Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling.

BACKGROUND: Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. METHODS: A retrospective review of MUP was performed at a tertiary referral cancer center. RESULTS: Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. CONCLUSION: Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.

Enhanced Recovery after Surgery for Gastric Cancer Patients Improves Clinical Outcomes at a US Cancer Center.

PURPOSE: Enhanced recovery after surgery (ERAS) protocols for gastric cancer patients have shown improved outcomes in Asia. However, data on gastric cancer ERAS (GC-ERAS) programs in the United States are sparse. The purpose of this study was to compare perioperative outcomes before and after implementation of an GC-ERAS protocol at a National Comprehensive Cancer Center in the United States. MATERIALS AND METHODS: We reviewed medical records of patients surgically treated for gastric cancer with curative intent from January 2012 to October 2016 and compared the GC-ERAS group (November 1, 2015-October 1, 2016) with the historical control (HC) group (January 1, 2012-October 31, 2015). Propensity score matching was used to adjust for age, sex, number of comorbidities, body mass index, stage of disease, and distal versus total gastrectomy. RESULTS: Of a total of 95 identified patients, matching analysis resulted in 20 and 40 patients in the GC-ERAS and HC groups, respectively. Lower rates of nasogastric tube (35% vs. 100%, P<0.001) and intraabdominal drain placement (25% vs. 85%, P<0.001), faster advancement of diet (P<0.001), and shorter length of hospital stay (5.5 vs. 7.8 days, P=0.01) were observed in the GC-ERAS group than in the HC group. The GC-ERAS group showed a trend toward increased use of minimally invasive surgery (P=0.06). There were similar complication and 30-day readmission rates between the two groups (P=0.57 and P=0.66, respectively). CONCLUSIONS: The implementation of a GC-ERAS protocol significantly improved perioperative outcomes in a western cancer center. This finding warrants further prospective investigation.

Evolving Role of Hepatic Resection for Metastatic Urologic Malignancies.

Liver resection for noncolorectal, nonneuroendocrine metastases remains controversial. Here, we evaluate a single institutional experience with hepatic resection for metastatic urologic malignancies. A single-institution review of patients who underwent hepatic resection for metastatic urologic tumors between the years of 2000 and 2013 was performed. Patient charts were analyzed for pathologic data and perioperative outcomes including short- and long-term morbidity, mortality, and overall and disease-free survival. Eleven patients were identified who underwent hepatic resection for metastatic urologic malignancy. The mean age was 63.5 years. All patients had an R0 resection. There were three major complications. Mean length of stay was 6.5 days and there was no 90-day mortality. Three patients have died of recurrent disease at an average of 11.2 months from resection to death. The remaining patients are still alive during a mean follow-up of 31.5 months. Five-year overall and disease-free survival was 50 and 21 months, respectively. Hepatic resection for metastatic urologic tumors is safe with low morbidity and mortality and durable long-term survival can be achieved. Liver resection for isolated hepatic disease should be considered for this rare metastatic disease to the liver.

Second Primary Melanoma: Risk Factors, Histopathologic Features, Survival, and Implications for Follow-Up.

The impact on survival of a second primary melanoma (SPM) is unclear. We used our melanoma center's database to examine clinicopathologic risk factors and outcomes of stage 0 to IV cutaneous melanoma in patients with one versus two primaries. Among 12,325 patients with primary melanoma, 969 (7.86%) developed SPM. SPMs were significantly thinner than autologous primary melanomas (P = 0.01), and 451 SPM patients had better overall and melanoma-specific survival than 451 prognostically matched non-SPM patients (P < 0.0001 and 0.0001, respectively) at a median follow-up of 142.37 months. Patients with cutaneous melanoma are at high risk for development of SPM, but the development of SPM does not seem to impair survival.

Accuracy of computed tomography in nodal staging of colon cancer patients.

