathologic complete responses in 111 patients. Our unique data suggest that if dGACs used glucose as an energy source then the prognosis was very poor while non-glucose sources improved prognosis. Multi-platform (including metabolomics) profiling of dGACs would yield useful biologic understanding.

Concurrent lymphovascular and perineural invasion after preoperative therapy for gastric adenocarcinoma is associated with decreased survival.

BACKGROUND AND OBJECTIVES: We sought to evaluate the impact of lymphovascular invasion (LVI) and perineural invasion (PNI) on survival outcomes in gastric cancer patients treated with preoperative therapy. METHODS: Patients with gastric cancer treated with preoperative therapy and potentially curative resection were stratified according to the presence of LVI, PNI, or both. Kaplan-Meier and Cox regression analyses were used to evaluate the impact on overall survival (OS) and disease-free survival (DFS). RESULTS: The study included 281 patients, of whom 93 (33%) had LVI, 69 (25%) had PNI, 51 (18%) had both LVI and PNI, and 170 (61%) had neither. LVI and PNI were each associated with higher ypT and ypN categories and more positive lymph nodes (all p < .001), associations that were emphasized with both factors present. On multivariable analyses, ypN (p < .001) and concurrent LVI/PNI (hazard ratio [HR]: 2.62; 95% confidence interval [CI]: 1.55-4.45; p = .001) were predictive of OS and DFS (ypN: p < .001; both LVI/PNI: HR: 2.27; 95% CI: 1.34-3.82; p = .002). CONCLUSIONS: Gastric cancer patients with concurrent LVI and PNI after preoperative therapy have more advanced disease and worse survival outcomes than patients with neither or only one of these factors.

Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma.

Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.

Tumor Regression Grade in Gastric Cancer After Preoperative Therapy.

BACKGROUND: The Cancer Staging Manual, 8th edition, now includes post-neoadjuvant therapy (ypTNM) staging for gastric cancer patients. Our purpose was to determine whether the tumor regression grade (TRG) of the primary tumor is useful for predicting the survival of these patients. METHODS: We performed a retrospective review of an institutional database and identified patients with clinically non-metastatic gastric adenocarcinoma who underwent preoperative chemotherapy or chemoradiation therapy before gastrectomy. Pathology reports were reviewed, and TRG was classified as follows: 0 (complete response), 1 (viable tumor cells ≤ 1-2%), 2 (viable cells ≤ 50%), or 3 (viable cells > 50%). RESULTS: Of the 356 patients identified, including 80 (23%) with a gastroesophageal junction tumor, 268 (75%) had undergone preoperative chemoradiation therapy. Fifty-six (16%) had TRG 0, 57 (16%) TRG 1, 128 (36%) TRG 2, and 115 (32%) TRG 3. No association between TRG and pretreatment factors was identified, except for signet-ring cell histologic type and tumor location. A higher TRG was associated with more advanced ypT and ypN categories (both p < 0.001), ypM1 (p = 0.004), and R1 resection (p = 0.052). The median overall survival (OS) duration was 6.6 years, and the 5-year OS rate was 54.1%. TRG 3 was associated with a shorter OS duration than were other TRG scores (p = 0.015), while the OS did not differ significantly among the TRG 0-2 groups (p = 0.803). On multivariable analysis, TRG was not associated with OS after adjustment for ypN status. CONCLUSION: In gastric cancer patients who underwent preoperative therapy, TRG 3 was associated with advanced ypStage and R1 resection. Patients with TRG 3 had a shorter OS duration because of associated advanced ypStage, particularly ypN+ status.

Genomic profiling of multifocal intrahepatic cholangiocarcinoma reveals intraindividual concordance of genetic alterations.

In multifocal intrahepatic cholangiocarcinoma (IHC), intrahepatic metastases (IM) represent a contraindication to surgical resection, whereas satellite nodules (SN) do not. However, no consensus criteria exist to distinguish IM from SN. The purpose of this study was to determine genetic alterations and clonal relationships in surgically resected multifocal IHC. Next-generation sequencing of 34 spatially separated IHC tumors was performed using a targeted panel of 201 cancer-associated genes. Proposed definitions in the literature were applied of SN located in the same liver segment and ≤2 cm from the primary tumor; and IM located in a different liver segment and/or >2 cm from the primary tumor. Somatic point mutations concordant across tumors from individual patients included BAP1, SMARCA4 and IDH1. Small insertions and deletions (indels) present at the same genome positions among all tumors from individuals included indels in DNA repair genes, CHEK1, ERCC5, ATR and MSH6. Copy number alterations were also similar between all tumors in each patient. In this cohort of multifocal IHC, genomic profiles were concordant across all tumors in each patient, suggesting a common progenitor cell origin, regardless of the location of tumors in the liver. The decision to perform surgery should not be based upon a perceived distinction between IM and SN.

Treatment Patterns for Gastroesophageal Junction Adenocarcinoma in the United States.

Despite the increasing incidence of gastroesophageal junction adenocarcinoma (GEJA), the optimal treatment strategy for the disease remains unknown. The objective of this study was to describe treatment patterns for GEJA in the United States. The National Cancer Database was searched to identify all patients who underwent resection of the lower esophagus, abdominal esophagus, and/or gastric cardia for GEJA between 2006 and 2016. Patients were grouped by clinical disease stage: early localized (L; T1-2N0), locally advanced (LA; T3-4N0), regional (R; T1-2N+), or regionally advanced (RA; T3-4N+). The search identified 28,852 GEJA patients. The dominant age range was 60-69 years (39%). Most patients were men (85%), and most were white (92%). Most L patients (69%) underwent upfront surgery, whereas most LA, R, and RA patients received neoadjuvant therapy (NAT; 86%, 80%, and 90%, respectively). Among patients who received NAT, 85% received chemoradiotherapy. Adjuvant therapy was relatively uncommon across all groups (15-20%). In the LA, R, and RA groups, overall survival was greater in patients who received NAT compared to upfront surgery (p < 0.001). With the exception of patients with early localized node-negative disease, most GEJA patients receive neoadjuvant chemoradiotherapy despite the lack of prospective trials reporting survival benefit over chemotherapy alone.