Rate of Peritoneal Carcinomatosis in Resected Stage II and III Colon Cancer.

INTRODUCTION: Incidence of peritoneal carcinomatosis (PC) after curative resection of stage II and III colon cancer varies widely. Although certain features are considered high risk for PC, the impact of these features on PC incidence is unclear. METHODS: A retrospective analysis was performed on patients ≥ 18 years old with resected stage II and III colonic adenocarcinoma treated at two academic institutions from 2007 to 2018. Clinicopathologic features, treatment and outcomes data were recorded. Patients with reported high-risk features (pT3N0-2 with mucinous/signet ring components, pT4, pN1c, perforation) were identified. The remaining stage II and III patients were used for comparison. RESULTS: Of 219 eligible patients, 93/219 (42.5%) were stage II and 126/219 (57.5%) were stage III. Median follow-up time was 25 (1-146) months. Adjuvant systemic treatment was administered to 133/219 (60.7%) patients. Overall incidence of PC was 14/219 (6.4%) and the median time to PC was 18 (1-37) months. The high-risk and comparison groups contained 113 and 106 patients, respectively. Incidence of PC was significantly different between groups (high-risk 9.7% vs comparison 2.8%, p = 0.04). Median time to PC was not significantly different between the groups [high-risk 17 (1-37) months vs comparison 20 (7-36) months, p = 0.88]. CONCLUSION: Overall PC incidence in patients with resected stage II and III colon cancer was 6.4%. Although the high-risk group developed PC at a significantly higher rate, the rate of PC in this group was still below 10%. The results of this study represent real-world rates of PC and should be taken into account when designing future studies.

Peritoneal carcinomatosis in gastric cancer: Are Hispanics at higher risk?

BACKGROUND: A recent study from our group identified Hispanic race/ethnicity as an independent predictor of peritoneal carcinomatosis (PC) in gastric cancer. We sought to identify the tumor factors that might contribute to this strong association in Hispanics. METHODS: California Cancer Registry data were used to identify patients diagnosed with gastric adenocarcinoma from 2004 to 2014. Logistic regression analyses were performed to determine odds ratios for cancer stage, tumor location, grade, histology, and PC. RESULTS: Of 16,275 patients with gastric adenocarcinoma who met inclusion criteria, 6463 (39.7%) were non-Hispanic White (NHW), 4953 (30.4%) were Hispanic, 1020 (6.3%) were non-Hispanic Black (NHB), and 3915 (23.6%) were Asian/other. Compared to NHW, Hispanics were more likely to have a poorly differentiated grade (65.9% vs. 57.6%; p < .001), signet ring adenocarcinoma (28.1% vs. 17.6%; p < .001) and stage IV (51.9% vs. 45.0%; p < .001) gastric cancer. The proportion of stage IV patients with PC was also significantly higher in Hispanics compared to NHW, NHB, and Asian/other (28.5% vs. 16.6%, 20.5%, and 25.2%, respectively; p < .001). CONCLUSIONS: Hispanic ethnicity is an independent predictor of aggressive tumor phenotype and PC. Disproportionate incidence of signet ring adenocarcinoma and PC highlight the need to explore the genomic differences in Hispanic gastric cancer.

Adjuvant intraperitoneal chemotherapy for the treatment of colorectal cancer at risk for peritoneal carcinomatosis: a systematic review.