AIM: To predict node-positive disease in colon cancer using computed tomography (CT). METHODS: American Joint Committee on Cancer stage I-III colon cancer patients who underwent curavtive-intent colectomy between 2007-2010 were identified at a single comprehensive cancer center. All patients had preoperative CT scans with original radiology reports from referring institutions. CT images underwent blinded secondary review by a surgeon and a dedicated abdominal radiologist at our institution to identify pericolonic lymph nodes (LNs). Comparison of outside CT reports to our independent imaging review was performed in order to highlight differences in detection in actual clinical practice. CT reviews were compared with final pathology. Results of the outside radiologist review, secondary radiologist review, and surgeon review were compared with the final pathologic exam to determine sensitivity, specificity, positive and negative predictive values, false positive and negative rates, and accuracy of each review. Exclusion criteria included evidence of metastatic disease on CT, rectal or appendiceal involvement, or absence of accompanying imaging from referring institutions. RESULTS: From 2007 to 2010, 64 stageI-III colon cancer patients met the eligibility criteria of our study. The mean age of the cohort was 68 years, and 26 (41%) patients were male and 38 (59%) patients were female. On final pathology, 26 of 64 (40.6%) patients had node-positive (LN+) disease and 38 of 64 (59.4%) patients had node-negative (LN-) disease. Outside radiologic review demonstrated sensitivity of 54% (14 of 26 patients) and specificity of 66% (25 of 38 patients) in predicting LN+ disease, whereas secondary radiologist review demonstrated 88% (23 of 26) sensitivity and 58% (22 of 38) specificity. On surgeon review, sensitivity was 69% (18 of 26) with 66% specificity (25 of 38). Secondary radiology review demonstrated the highest accuracy (70%) and the lowest false negative rate (12%), compared to the surgeon review at 67% accuracy and 31% false negative rate and the outside radiology review at 61% accuracy and 46% false negative rate. CONCLUSION: CT LN staging of colon cancer has moderate accuracy, with administration of NCT based on CT potentially resulting in overtreatment. Active search for LN+ may improve sensitivity at the cost of specificity.

Beyond the whipple operation: radical resections for cancers of the head of the pancreas.

Pancreatic adenocarcinoma is the most common pancreatic malignancy, and it occurs most commonly in the pancreatic head. It has a relatively low incidence; however it is a deadly disease and is the fourth most common cause of cancer deaths for males and females in the United States. Surgical resection in the form of pancreaticoduodenectomy is the mainstay of treatment and can lead to improved overall survival as well as the possibility of a cure, although only 10 % of patients are resectable at presentation. In an attempt to improve outcomes and survival, surgeons over the decades have employed various aggressive resectional strategies to combat this disease. In this paper we review the development of pancreaticoduodenectomy and touch on the role played by the American surgeon Allan Whipple in this development. We review modern data regarding radical pancreaticoduodenectomy and extended lymphadenectomy for pancreatic head cancers, as well as data and controversies regarding arterial and venous resection performed during the course of pancreaticoduodenectomy. The role of extended and vascular resections in the treatment of pancreatic neuroendocrine tumors in contrast to adenocarcinomas is also examined. We summarize the current state of data regarding radical pancreaticoduodenectomy and discuss pushing the boundaries of surgical resection to help improve outcomes for select groups of patients.

Colorectal liver metastases: making the unresectable resectable using irreversible electroporation for microscopic positive margins - a case report.

