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Sarcomas are rare mesenchymal tumors with a propensity for hematogenous metastasis. Gastrointestinal stromal tumor (GIST) is the most common histologic subtype and the most common source of hepatic metastases. In the case of metastatic GIST, neoadjuvant imatinib can be used as a selection tool for the judicious application of surgery, where treatment-responsive patients who undergo resection to prevent the development of treatment-resistant clones have associated 10-year actuarial survival of 40%. Further advances for many of the non-GIST sarcoma subtypes will depend on the development of improved systemic therapies and evaluation of their activity in subtype or molecularly defined trials.

IMPORTANCE: Ampullary adenocarcinoma (AA) is characterized by clinical and genomic heterogeneity. A previously developed genomic classifier defined biologically distinct phenotypes with greater accuracy than standard histologic classification. External validation is needed before routine clinical use. OBJECTIVE: To test external validity of the prognostic value of the hidden genome classifier of AA. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study took place at 6 international academic institutions. Consecutive patients (n = 192) who underwent curative-intent resection of histologically confirmed AA were included. The data were analyzed from January 2005 through July 2020. EXPOSURES: The multilevel meta-feature regression model previously trained on a prospectively sequenced cohort of 3411 patients (1001 pancreatic adenocarcinoma, 165 distal bile duct adenocarcinoma, and 2245 colorectal adenocarcinoma) was applied to AA sequencing data to quantify the relative proportions of parental cell of origin. MAIN OUTCOME AND MEASURES: Genomic classification was correlated with immunohistologic subtype (intestinal [INT] or pancreatobiliary [PB]) and with overall survival (OS), using the log-rank test and Cox proportional hazard models. RESULTS: Among 192 patients with AA (median age, 69.0 [IQR, 60.0-74.0] years and 134 were male [64%]), concordance between immunohistologic and genomic subtypes was 55%. Most INT subtype tumors were categorized into the colorectal genomic subtype (43 of 57 [72.9%]). Of the 114 PB subtype tumors, 29 had a pancreatic genomic profile (25.4%) and 24 had a distal bile duct genomic profile (21.1%). Whereas the standard immunohistologic subtypes were not associated with survival (log rank P = .26), predicted genomic probabilities were correlated with survival probability. Genomic scores with higher colorectal probability were associated with higher survival probability; higher pancreatic and distal bile duct probabilities were associated with lower survival probability. CONCLUSIONS AND RELEVANCE: The AA genomic classifier is reproducible with available molecular testing in a diverse international cohort of patients and improves stratification of the divergent clinical outcomes beyond standard immunohistologic classification. These data provide a molecular classification that may be incorporated into clinical trials for prospective validation.

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Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells—in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1–3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4–8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.

Sarcomas are rare mesenchymal tumors with a propensity for hematogenous metastasis. Gastrointestinal stromal tumor (GIST) is the most common histologic subtype and the most common source of hepatic metastases. In the case of metastatic GIST, neoadjuvant imatinib can be used as a selection tool for the judicious application of surgery, where treatment-responsive patients who undergo resection to prevent the development of treatment-resistant clones have associated 10-year actuarial survival of 40%. Further advances for many of the non-GIST sarcoma subtypes will depend on the development of improved systemic therapies and evaluation of their activity in subtype or molecularly defined trials.

