Immune sensing of microbial metabolites: Action at the tumor.

The microbiome affects establishment and growth of tumors as well as response to immune-based therapies. In this issue of Immunity, Hezaveh et al. (2022) reveal that metabolites of dietary tryptophan generated by the gut microbiota activate the aryl hydrocarbon receptor in myeloid cells, promoting an immune suppressive tumor microenvironment and facilitating pancreatic ductal adenocarcinoma growth.

CD200 is overexpressed in the pancreatic tumor microenvironment and predictive of overall survival.

Pancreatic cancer is an aggressive disease with a 5 year survival rate of 13%. This poor survival is attributed, in part, to limited and ineffective treatments for patients with metastatic disease, highlighting a need to identify molecular drivers of pancreatic cancer to target for more effective treatment. CD200 is a glycoprotein that interacts with the receptor CD200R and elicits an immunosuppressive response. Overexpression of CD200 has been associated with differential outcomes, depending on the tumor type. In the context of pancreatic cancer, we have previously reported that CD200 is expressed in the pancreatic tumor microenvironment (TME), and that targeting CD200 in murine tumor models reduces tumor burden. We hypothesized that CD200 is overexpressed on tumor and stromal populations in the pancreatic TME and that circulating levels of soluble CD200 (sCD200) have prognostic value for overall survival. We discovered that CD200 was overexpressed on immune, stromal, and tumor populations in the pancreatic TME. Particularly, single-cell RNA-sequencing indicated that CD200 was upregulated on inflammatory cancer-associated fibroblasts. Cytometry by time of flight analysis of PBMCs indicated that CD200 was overexpressed on innate immune populations, including monocytes, dendritic cells, and monocytic myeloid-derived suppressor cells. High sCD200 levels in plasma correlated with significantly worse overall and progression-free survival. Additionally, sCD200 correlated with the ratio of circulating matrix metalloproteinase (MMP) 3: tissue inhibitor of metalloproteinase (TIMP) 3 and MMP11/TIMP3. This study highlights the importance of CD200 expression in pancreatic cancer and provides the rationale for designing novel therapeutic strategies that target this protein.

A Comparison of Spatial and Phenotypic Immune Profiles of Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 12.5%. PDAC predominantly arises from non-cystic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). We used multiplex immunofluorescence and computational imaging technology to characterize, map, and compare the immune microenvironments (IMEs) of PDAC and its precursor lesions. We demonstrate that the IME of IPMN was abundantly infiltrated with CD8+ T cells and PD-L1-positive antigen-presenting cells (APCs), whereas the IME of PanIN contained fewer CD8+ T cells and fewer PD-L1-positive APCs but elevated numbers of immunosuppressive regulatory T cells (Tregs). Thus, immunosuppression in IPMN and PanIN seems to be mediated by different mechanisms. While immunosuppression in IPMN is facilitated by PD-L1 expression on APCs, Tregs seem to play a key role in PanIN. Our findings suggest potential immunotherapeutic interventions for high-risk precursor lesions, namely, targeting PD-1/PD-L1 in IPMN and CTLA-4-positive Tregs in PanIN to restore immunosurveillance and prevent progression to cancer. Tregs accumulate with malignant transformation, as observed in PDAC, and to a lesser extent in IPMN-associated PDAC (IAPA). High numbers of Tregs in the microenvironment of PDAC went along with a markedly decreased interaction between CD8+ T cells and cancerous epithelial cells (ECs), highlighting the importance of Tregs as key players in immunosuppression in PDAC. We found evidence that a defect in antigen presentation, further aggravated by PD-L1 expression on APC, may contribute to immunosuppression in IAPA, suggesting a role for PD-L1/PD-1 immune checkpoint inhibitors in the treatment of IAPA.

Multiplex Immunohistochemistry and Immunofluorescence: A Practical Update for Pathologists.