BACKGROUND: Irreversible electroporation (IRE) is a non-thermal injury tissue ablation technique that uses electrical pulses to cause cell death. IRE damages the endothelial cells of blood vessels; however these cells re-grow, and thus IRE does not result in permanent damage to blood vessels. We report the novel use of IRE for ablation of microscopically positive margins after resection of colorectal liver metastases (CRLM) impinging on hepatic veins. CASE PRESENTATION: A 68-year-old female was found to have colon cancer and synchronous bilateral unresectable liver metastases. Chemotherapy with FOLFOX and cetuximab was initiated, with subsequent conversion to resectability of the CRLM. The patient underwent colectomy followed by right liver posterior sectionectomy with wedge resection of segment 5. Resection of tumor impinging on the left and middle hepatic veins would have required left hepatectomy, with insufficient remnant liver volume. The CRLM were meticulously dissected off the hepatic veins leaving a microscopically positive margin, and IRE was then used for margin ablation, leaving intact hepatic veins and venous blood flow. The patient is alive and without recurrent disease now 30 months after resection. Herein we review the IRE technology and its use in ablation of liver metastases. CONCLUSIONS: Use of IRE margin ablation for microscopically-positive CRLM resection may lead to long-term patient survival; further prospective randomized trials are needed to confirm this finding.

Techniques for prevention of pancreatic leak after pancreatectomy.

Pancreatic resections are some of the most technically challenging operations performed by surgeons, and post-operative pancreatic fistula (POPF) are not uncommon, developing in approximately 13% of pancreaticoduodenectomies and 30% of distal pancreatectomies. Multiple trials of various operative techniques in the creation of the pancreatic ductal anastomosis have been conducted throughout the years, and herein we review the literature and outcomes data regarding these techniques, although no one technique of pancreatic ductal anastomosis has been shown to be superior in decreasing rate of POPF. Similarly, we review the literature regarding techniques of pancreatic closure after distal pancreatectomy. Again, no one technique has been shown to be superior in preventing POPF; however the use of buttressing material on the pancreatic staple line in the future may be a successful means of decreasing POPF. We review adjunctive techniques to decrease POPF such as pancreatic ductal stenting, the use of various topical biologic glues, and the use of somatostatin analogue medications. We conclude that future trials will need to be conducted to find optimal techniques to decrease POPF, and meticulous attention to intra-operative details and post-operative care by surgeons is necessary to prevent POPF and optimally care for patients undergoing pancreatic resection.

Complete pathologic response of HER2-positive breast cancer liver metastasis with dual anti-HER2 antagonism.

BACKGROUND: Although breast cancer frequently metastasizes to the bones and brain, rarely breast cancer patients may develop isolated liver metastasis. There is increasing data that anti-HER2 targeted therapy in conjunction with systemic chemotherapy may lead to increased rates of pathologic complete response in the primary breast cancer. However, little is known about its effects on metastatic liver disease. CASE PRESENTATION: We report the treatment of a 54-year-old female who was diagnosed with HER2-positive invasive ductal carcinoma and synchronous breast cancer liver metastasis (BCLM). The patient underwent eight cycles of standard docetaxel with two anti-HER2 targeted agents, trastuzumab and pertuzumab. Subsequent radiographic imaging demonstrated complete radiographic response in the primary lesion with an approximate 75% decrease in the liver metastasis. After informed consent the patient underwent modified radical mastectomy that revealed pathologic complete response. Re-staging demonstrated no new disease outside the liver and a left hepatectomy was performed for resection of BCLM. Final pathologic examination revealed no residual malignant cells in the liver specimen, indicating pathologic complete response. Herein, we discuss the anti-HER2 targeted agents trastuzumab and pertuzumab and review the data on dual HER2 antagonism for HER2-positive breast cancer and the role of surgical resection of BCLM. CONCLUSIONS: The role of targeted agents for metastatic HER2-positive breast cancer is under active clinical trial investigation and we await the maturation of trial results and long-term survival data. Our results suggest that these agents may also be effective for producing considerable pathologic response in patients with BCLM.

Incidence of inflammatory breast cancer in women, 1992-2009, United States.