BACKGROUND: The peritoneal surface is the second most common site of disease recurrence, after the liver, following definitive surgery for colorectal cancer. Adjuvant intraperitoneal (IP) chemotherapy delivered at time of surgical resection has the potential to delay or prevent future spread to the peritoneal surface and improve clinical outcome. The exact role of adjuvant IP chemotherapy in colorectal cancer, including its associated morbidity and mortality, is not well defined. STUDY DESIGN: Systematic review and pooled random effect analysis of comparative trials examining the addition of adjuvant IP chemotherapy compared to surgery alone in colorectal cancer. The primary outcome was overall survival, and the secondary outcomes were of post-operative morbidity and mortality. RESULTS: In nine colorectal cancer studies identified, seven were two-arm trials comparing adjuvant IP chemotherapy to surgery alone. Of these, four trials had outcome reporting and met criteria that allowed inclusion into a random effects model. Heterogeneity was measured by Cochran's Q-test (Q = 13.9; p = 0.01) and random effect models were utilised. Pooling eligible trials together revealed a 0.55 odds ratio of death associated with the administration of IP chemotherapy compared to surgery alone (CI = 0.31, 0.98; p = 0.04). Trials selecting patients at elevated risk for the development of peritoneal carcinomatosis by clinicopathological biomarkers for administration of adjuvant IP chemotherapy reported more favourable overall outcomes. There was no increase in mortalities or IP chemotherapy-related abdominal complication rates among patients undergoing IP chemotherapy (OR = 1.4; CI = 0.52, 3.8; p = 0.5). CONCLUSIONS: This systematic review supports the use of adjuvant IP chemotherapy in resectable colorectal cancer at risk for peritoneal spread. Future trials should seek to standardise inclusion criteria and IP chemotherapy modalities to better define the role of this treatment in patients with resectable colorectal cancer.

Adjuvant intraperitoneal chemotherapy for the treatment of gastric cancer at risk for peritoneal carcinomatosis: A systematic review.

The peritoneal surface is a frequent site of recurrence following surgery for gastric cancer. A systematic review and random effect analysis was undertaken to analyze current literature regarding the role of adjuvant intraperitoneal chemotherapy in gastric cancer. While pooled analysis supports the use of adjuvant IP chemotherapy in resectable gastric cancer, maximal benefit occured with intra-operative delivery, and possibly the use of MMC. J. Surg. Oncol. 2017;115:192-201. © 2016 Wiley Periodicals, Inc.

Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results.

Adoptive cell transfer (ACT) with neoantigen-reactive T lymphocytes can mediate cancer regression. Here we isolated unique, personalized, neoantigen-reactive T cell receptors (TCRs) from tumor-infiltrating lymphocytes of patients with metastatic gastrointestinal cancers and incorporated the TCR α and ß chains into gamma retroviral vectors. We transduced autologous peripheral blood lymphocytes and adoptively transferred these cells into patients after lymphodepleting chemotherapy. In a phase 2 single-arm study, we treated seven patients with metastatic, mismatch repair-proficient colorectal cancers who had progressive disease following multiple previous therapies. The primary end point of the study was the objective response rate as measured using RECIST 1.1, and the secondary end points were safety and tolerability. There was no prespecified interim analysis defined in this study. Three patients had objective clinical responses by RECIST criteria including regressions of metastases to the liver, lungs and lymph nodes lasting 4 to 7 months. All patients received T cell populations containing ≥50% TCR-transduced cells, and all T cell populations were polyfunctional in that they secreted IFNγ, GM-CSF, IL-2 and granzyme B specifically in response to mutant peptides compared with wild-type counterparts. TCR-transduced cells were detected in the peripheral blood of five patients, including the three responders, at levels ≥10% of CD3+ cells 1 month post-ACT. In one patient who responded to therapy, ~20% of CD3+ peripheral blood lymphocytes expressed transduced TCRs more than 2 years after treatment. This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and can mediate tumor regression in patients with metastatic colorectal cancers. ClinicalTrials.gov registration: NCT03412877 .

Middle Colic Artery Originating from the Gastroduodenal Artery Discovered during a Whipple.

Hepatic artery variations occur in about one-fourth of the population, are frequent questions on standardized surgery exams, and are often discussed on teaching rounds with an attending surgeon. Intraoperatively, it is important to be aware of possible vascular anomalies in order to prevent ligation or injury of an essential vessel. This case report describes an extremely rare vascular anomaly encountered during a pancreaticoduodenectomy (Whipple operation). Our patient was a middle-aged woman who was incidentally diagnosed with a cystic pancreatic lesion. During the operation, an aberrant middle colic artery was found to be originating from the gastroduodenal artery instead of its usual origin at the superior mesenteric artery. This anomalous middle colic artery has not been previously reported in a live patient. It underscores the importance of being aware of possible vascular variations that may be encountered intraoperatively in order to prevent morbidity and mortality.