Our understanding of the biology and management of human disease has undergone a remarkable evolution in recent decades. Improved understanding of the roles of complex immune populations in the tumor microenvironment has advanced our knowledge of antitumor immunity, and immunotherapy has radically improved outcomes for many advanced cancers. Digital pathology has unlocked new possibilities for the assessment and discovery of the tumor microenvironment, such as quantitative and spatial image analysis. Despite these advances, tissue-based evaluations for diagnosis and prognosis continue to rely on traditional practices, such as hematoxylin and eosin staining, supplemented by the assessment of single biomarkers largely using chromogenic immunohistochemistry (IHC). Such approaches are poorly suited to complex quantitative analyses and the simultaneous evaluation of multiple biomarkers. Thus, multiplex staining techniques have significant potential to improve diagnostic practice and immuno-oncology research. The different approaches to achieve multiplexed IHC and immunofluorescence are described in this study. Alternatives to multiplex immunofluorescence/IHC include epitope-based tissue mass spectrometry and digital spatial profiling (DSP), which require specialized platforms not available to most clinical laboratories. Virtual multiplexing, which involves digitally coregistering singleplex IHC stains performed on serial sections, is another alternative to multiplex staining. Regardless of the approach, analysis of multiplexed stains sequentially or simultaneously will benefit from standardized protocols and digital pathology workflows. Although this is a complex and rapidly advancing field, multiplex staining is now technically feasible for most clinical laboratories and may soon be leveraged for routine diagnostic use. This review provides an update on the current state of the art for tissue multiplexing, including the capabilities and limitations of different techniques, with an emphasis on potential relevance to clinical diagnostic practice.

Association of Adjuvant Radiotherapy With Survival After Margin-negative Resection of Pancreatic Ductal Adenocarcinoma: A Propensity-matched National Cancer Database (NCDB) Analysis.

INTRODUCTION: There is conflicting evidence for the benefit of adjuvant radiotherapy (RT) after resection of pancreatic ductal adenocarcinoma (PDAC), especially for margin-negative (R0) resections. We aimed to evaluate the association of adjuvant RT with survival after R0 resection of PDAC. METHODS: Using National Cancer Database (NCDB) data from 2004 to 2013, we identified patients with R0 resection of nonmetastatic PDAC. Patients with neoadjuvant radiotherapy and chemotherapy and survival <6 months were excluded. Propensity score matching was used to account for treatment selection bias. A multivariable Cox proportional hazards model was then used to analyze the association of RT with survival. RESULTS: Of 4547 (36%) RT and 7925 (64%) non-RT patients, 3860 RT and 3860 non-RT patients remained in the cohort after matching. Clinicopathologic and demographic variables were well balanced after matching. Lymph node metastases were present in 68% (44% N1, 24% N2). After matching, RT was associated with higher survival (median 25.8 vs 23.9 mo, 5-yr 27% vs 24%, P < 0.001). After multivariable adjustment, RT remained associated with a survival benefit (HR 0.89, 95% CI 0.84-0.94, P < 0.001). Stratified and multivariable interaction analyses showed that this benefit was restricted to patients with node-positive disease: N1 (HR: 0.68, CI95%: 0.62-0.76, P = 0.007) and N2 (HR: 0.59, CI95%: 0.54-0.64, P = 0.04). CONCLUSIONS: In this large retrospective cohort study, adjuvant RT after R0 PDAC resection was associated with a survival benefit in patients with node-positive disease. Adjuvant RT should be considered after R0 resection of PDAC with node-positive disease.