BACKGROUND: The annual incidence of inflammatory breast cancer (IBC) in the United States reportedly increased during the last quarter of the twentieth century. We investigated whether that increase has continued into the twenty-first century. METHODS: We queried the Surveillance Epidemiology and End Results database for all cases of IBC in women age 20 and older between 1992 and 2009. Cases were breast tumors with at least one of the following codes: extent of disease size 998, extension 70, or ICD-3-O morphology 8530 or 8533. Age-adjusted incidence was also examined. RESULTS: During 1992-2009, the annual incidence of IBC did not increase over time in any age group, nor did it vary significantly from year to year, except between 2003 and 2004, when there was a jump from 1.6 (95 % confidence interval 1.4-1.8) to 3.1 (2.8-3.4) cases per 100,000 women. Similar changes occurred in all age and racial groups before gradually returning to prejump levels. Overall, the incidence of IBC rose steeply with age until reaching a plateau at age 65. The incidence was greatest among black women (3.0; 2.8-3.2), intermediate among white women (2.1; 2.1-2.2), and lowest among Asian women (1.4; 1.3-1.6). CONCLUSIONS: The incidence of IBC has remained essentially stable for nearly two decades. A transient jump in 2003-2004 occurred in all age and racial groups, suggesting adjustment to coding changes at that time. Often described as a disease of younger women, IBC in fact disproportionately affects older women. Racial/ethnic variation in the incidence of IBC suggests that dietary, lifestyle, or genetic factors contribute to its pathogenesis.

Synchronous metastatic rectal cancer completely resected after multidisciplinary planning and treatment: a case report.

Colorectal cancer is a common and significant public health concern. The liver is the most common site of metastasis, and colorectal cancer liver metastases (CRLM) may affect up to 60% of patients at some time during the course of their disease. Approximately 25% of patients are found to have synchronous CRLM at the time of diagnosis, and these patients have a worse prognosis than those who develop metastases later in their disease course. In the absence of extrahepatic disease, resection of CRLM with negative margins along with chemotherapy can lead to a 5-year overall survival rate of up to 60%. This report presents the case of a 48-year-old man diagnosed with rectal cancer and synchronous liver metastases that a multidisciplinary tumor board initially deemed to be unresectable because of large size and insufficient future liver remnant. The patient underwent FOLFOX chemotherapy with bevacizumab and experienced conversion to resectable hepatic disease. After neoadjuvant short-course radiation treatment to the rectum, the patient underwent combined low anterior resection of the rectum and a right hepatectomy and was rendered disease-free. The management of the patient's clinical course with correlation to the NCCN Clinical Practice Guidelines in Oncology for Rectal Cancer is presented in this report, including discussion of the role of chemotherapy in the conversion of CRLM to resectable status, the role of surgical metastasectomy, and postoperative surveillance of patients with colorectal cancer.

Targeted therapies in colorectal cancer: surgical considerations.

Colorectal cancer (CRC) is a leading worldwide health concern that is responsible for thousands of deaths each year. The primary source of mortality for patients with CRC is the development and subsequent progression of metastatic disease. The most common site for distant metastatic disease is the liver. Although patients with metastatic disease to the liver have several effective treatment options, the only one for cure remains surgical resection of the liver metastases. Historically, most patients with liver metastases have had unresectable disease, and only a small percentage of patients have undergone complete curative resection. However, improved systemic therapies have led to an evolution in strategies to treat metastatic CRC to the liver. Under most conditions the management of these patients remains complex; and as chemotherapy options and new targeted therapies continue to improve outcomes, it is clear that a multidisciplinary approach must be the foundation on which advanced surgical and medical techniques are employed. Here, in this review, we highlight the role of targeted therapies in the surgical management of patients with metastatic CRC to the liver.

Trends in radiotherapy after breast-conserving surgery in elderly patients with early-stage breast cancer.