Port site metastases after minimally invasive resection for colorectal cancer: A retrospective study of 13 patients.

BACKGROUND: Minimally invasive surgeries are increasingly being performed for primary colon cancer resections since laparoscopic and robotic surgeries have less post-operative pain, shorter length of hospitalization, less morbidity, improved patient satisfaction and equivalent R0 resection rates compared to laparotomy. METHODS: To analyze characteristics of patients who developed port site metastases after minimally invasive colectomy, a retrospective case series of a single institution from 2004 to 2017 was performed. The study included patients who had a minimally invasive resection of the primary colon cancer and subsequent cytoreduction and heated intraperitoneal chemotherapy (CRS/HIPEC) for peritoneal metastases. Patient characteristics, histology, pathology, prior treatments, time between surgeries, carcinoembryonic antigen (CEA) levels and survival were reviewed. RESULTS: There were 123 patients who had CRS/HIPEC and 13 of them had a history of laparoscopic or robotic colectomy followed by the development of port site disease. Four were females, nine were males. Median age was 48 years (range, 19-64). Eleven of 13 primary colon cancers were T3 or T4. Ten of 13 patients had no clinical evidence of peritoneal metastases at the time of initial resection. All 13 patients had metastatic deposits at port sites that were confirmed histopathologically at the time of CRS/HIPEC. CONCLUSIONS: Port site metastases were present concomitantly with peritoneal metastases in 13 patients. An advanced T-stage of disease occurred in 85% of patients. Port site metastases do occur after minimally invasive colon resection.

Response to Neoadjuvant Treatment Is Influenced by Grade in Gastric Cancer.

Neoadjuvant therapy is commonly used in the management of gastric cancer. Primary tumor response to treatment correlates with prognosis. Published studies have compared efficacy of neoadjuvant therapy based on stage but not grade. The objective of this study was to determine the change in staging of gastric cancer after neoadjuvant therapy and resection based on grade. A retrospective analysis of gastric cancer patients treated at our institution between 2005 and 2017 was performed. Patient demographics, tumor characteristics, clinical and pathological stage, and microscopic treatment response were analyzed based on grade. Of the 269 patients identified during this period, 82 patients underwent definitive surgical resection, of which 38 patients received neoadjuvant therapy (low grade (grades 1 and 2), n = 17; high grade (grade 3), n = 18; and unknown grade, n = 3). Pathologic downstaging was observed in 52.9 per cent (9/17) of low-grade tumors compared with 22.2 per cent (4/18) of high-grade tumors. Majority of high-grade tumors (77.8%, 14/18) had either upstaging or unchanged stage. High-grade gastric cancers often lack response to neoadjuvant therapy. Novel targeted therapies based on biologic behavior should be evaluated and incorporated into neoadjuvant treatment. Neoadjuvant studies should stratify patients based on grade and report response by grade.

T-Cell Receptor Gene Therapy for Human Papillomavirus-Associated Epithelial Cancers: A First-in-Human, Phase I/II Study.