Interleukin 22 Signaling Regulates Acinar Cell Plasticity to Promote Pancreatic Tumor Development in Mice.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that invades surrounding structures and metastasizes rapidly. Although inflammation is associated with tumor formation and progression, little is known about the mechanisms of this connection. We investigate the effects of interleukin (IL) 22 in the development of pancreatic tumors in mice. METHODS: We performed studies with Pdx1-Cre;LSL-KrasG12D;Trp53+/-;Rosa26EYFP/+ (PKCY) mice, which develop pancreatic tumors, and PKCY mice with disruption of IL22 (PKCY Il22-/-mice). Pancreata were collected at different stages of tumor development and analyzed by immunohistochemistry, immunoblotting, real-time polymerase chain reaction, and flow cytometry. Some mice were given cerulean to induce pancreatitis. Pancreatic cancer cell lines (PD2560) were orthotopically injected into C57BL/6 mice or Il22-/-mice, and tumor development was monitored. Pancreatic cells were injected into the tail veins of mice, and lung metastases were quantified. Acini were collected from C57BL/6 mice and resected human pancreata and were cultured. Cell lines and acini cultures were incubated with IL22 and pharmacologic inhibitors, and protein levels were knocked down with small hairpin RNAs. We performed immunohistochemical analyses of 26 PDACs and 5 nonneoplastic pancreas specimens. RESULTS: We observed increased expression of IL22 and the IL22 receptor (IL22R) in the pancreas compared with other tissues in mice; IL22 increased with pancreatitis and tumorigenesis. Flow cytometry indicated that the IL22 was produced primarily by T-helper 22 cells. PKCY Il22-/-mice did not develop precancerous lesions or pancreatic tumors. The addition of IL22 to cultured acinar cells increased their expression of markers of ductal metaplasia; these effects of IL22 were prevented with inhibitors of Janus kinase signaling to signal transducer and activator of transcription (STAT) (ruxolitinib) or mitogen-activated protein kinase kinase (MEK) (trametinib) and with STAT3 knockdown. Pancreatic cells injected into Il22-/- mice formed smaller tumors than those injected into C57BL/6. Incubation of IL22R-expressing PDAC cells with IL22 promoted spheroid formation and invasive activity, resulting in increased expression of stem-associated transcription factors (GATA4, SOX2, SOX17, and NANOG), and increased markers of the epithelial-mesenchymal transition (CDH1, SNAI2, TWIST1, and beta catenin); ruxolitinib blocked these effects. Human PDAC tissues had higher levels of IL22, phosphorylated STAT3, and markers of the epithelial-mesenchymal transition than nonneoplastic tissues. An increased level of STAT3 in IL22R-positive cells was associated with shorter survival times of patients. CONCLUSIONS: We found levels of IL22 to be increased during pancreatitis and pancreatic tumor development and to be required for tumor development and progression in mice. IL22 promotes acinar to ductal metaplasia, stem cell features, and increased expression of markers of the epithelial-mesenchymal transition; inhibitors of STAT3 block these effects. Increased expression of IL22 by PDACs is associated with reduced survival times.

Association of RAS Mutation Location and Oncologic Outcomes After Resection of Colorectal Liver Metastases.

BACKGROUND: RAS mutations are prognostic for patients with metastatic colorectal cancer (mCRC). We investigated clinical, pathologic, and survival differences based on RAS exon for patients with colorectal liver metastases (CRLM). METHODS: This retrospective, single-center study included patients with R0/R1 resection of CRLM from 1992 to 2016. Patients with unresected extrahepatic disease or liver-first resection were excluded. Overall survival (OS) and recurrence-free survival were assessed and stratified by mutation status and location. Fisher's exact test, Wilcoxon rank-sum test, and log-rank test were used, where appropriate. RESULTS: A total of 938 mCRC patients were identified with median age of 57 (range 19-91). Of the 445 patients with KRAS mutations, 407 (91%) had a mutation in exon 2, 14 (3%) exon 3, and 24 (5%) exon 4. Median OS was 71.4 months (95% confidence interval [CI] 66.1-76.5). Patients with KRAS mutations had worse OS compared with KRAS wild-type patients (median 55.5 vs. 91.3 months, p < 0.001). While there was no significant difference in OS based on the exon mutated (p = 0.12), 5-year OS was higher for patients with exon 4 mutations [68.8% (95% CI 0.45-0.84)] compared with those with mutations in exon 2 [45.7% (95% CI 0.40-0.51)] or exon 3 [39.1% (95% CI: 0.11-0.68)]. Patients with NRAS mutant tumors also had worse OS compared with NRAS wild-type patients (median 50.9 vs. 73.3 months, p = 0.03). CONCLUSIONS: NRAS and KRAS exon 3/4 mutations are present in a minority of mCRC patients. Patients with exon 4 mutant tumors may have a more favorable prognosis, although the difference in oncologic outcomes based on mutated exon appears to be smaller than previously reported.

Immunotherapy for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer with an urgent need for better medical therapies. Efforts have been made to investigate the efficacy of immunotherapy, particularly given the hallmarks of immune suppression and exhaustion in PDAC tumors. Here, we review the molecular components responsible for the immune-privileged state in PDAC and provide an overview of the immunotherapeutic strategies for PDAC including vaccine therapy, checkpoint blockade, myeloid-targeted therapy, and immune agonist therapy.

