VirMAP for Cancer: Characterization of the Intratumoral Virome in Virally-Associated Cancers and a Resource for Investigators

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Pancreatic Ductal Adenocarcinoma: Long-Term Survival Does Not Equal Cure

Background: Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology. Methods: Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival. Results: Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins. Conclusion: Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient's prognosis

Does the Mechanism of Lymph Node Invasion Affect Survival in Patients with Pancreatic Ductal Adenocarcinoma?

Background: Lymph node metastases are prognostically significant in pancreatic ductal adenocarcinoma. Little is known about the significance of direct lymph node invasion. Aim: The aim of this study is to find out whether direct lymph node invasion has the same prognostic significance as regional nodal metastases. Methods: Retrospective review of patients resected between 1/1/1993 and 7/31/2008. “Direct” was defined as tumor extension into adjacent nodes, and “regional” was defined as metastases to peripancreatic nodes. Results: Overall, 517 patients underwent pancreatic resection for adenocarcinoma, of whom 89 had one positive node (direct 26, regional 63), and 79 had two positive nodes (direct 6, regional 68, both 5). Overall, survival of node-negative patients was improved compared to patients with positive nodes (N0 30.8 months vs. N1 16.4 months; p < 0.001). There was no survival difference for patients with direct vs. regional lymph node invasion (p = 0.67). Patients with one positive node had a better overall survival compared to patients with ≥2 positive nodes (22.3 and 15 months, respectively; p < 0.001). The lymph node ratio (+LN/total LN) was prognostically significant after Cox regression (p < 0.001). Conclusions: Isolated direct invasion occurs in 20% of patients with one to two positive nodes. Node involvement by metastasis or by direct invasion are equally significant predictors of reduced survival. Both the number of positive nodes and the lymph node ratio are significant prognostic factors

HPV-Related Anal Cancer Is Associated With Changes in the Anorectal Microbiome During Cancer Development

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare gastrointestinal cancer. Factors associated with progression of HPV infection to anal dysplasia and cancer are unclear and screening guidelines and approaches for anal dysplasia are less clear than for cervical dysplasia. One potential contributing factor is the anorectal microbiome. In this study, we aimed to identify differences in anal microbiome composition in the settings of HPV infection, anal dysplasia, and anal cancer in this rare disease. METHODS: Patients were enrolled in two prospective studies. Patients with anal dysplasia were part of a cross-sectional cohort that enrolled women with high-grade lower genital tract dysplasia. Anorectal tumor swabs were prospectively collected from patients with biopsy-confirmed locally advanced SCCA prior to receiving standard-of-care chemoradiotherapy (CRT). Patients with high-grade lower genital tract dysplasia without anal dysplasia were considered high-risk (HR Normal). 16S V4 rRNA Microbiome sequencing was performed for anal swabs. Alpha and Beta Diversity and composition were compared for HR Normal, anal dysplasia, and anal cancer. RESULTS: 60 patients with high-grade lower genital tract dysplasia were initially enrolled. Seven patients had concurrent anal dysplasia and 44 patients were considered HR Normal. Anorectal swabs from 21 patients with localized SCCA were included, sequenced, and analyzed in the study. Analysis of weighted and unweighted UniFrac distances demonstrated significant differences in microbial community composition between anal cancer and HR normal (p CONCLUSION: Although alpha diversity was similar between HR Normal, dysplasia and cancer patients, composition differed significantly between the three groups. Increased anorecta

Tumor-Resident Lactobacillus iners Confer Chemoradiation Resistance Through Lactate-Induced Metabolic Rewiring

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types

Tertiary lymphoid structures with overlapping histopathologic features of cutaneous marginal zone lymphoma during neoadjuvant cemiplimab therapy are associated with antitumor response

The development of immune checkpoint inhibitor (ICI) therapy with anti‐CTLA‐4 and anti‐PD‐1/L1 monoclonal antibodies has led to a paradigm shift in cancer therapy. ICI neoadjuvant therapy followed by surgery has become the standard of care for several advanced‐stage cancers. The pathology associated with ICI therapy is vast and includes neoadjuvant‐associated tissue reactions and activation of tertiary lymphoid structures (TLSs) at the site of the tumor bed and off‐target immune‐related adverse events. TLSs are thought to recapitulate lymph node function and may act as localized immune machinery to mount an antitumor response. B‐cell activation in TLSs during neoadjuvant ICI therapy has been correlated with antitumor response. We report a patient with a history of sarcomatoid squamous cell carcinoma treated with neoadjuvant ICI cemiplimab who developed clonal expansion of B‐cells in the TLSs of the tumor bed. The TLSs morphologically mimicked a cutaneous marginal zone lymphoma with plasmacytic differentiation. Awareness of clonal expansion of B‐cells in TLSs during neoadjuvant ICI therapy is critical to recognize a response to ICI therapy and to avoiding an incorrect diagnosis of low‐grade B‐cell lymphoma

Pancreatic Ductal Adenocarcinoma

Objective: Patients who undergo an R0 resection of their pancreatic ductal adenocarcinoma (PDAC) have an improved survival compared with patients who undergo an R1 resection. It is unclear whether an R1 resection confers a survival benefit over locally advanced (LA) unresectable tumors. Our aim was to compare the survival of patients undergoing an R1 resection with those having LA tumors and to explore the prognostic significance of a 1-mm surgical margin. Methods: Clinicopathologic data from a pancreatic cancer database between January 1993 and July 2008 were reviewed. Locally advanced tumors had no evidence of metastatic disease at exploration. Results: A total of 1705 patients were evaluated for PDAC in the Department of Surgery. Of the 1084 (64%) patients who were surgically explored, 530 (49%) were considered unresectable (286 locally unresectable, 244 with distant metastasis). One hundred fifty-seven (28%) of the resected PDACs had an R1 resection. Patients undergoing an R1 resection had a slightly longer survival compared with those who had locally advanced unresectable cancers (14 vs 11 months; P < 0.001). Patients with R0 resections had a favorable survival compared with those with R1 resections (23 vs 14 months; P < 0.001), but survival after resections with 1-mm margin or less (R0-close) were similar to R1 resections: both groups had a significantly shorter median survival than patients with a margin of greater than 1 mm (R0-wide) (16 vs 14 vs 35 months, respectively; P < 0.001). Conclusions: Patients undergoing an R1 resection still have an improved survival compared with patients with locally advanced unresectable pancreatic adenocarcinoma. R0 resections have an improved survival compared with R1 resections, but this survival benefit is lost when the tumor is within 1 mm of the resection margin