PURPOSE: Genetically engineered T-cell therapy is an emerging treatment of hematologic cancers with potential utility in epithelial cancers. We investigated T-cell therapy for the treatment of metastatic human papillomavirus (HPV)-associated epithelial cancers. METHODS: This phase I/II, single-center trial enrolled patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy. Treatment consisted of autologous genetically engineered T cells expressing a T-cell receptor directed against HPV16 E6 (E6 T-cell receptor T cells), a conditioning regimen, and systemic aldesleukin. RESULTS: Twelve patients were treated in the study. No dose-limiting toxicities were observed in the phase I portion. Two patients, both in the highest-dose cohort, experienced objective tumor responses. A patient with three lung metastases experienced complete regression of one tumor and partial regression of two tumors, which were subsequently resected; she has no evidence of disease 3 years after treatment. All patients demonstrated high levels of peripheral blood engraftment with E6 T-cell receptor T cells 1 month after treatment (median, 30%; range, 4% to 53%). One patient's resistant tumor demonstrated a frameshift deletion in interferon gamma receptor 1, which mediates response to interferon gamma, an essential molecule for T-cell-mediated antitumor activity. Another patient's resistant tumor demonstrated loss of HLA-A*02:01, the antigen presentation molecule required for this therapy. A tumor from a patient who responded to treatment did not demonstrate genetic defects in interferon gamma response or antigen presentation. CONCLUSION: Engineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed death-1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers.

A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus-associated Epithelial Cancers.

PURPOSE: Cellular therapy is an emerging cancer treatment modality, but its application to epithelial cancers has been limited. This clinical trial evaluated tumor-infiltrating lymphocyte (TIL) therapy for the treatment of patients with metastatic human papillomavirus (HPV)-associated carcinomas. PATIENTS AND METHODS: The trial was a phase II design with two cohorts, cervical cancers and noncervical cancers. Cell infusion was preceded by a lymphocyte-depleting conditioning regimen and followed by systemic high-dose aldesleukin. RESULTS: Objective tumor responses occurred in 5 of 18 (28%) patients in the cervical cancer cohort and 2 of 11 (18%) patients in the noncervical cancer cohort. Two of the responses in cervical cancer were complete and are ongoing 67 and 53 months after treatment. Responses in the noncervical cancer cohort were in anal cancer and oropharyngeal cancer. The HPV reactivity of the infused T cells correlated with clinical response. Peripheral blood repopulation with HPV-reactive T cells also correlated with clinical response. CONCLUSIONS: These findings support the concept that cellular therapy can mediate the regression of epithelial cancers, and they suggest the importance of predictive biomarkers and novel treatment platforms for more effective therapies.

Human Papillomavirus T-Cell Cross-reactivity in Cervical Cancer: Implications for Immunotherapy Clinical Trial Design.

Importance: Clinical trials are testing vaccines that target human papillomavirus 16 (HPV-16) oncoproteins for the treatment of cervical cancer regardless of the HPV type of the tumor. For patients with HPV-18-positive cancers, this strategy relies on cross-reactivity of HPV-16-reactive T cells against the HPV-18 oncoproteins. Objectives: To determine the prevalence of HPV-16 and HPV-18 metastatic cervical cancers in women enrolling in clinical trials at a US medical center and to assess whether HPV oncoprotein-targeting tumor-infiltrating lymphocytes (TILs) and T-cell receptors (TCRs) possess HPV-16/HPV-18 oncoprotein cross-reactivity. Design, Setting, and Participants: This study was conducted at the National Institutes of Health Clinical Center, a tertiary care research hospital in the United States. The HPV type of the tumors from 65 consecutive patients with cervical cancer who were evaluated for participation in clinical trials was determined by retrospective medical record review. Immunological assays testing HPV cross-reactivity were conducted on all available archived samples of oncoprotein-reactive TILs from HPV-positive tumors (n = 16) and on a library of previously identified TCRs (n = 10). Interventions: The HPV genotype of each patient's tumor was determined. The cross-reactivity of archived TILs and a library of TCRs was assessed. Main Outcomes and Measures: The main outcomes were the prevalence of each HPV genotype and the frequency of TILs or TCRs with HPV oncoprotein-T-cell cross-reactivity. Cross-reactivity was assessed by enzyme-linked immunospot assays and interferon-γ production assays. Results: The median (range) age of 65 referred patients was 44 (24-64) years. Ethnicity was recorded for 39 of 65 patients; 35 (89.7%) were white, 3 (7.7%) were Asian, and 1 (2.6%) was American Indian/Alaskan Native. Histologic tumor subtype was recorded for 41 of 65 patients; 25 (61.0%) were squamous cell carcinomas, 12 (29.3%) were adenocarcinomas, 2 (4.9%) were adenosquamous cell carcinomas, and 2 (4.9%) were neuroendocrine tumors. Thirty-nine of 65 patients (60.0%) had HPV-16-positive tumors and 21 patients (32.3%) had HPV-18-positive tumors. In the analysis of cross-reactivity, 1 of 16 oncoprotein-reactive archived TILs (9 from cervical cancers and 7 from other cancers) displayed HPV-16/HPV-18 cross-reactivity. None of the 10 oncoprotein-reactive TCRs displayed HPV-16/HPV-18 cross-reactivity. Conclusions and Relevance: Cervical cancers that tested positive for HPV-18 were common in this study and may be common in other US clinical trial populations. Results showed that HPV-16/HPV-18 intergenotype T-cell cross-reactivity of T cells from HPV-16-positive and HPV-18-positive cancers was uncommon. These findings support clinical trial designs in which the HPV type targeted by a therapeutic vaccine is matched with the HPV type of a cancer and suggest a change is necessary in the design of active clinical trials.