Management of early hepatocellular carcinoma: results of the Delphi consensus process of the Americas Hepato-Pancreato-Biliary Association.

BACKGROUND: There are many potential treatment options for patients with early stage hepatocellular carcinoma (HCC) and practice patterns vary widely. This project aimed to use a Delphi conference to generate consensus regarding the management of small resectable HCC. METHODS: A base case was established with review by members of AHPBA Research Committee. The Delphi panel of experts reviewed the literature and scored clinical case statements to identify areas of agreement and disagreement. Following initial scoring, discussion was undertaken, questions were amended, and scoring was repeated. This cycle was repeated until no further likelihood of reaching consensus existed. RESULTS: The panel achieved agreement or disagreement consensus regarding 27 statements. The overarching themes included that resection, ablation, transplantation, or any locoregional therapy as a bridge to transplant were all appropriate modalities for early or recurrent HCC. For larger lesions, consensus was reached that radiofrequency ablation and microwave ablation were not appropriate treatments. CONCLUSION: Using a validated system for identifying consensus, an expert panel agreed that multiple treatment modalities are appropriate for early stage HCC. These consensus guidelines are intended to help guide physicians through treatment modalities for early HCC; however, clinical decisions should continue to be made on a patient-specific basis.

Mathematical Modeling of the Metastatic Colorectal Cancer Microenvironment Defines the Importance of Cytotoxic Lymphocyte Infiltration and Presence of PD-L1 on Antigen Presenting Cells.

BACKGROUND: Although immune-based therapy has proven efficacious for some patients with microsatellite instability (MSI) colon cancers, a majority of patients receive limited benefit. Conversely, select patients with microsatellite stable (MSS) tumors respond to checkpoint blockade, necessitating novel ways to study the immune tumor microenvironment (TME). We used phenotypic and spatial data from infiltrating immune and tumor cells to model cellular mixing to predict disease specific outcomes in patients with colorectal liver metastases. METHODS: Formalin fixed paraffin embedded metastatic colon cancer tissue from 195 patients were subjected to multiplex immunohistochemistry (mfIHC). After phenotyping, the G-function was calculated for each patient and cell type. Data was correlated with clinical outcomes and survival. RESULTS: High tumor cell to cytotoxic T lymphocyte (TC-CTL) mixing was associated with both a pro-inflammatory and immunosuppressive TME characterized by increased CTL infiltration and PD-L1+ expression, respectively. Presence and engagement of antigen presenting cells (APC) and helper T cells (Th) were associated with greater TC-CTL mixing and improved 5-year disease specific survival compared to patients with a low degree of mixing (42% vs. 16%, p = 0.0275). Comparison of measured mixing to a calculated theoretical random mixing revealed that PD-L1 expression on APCs resulted in an environment where CTLs were non-randomly less associated with TCs, highlighting their biologic significance. CONCLUSION: Evaluation of immune interactions within the TME of metastatic colon cancer using mfIHC in combination with mathematical modeling characterized cellular mixing of TCs and CTLs, providing a novel strategy to better predict clinical outcomes while identifying potential candidates for immune based therapies.

Tracking Macrophage Infiltration in a Mouse Model of Pancreatic Cancer with the Positron Emission Tomography Tracer [11C]PBR28.