IMPORTANCE: Ampullary adenocarcinoma is a rare malignant neoplasm that arises within the duodenal ampullary complex. The role of adjuvant therapy (AT) in the treatment of ampullary adenocarcinoma has not been clearly defined. OBJECTIVE: To determine if long-term survival after curative-intent resection of ampullary adenocarcinoma may be improved by selection of patients for AT directed by histologic subtype. DESIGN, SETTING, AND PARTICIPANTS: This multinational, retrospective cohort study was conducted at 12 institutions from April 1, 2000, to July 31, 2017, among 357 patients with resected, nonmetastatic ampullary adenocarcinoma receiving surgery alone or AT. Cox proportional hazards regression was used to identify covariates associated with overall survival. The surgery alone and AT cohorts were matched 1:1 by propensity scores based on the likelihood of receiving AT or by survival hazard from Cox modeling. Overall survival was compared with Kaplan-Meier estimates. EXPOSURES: Adjuvant chemotherapy (fluorouracil- or gemcitabine-based) with or without radiotherapy. MAIN OUTCOMES AND MEASURES: Overall survival. RESULTS: A total of 357 patients (156 women and 201 men; median age, 65.8 years [interquartile range, 58-74 years]) underwent curative-intent resection of ampullary adenocarcinoma. Patients with intestinal subtype had a longer median overall survival compared with those with pancreatobiliary subtype (77 vs 54 months; P = .05). Histologic subtype was not associated with AT administration (intestinal, 52.9% [101 of 191]; and pancreatobiliary, 59.5% [78 of 131]; P = .24). Patients with pancreatobiliary histologic subtype most commonly received gemcitabine-based regimens (71.0% [22 of 31]) or combinations of gemcitabine and fluorouracil (12.9% [4 of 31]), whereas treatment of those with intestinal histologic subtype was more varied (fluorouracil, 50.0% [17 of 34]; gemcitabine, 44.1% [15 of 34]; P = .01). In the propensity score–matched cohort, AT was not associated with a survival benefit for either histologic subtype (intestinal: hazard ratio, 1.21; 95% CI, 0.67-2.16; P = .53; pancreatobiliary: hazard ratio, 1.35; 95% CI, 0.66-2.76; P = .41). CONCLUSIONS AND RELEVANCE: Adjuvant therapy was more frequently used in patients with poor prognostic factors but was not associated with demonstrable improvements in survival, regardless of tumor histologic subtype. The value of a multimodality regimen remains poorly defined.

Soft tissue sarcomas (STS) represent a rare and heterogeneous group of tumors. We sought to characterize national trends in referral patterns, treatment strategies, and overall survival (OS) over the course of a decade.

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Understaging is the Achilles heel of liver transplantation for HCC. As might be expected, the authors show that understaging is associated with worse outcomes, but identify AFP as a potentially useful predictor of this higher risk group that could be targeted for interventions. Supplemental digital content is available in the text.

IMPORTANCE: Blood transfusion can be a lifesaving treatment for the surgical patient, yet transfusion-related immunomodulation may underlie the association of allogeneic transfusion with increased perioperative morbidity and possibly poorer long-term oncologic outcomes. OBJECTIVE: To evaluate trends in transfusion rates for major abdominal oncologic resections to assess changes in recent clinical practice (given the accumulating evidence of the deleterious effects of blood transfusion). DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of a population-based registry of all hospitals participating in the American College of Surgeons National Surgical Quality Improvement Project (2005-2013 Participant Use Data Files), which was queried for patients who underwent major resection of a pancreatic, hepatic, or gastric malignant tumor. Data analysis was performed from July to August 2015. MAIN OUTCOME AND MEASURES: The primary outcome was the transfusion of any quantity of packed red blood cells. Transfusion rates were calculated for the perioperative period, which was defined as the time from the start of surgery to 72 hours after surgery. Secondary outcomes included wound infection, myocardial infarction, and renal insufficiency, and the rates of these complications were calculated as well. Trend analysis was performed for each year of data to evaluate for changes over the study period. RESULTS: A total of 19 680 patients (median age, 65.0 years [interquartile range, 57.0-73.0 years]) were identified, of whom 5900 (30.0%) received a blood transfusion (of 13 657 patients who underwent a pancreatic resection, 4074 required transfusion [29.8%]; of 1605 patients who underwent a gastric resection, 378 required transfusion [23.6%]; and of 4418 patients who underwent a hepatic resection, 1448 required transfusion [32.8%]). There was a significant trend toward decreasing rates of transfusion during the study period (z = −7.89, P < .001), which corresponded to an absolute 6.1% decrease in the rate of transfusion of packed red blood cells from 2005 to 2013 (ie, from 32.8% to 26.7%). There was no significant change in the rates of postoperative wound infection or renal insufficiency during this time period, but there was an increased rate of perioperative myocardial infarction during the study period (0.33% absolute increase; z = 3.15, P = .002). CONCLUSIONS AND RELEVANCE: Over 9 years of contemporary practice, a trend of less perioperative blood transfusions for oncologic abdominal surgery was observed. Further studies are needed to assess whether these trends reflect changes in operative techniques, hospital cohorts, or transfusion thresholds.

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