A Pilot Trial of the Combination of Vemurafenib with Adoptive Cell Therapy in Patients with Metastatic Melanoma.

PURPOSE: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAFV600 mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. EXPERIMENTAL DESIGN: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration. Vemurafenib was restarted at the time of TIL infusion and was continued for 2 years or until disease progression. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Metastases resected prior to and after 2 weeks of vemurafenib were compared using TCRB deep sequencing, immunohistochemistry, proliferation, and recognition of autologous tumor. RESULTS: The treatment was well tolerated and had a safety profile similar to that of TIL or vemurafenib alone. Seven of 11 patients (64%) experienced an objective clinical response, and 2 patients (18%) had a complete response for 3 years (one response is ongoing at 46 months). Proliferation and viability of infusion bag TILs and peripheral blood T cells were inhibited in vitro by research-grade vemurafenib (PLX4032) when approaching the maximum serum concentration of vemurafenib. TCRB repertoire (clonotypes numbers, clonality, and frequency) did not significantly change between pre- and post-vemurafenib lesions. Recognition of autologous tumor by T cells was similar between TILs grown from pre- and post-vemurafenib metastases. CONCLUSIONS: Coadministration of vemurafenib and TILs was safe and feasible and generated objective clinical responses in this small pilot clinical trial. Clin Cancer Res; 23(2); 351-62. ©2016 AACRSee related commentary by Cogdill et al., p. 327.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer and other less common disease histologies: is it time?

Gastric cancer is the fourth most commonly diagnosed cancer worldwide, and once spread to the peritoneum, has a 5-year survival of less than 5%. Recent years have demonstrated advances in the use of cytoreductive surgery (CRS) in combination with heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis due to various malignancies. The frequent desmoplastic stroma and poor vascularization impeding drug delivery particularly in the diffuse form of gastric cancer is thought to provide a sound rationale for a regionalized treatment approach in this disease. Here, we seek to review the available data to define the role of CRS and HIPEC in gastric cancer metastatic to the peritoneal surface, and furthermore, analyze the use of CRS and HIPEC in malignancies less commonly treated with the regionalized perfusion approach.

Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients With Metastatic Melanoma.