BACKGROUND: The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) contains abundant immunosuppressive tumor-associated macrophages. High level of infiltration is associated with poor outcome and is thought to represent a major roadblock to lymphocyte-based immunotherapy. Efforts to block macrophage infiltration have been met with some success, but noninvasive means to track tumor-associated macrophagess in PDAC are lacking. Translocator protein (TSPO) is a mitochondrial membrane receptor which is upregulated in activated macrophages. We sought to identify if a radiotracer-labeled cognate ligand could track macrophages in PDAC. MATERIALS AND METHODS: A murine PDAC cell line was established from a transgenic mouse with pancreas-specific mutations in KRAS and p53. After confirming lack of endogenous TSPO expression, tumors were established in syngeneic mice. A radiolabeled TSPO-specific ligand ([11C] peripheral benzodiazepine receptor [PBR]28) was delivered intravenously, and tumor uptake was assessed by autoradiography, ex vivo, or micro-positron emission tomography imaging. RESULTS: Resected tumors contained abundant macrophages as determined by immunohistochemistry and flow cytometry. Immunoblotting revealed murine macrophages expressed TSPO with increasing concentration on activation and polarization. Autoradiography of resected tumors confirmed [11C]PBR28 uptake, and whole mount sections demonstrated the ability to localize tumors. To confirm the findings were macrophage specific, experiments were repeated in CD11b-deficient mice, and the radiotracer uptake was diminished. Micro-positron emission tomography imaging validated radiotracer uptake and tumor localization in a clinically applicable manner. CONCLUSIONS: As new immunotherapeutics reshape the PDAC microenvironment, tools are needed to better measure and track immune cell subsets. We have demonstrated the potential to measure changes in macrophage infiltration in PDAC using [11C]PBR28.

Critical evaluation of the American Joint Commission on Cancer (AJCC) 8th edition staging system for patients with Hepatocellular Carcinoma (HCC): A Surveillance, Epidemiology, End Results (SEER) analysis.

BACKGROUND: Recently, the American Joint Committee on Cancer (AJCC) released its 8th edition changes to the staging system for hepatocellular cancer (HCC). We sought to validate the 8th edition staging system and compare the performance to the 7th edition using a population-based data set. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database (1998-2013), patients undergoing resection or transplant for non-metastatic HCC were identified. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Concordance indices (c-indices) were calculated from Cox proportional hazards models to evaluate discriminatory power. RESULTS: The study included 8918 patients resected (63%) or transplanted (37%) for HCC. Nodal staging was performed in 19%, of whom 5% had positive nodes. The c-index for the AJCC 8th edition staging system was 0.60, similar to that for the 7th edition (0.59). Survival was better for solitary tumors >2 cm with vascular invasion than for multifocal tumors <5 cm (median not reached vs 57 months, P < 0.0001), although the staging system groups these tumors together as T2. For multifocal tumors ≤5 cm, those with vascular invasion had worse survival than those without (median 42 vs 50 months, P < 0.001), although the staging system draws no such distinction. CONCLUSION: The AJCC 8th edition staging system for HCC performs similarly to the 7th edition. Future revisions should consider substratification of early HCC, specifically by distinguishing solitary tumors >2 cm from multifocal tumors ≤5 cm, and by considering the prognostic impact of vascular invasion in multifocal tumors ≤5 cm. Future studies should aim to validate these findings.

Mutation location on the RAS oncogene affects pathologic features and survival after resection of colorectal liver metastases.

BACKGROUND: In the past 3 decades, a better understanding of gene mutations and their role in carcinogenesis has led to improvement in our ability to treat patients with metastatic disease. The objective of the current study was to determine whether the location of a driver mutation within an affected gene impacts the biology of metastatic colorectal cancer. METHODS: DNA was collected from 165 randomly selected specimens of patients who underwent margin-negative resection of colorectal liver metastases with curative intent. Sequenom analysis and Sanger sequencing were used to evaluate mutations in K/NRAS, PIK3CA, BRAF, and TP53. RESULTS: BRAF mutation was associated with early recurrence and death, whereas no impact of TP53 or PIK3CA mutation was identified. Although K/NRAS mutation was associated with worse survival in this cohort, this difference was no longer evident when those who had received anti-EGFR therapy were excluded. When stratifying patients according to the exon on which K/NRAS was mutated, there were dramatic differences in both survival and pathologic features. Exon 4 mutations were associated with large, solitary metastases occurring at long disease-free intervals compared with exon 3 mutations, which presented with small, numerous lesions. Patients who had exon 4 mutations recurred infrequently and had significantly longer survival compared with those who had wild type or other mutations. CONCLUSIONS: By using this model of curative-intent, margin-negative resection in patients at high risk of recurrence, the authors were able to establish a link between mutation location within the K/NRAS gene and the biology of metastatic colorectal cancer. Cancer 2017;123:568-575. © 2016 American Cancer Society.

Validation of the American Joint Commission on Cancer (AJCC) 8th Edition Staging System for Patients with Pancreatic Adenocarcinoma: A Surveillance, Epidemiology and End Results (SEER) Analysis.