PURPOSE: Adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, can mediate objective tumor regression in a majority of patients with metastatic melanoma (52 of 93; 56%). Addition and intensification of total body irradiation (TBI) to the preparative lymphodepleting chemotherapy regimen in sequential trials improved objective partial and complete response (CR) rates. Here, we evaluated the importance of adding TBI to the adoptive transfer of tumor-infiltrating lymphocytes (TIL) in a randomized fashion. PATIENTS AND METHODS: A total of 101 patients with metastatic melanoma, including 76 patients with M1c disease, were randomly assigned to receive nonmyeloablative chemotherapy with or without 1,200 cGy TBI before transfer of tumor-infiltrating lymphcytes. Primary end points were CR rate (as defined by Response Evaluation Criteria in Solid Tumors v1.0) and overall survival (OS). Clinical and laboratory data were analyzed for correlates of response. RESULTS: CR rates were 24% in both groups (12 of 50 v 12 of 51), and OS was also similar (median OS, 38.2 v 36.6 months; hazard ratio, 1.11; 95% CI, 0.65 to 1.91; P = .71). Thrombotic microangiopathy was an adverse event unique to the TBI arm and occurred in 13 of 48 treated patients. With a median potential follow-up of 40.9 months, only one of 24 patients who achieved a CR recurred. CONCLUSION: Adoptive cell transfer can mediate durable complete regressions in 24% of patients with metastatic melanoma, with median survival > 3 years. Results were similar using chemotherapy preparative regimens with or without addition of TBI.

Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6.

PURPOSE: The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in principle ideal immunotherapeutic targets, but evidence that T cells specific for these antigens can recognize and kill HPV(+) tumor cells is limited. We sought to determine whether TCR gene engineered T cells directed against an HPV oncoprotein can successfully target HPV(+) tumor cells. EXPERIMENTAL DESIGN: T-cell responses against the HPV-16 oncoproteins were investigated in a patient with an ongoing 22-month disease-free interval after her second resection of distant metastatic anal cancer. T cells genetically engineered to express an oncoprotein-specific TCR from this patient's tumor-infiltrating T cells were tested for specific reactivity against HPV(+) epithelial tumor cells. RESULTS: We identified, from an excised metastatic anal cancer tumor, T cells that recognized an HLA-A*02:01-restricted epitope of HPV-16 E6. The frequency of the dominant T-cell clonotype from these cells was approximately 400-fold greater in the patient's tumor than in her peripheral blood. T cells genetically engineered to express the TCR from this clonotype displayed high avidity for an HLA-A*02:01-restricted epitope of HPV-16, and they showed specific recognition and killing of HPV-16(+) cervical, and head and neck cancer cell lines. CONCLUSIONS: These findings demonstrate that HPV-16(+) tumors can be targeted by E6-specific TCR gene engineered T cells, and they provide the foundation for a novel cellular therapy directed against HPV-16(+) malignancies, including cervical, oropharyngeal, anal, vulvar, vaginal, and penile cancers.

Adoptive T-cell transfer therapy and oncogene-targeted therapy for melanoma: the search for synergy.

The clinical strengths of immunotherapy and small-molecule inhibitors targeting the mitogen-activated protein kinase (MAPK) pathway appear to be largely complementary for the treatment of advanced melanoma. In current practice, most patients with BRAF V600 mutant melanomas will see both modalities. Several in vitro and in vivo studies suggest that combining immunotherapy with MAPK inhibition may have synergistic effects. First, mouse models show that adoptive cell therapy (ACT) can be enhanced by vaccination. Rapid tumor destruction by vemurafenib could provide a vaccine-like stimulus to adoptively transferred T cells. Second, both in mice and in early clinical trials, melanoma metastases treated with MAPK inhibitors seem to display increased T-cell infiltrates. Third, MAPK inhibition upregulates the expression of some melanoma antigens and, therefore, may enhance T-cell recognition of vemurafenib-treated melanomas. Fourth, vemurafenib may sensitize tumor cells to immune destruction. Finally, some investigators have found that an optimal antitumor effect from MAPK inhibition is dependent on an intact host immune response. Currently, the Surgery Branch of the National Cancer Institute has initiated a phase II trial combining the BRAF inhibitor vemurafenib with ACT using tumor-infiltrating lymphocytes in patients with BRAF-mutant tumors to investigate the safety and efficacy of this combination. The proposed mechanisms for synergy between these two modalities can be complex, and their optimal combination may require testing a variety of sequences and schedules.