BACKGROUND: The 8th edition of the AJCC staging system for pancreatic cancer incorporated several significant changes. This study sought to evaluate this staging system and assess its strengths and weaknesses relative to the 7th edition AJCC staging system. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) database (2004-2013), 8960 patients undergoing surgical resection for non-metastatic pancreatic adenocarcinoma were identified. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Concordance indices (c-index) were calculated to evaluate the discriminatory power of both staging systems. The Cox proportional hazards model was used to determine the impact of T and N classification on overall survival. RESULTS: The c-index for the AJCC 8th staging system [0.60; 95% confidence interval (CI), 0.59-0.61] was comparable with that for the 7th edition AJCC staging system (0.59; 95% CI, 0.58-0.60). Stratified analyses for each N classification system demonstrated a diminishing impact of T classification on overall survival with increasing nodal involvement. The corresponding c-indices were 0.58 (95% CI, 0.55-0.60) for N0, 0.53 (95% CI, 0.51-0.55) for N1, and 0.53 (95% CI, 0.50-0.56) for N2 classification. CONCLUSION: This is the first large-scale validation of the AJCC 8th edition staging system for pancreatic cancer. The revised system provides discrimination similar to that of the 7th-edition system. However, the 8th-edition system allows for finer stratification of patients with resected tumors according to extent of nodal involvement.

National trends in resection of cystic lesions of the pancreas.

BACKGROUND: Management of cystic lesions of the pancreas (CLP) is controversial. In this study, we sought to evaluate national changes in the resection of CLP over time, to better understand the impact of evolving guidelines on CLP management. METHODS: We used Medicare data to examine CLP resection among patients undergoing pancreatic resection between 2001 and 2012. Patients with a diagnosis of CLP were identified and compared to patients with non-CLP indications. We then examined changes over time in patient and hospital characteristics and outcomes among patients with a CLP diagnosis. RESULTS: We identified 56,419 Medicare patients undergoing pancreatic resection, of which 2129 had a CLP diagnosis. The annual number of CLP resections, and proportion of all resections performed for CLP increased significantly during the period, from 2.1% (65/3072) resections in 2001, to 4.5% (286/6348) in 2012 (p < 0.001). The proportion of CLP resections with a malignant diagnosis did not change (15.5% in 2001-2003 vs. 13.1% in 2010-2012, p = 0.4). Overall rates of 30-day mortality decreased significantly during the period (9.6% in 2001-2003 vs. 5.5% in 2010-2012, p < 0.001). DISCUSSION: CLP resections were performed with increasing frequency in Medicare patients between 2001 and 2012, but this did not correspond to increased diagnosis of malignancy. Additional research is needed to understand the influence of recent guidelines on management of CLP.

Pancreatic Resection Results in a Statewide Surgical Collaborative.

BACKGROUND: A strong relationship between hospital caseload and adverse outcomes has been demonstrated for pancreatic resections. Participation in regional surgical collaboratives may mitigate this phenomenon. This study sought to investigate changes over time in adverse outcomes after pancreatectomy across hospitals with different caseloads in a statewide surgical collaborative. METHODS: The study investigated patients undergoing pancreatic resection from January 2008 to August 2013 at Michigan Surgical Quality Collaborative (MSQC) hospitals (1007 patients in 19 academic and community hospitals). Risk-adjusted rates of major complications, mortality, and failure to rescue were compared between hospitals based on caseloads (low, medium, and high) in early (2008-2010) and later (2011-2013) periods. Finally, the degree to which different complications explained changes in hospital outcome variation was assessed. RESULTS: Adjusted rates of major complications and mortality decreased over time, driven largely by improvements at low-caseload hospitals. In 2008-2010, risk-adjusted major complication rates were higher for low-caseload than for high-caseload hospitals (27.8 vs. 17.8 %; p = 0.02). However, these differences were attenuated in 2011-2013 (22.2 vs. 20.0 %; p = 0.74). Similarly, adjusted mortality rates were higher in low-caseload hospitals in 2008-2010 (6.2 vs. 0.8 %; p = 0.02), but these differences were attenuated in 2011-2013 (3.3 vs. 1.1 %; p = 0.18). Variation in major complications decreased, largely due to decreased variation in "medical" complication rates, with less change in surgical-site complications. CONCLUSION: Participation in regional quality collaboratives by lower-volume hospitals can attenuate the volume-outcome relationship for pancreatic surgery. Continued work in collaboratives with an emphasis on technical and intraoperative aspects of care may improve overall quality of care.

Surgical Referral for Colorectal Liver Metastases: A Population-Based Survey.

BACKGROUND: Surgical resection is underutilized for patients with colorectal liver metastases (CLM). Although the causes of underutilization are poorly understood, provider attitudes towards surgical referral may be contributory. We sought to understand medical oncologists' perspectives on referral for CLM. METHODS: Medical oncologists who treat colorectal cancer in the US state of Michigan were surveyed. We characterized respondents' attitudes regarding clinical and tumor-related contraindications to liver resection for CLM, as well as referral and treatment preferences using case-based scenarios. We then evaluated practice characteristics and treatment preferences between physicians. RESULTS: A total of 112 eligible responses were received (46 % response rate). Nearly 40 % of respondents reported having no liver surgeons in their practice area. Commonly perceived contraindications to liver resection included extrahepatic disease (80.3 %), poor performance status (77.7 %), the presence of >4 metastases (62.5 %), bilobar metastases (43.8 %), and metastasis size >5 cm (40.2 %). Compared with high-referring physicians, low-referring physicians were just as likely to refer a patient with very low recurrence risk (89.3 vs. 98.3 %; p = 0.099), but much less likely to refer a patient with moderate risk (0 vs. 82.8 %; p < 0.001). High-referring physicians were more likely to consider resection for scenarios consistent with higher recurrence risk (31.0 vs. 10.7 %; p = 0.05). CONCLUSIONS: We found wide variation in surgical referral patterns for CLM. Many felt that bilobar disease and tumor size were contraindications to liver-directed therapy despite a lack of supporting data. These findings suggest an urgent need to increase dissemination of evidence and guidance regarding management for CLM, perhaps through increased specialist participation in tumor boards.

International multi-institutional management and outcome of melanoma patients with positive sentinel lymph nodes in more than one nodal basin.

BACKGROUND: Melanoma patients with palpable nodal disease in more than one basin have a worse prognosis than those with single-basin disease. Little is known about the outcome of patients with microscopically positive nodal disease in more than one basin, or how they are currently managed at tertiary referral centers. METHODS: We identified 97 patients with positive sentinel lymph nodes (SLNs) in more than one lymph node basin from 1994 to 2010 from three tertiary care centers. Clinical and pathologic outcome variables were analyzed. RESULTS: Ninety-seven patients (72 men, 25 women) were identified with at least one positive SLN in at least two node basins. Most primary tumors were truncal (68, 70 %) followed by extremity (16, 17 %) and head/neck (13, 13 %). The median Breslow depth was 3.2 mm (range 0.8-12 mm), and 49 (51 %) were ulcerated. The most frequently involved nodal basins were the axilla (112, 57 %), neck (40, 20 %), and groin (24, 12 %). Seventy-seven percent (153 of 198) of all positive SLN basins underwent completion lymph node dissection (CLND). Most patients (54, 56 %) developed recurrent disease, with a median time to recurrence of 20 months. The majority of first recurrences were distant (42, 43 %), followed by regional nonnodal metastases (17, 18 %) and regional nodal metastases (16, 16 %). There was no significant difference in median overall survival between CLND versus no-CLND groups (45 vs. 30 months, respectively). CONCLUSIONS: Most melanoma patients with more than one SLN-positive basin are currently managed with CLND. Outcomes after CLND and no CLND are similarly poor; therefore, consideration of close nodal observation may be more appropriate.

Hepatic resection for colorectal metastases.

The liver represents a common site for metastasis in colorectal cancer. Improvements in patient selection and surgical techniques has resulted in improved outcomes following hepatic metastasectomy with large series reporting 5- and 10-year overall survival rates of 40% and 20%, respectively. In recent years, criteria for resectability has expanded with the use of forced liver hypertrophy and staged resection. The role of perioperative chemotherapy remains controversial with a slight increase in survival and operative morbidity.