BACKGROUND: The benefit of adjuvant radiotherapy (RT) in elderly breast cancer patients is debatable. The purpose of this study was to evaluate trends in RT rates after breast-conserving surgery. METHODS: Breast cancer patients ≥70 years treated from 2000 to 2009 were identified using the Surveillance, Epidemiology, and End Results (SEER) database. Patients were estrogen receptor positive with negative or unknown lymph node status. Trends in RT recommendation over years were evaluated with the Jonckheere-Terpstra test. Multiple logistic regression and Cox proportional hazard tests were used to determine factors associated with radiation recommendation and survival. RESULTS: Of 46,581 patients, 31,989 (68.7 %) were recommended RT and 14,592 (31.3 %) were not. The recommendation for RT decreased from 70.3 % in 2000 to 67.4 % in 2009 (p < 0.0001). Seven of 18 registries exhibited decreased radiation recommendation rates, and 4 of 18 exhibited an increase. Recommendation of RT was associated with earlier year of diagnosis, younger age, Asian/Pacific Islander race, and negative lymph nodes. Predictors of worse survival were no radiation [hazard ratio (HR) 1.68, 95 % confidence interval (CI) 1.61-1.75], no nodes examined (HR 1.83, 95 % CI 1.75-1.91), large (>2-5 cm) tumor size (HR 2.02, 95 % CI 1.86-2.19), older age (80+, HR 2.38, 95 % CI 2.25-2.53), and black race (HR 1.13, 95 % CI1.03-1.23). CONCLUSIONS: Rates of radiation recommendation in the elderly have been steadily decreasing without appreciable acceleration in this decline. This trend was not consistent across all registries. Continued research is necessary to assess differences in clinical practice and its impact on patient outcomes.

Massive intra-abdominal imatinib-resistant gastrointestinal stromal tumor in a 21-year-old male.

Gastrointestinal stromal tumors (GISTs) in adolescence are far less common than adult GISTs and have varied GIST genotypes that present diagnostic and therapeutic challenges. Here, we discuss a 21-year-old male with diagnosis of unresectable, imatinib-resistant GIST. At initial evaluation, a neoadjuvant treatment approach was recommended. As such, the patient received imatinib over the course of one year. Unfortunately, the GIST increased in size, and a subsequent attempt at surgical resection was aborted fearing infiltration of major vascular structures. The patient was then referred to our institution, at which time imatinib therapy was discontinued. Surgical intervention was again considered and the patient underwent successful resection of massive intra-abdominal GIST with total gastrectomy and Roux-en-Y esophagojejunostomy. Since pediatric GISTs are typically resistant to imatinib, we performed genotype analysis of the operative specimen that revealed KIT mutations associated with imatinib sensitivity and resistance. Given the sequencing data and operative findings, the patient was started postoperatively on sunitinib. This case illustrates the importance of understanding both adult and pediatric GISTs when implementing appropriate treatment regimens. Since the genotype of GISTs dictates phenotypic behavior, mutational analysis is an important component of care especially for adolescents whose disease may mirror the pediatric or adult population.

Designing liver resections and pushing the envelope with resections for hepatic colorectal metastases.

Current concepts in the management of hepatic metastases have changed dramatically over the past two decades. Multidisciplinary therapies including chemotherapy, surgery, and regional therapy have alone and in combination significantly improved the survival of patients with metastatic colorectal cancer. Conditions that were previously considered hopeless and treated merely for palliation can now be approached with curative intent. In this paper, we review the surgical treatment for colorectal cancer liver metastasis (CRLM) and describe a paradigm-shift in the management of complex heretofore-considered unresectable CRLM. Utilizing advanced multidisciplinary treatment strategies has improved the prognosis of patients with stage IV colorectal cancer to the point where we may question whether CRLM are now a chronic disease.

Redirected lysis of human melanoma cells by a MCSP/CD3-bispecific BiTE antibody that engages patient-derived T cells.

Melanoma-associated chondroitin sulfate proteoglycan (MCSP; also called HMW-MAA, CSPG4, NG2, MSK16, MCSPG, MEL-CSPG, or gp240) is a well characterized melanoma cell-surface antigen. In this study, a new bispecific T-cell engaging (BiTE) antibody that binds to MCSP and human CD3 (MCSP-BiTE) was tested for its cytotoxic activity against human melanoma cell lines. When unstimulated peripheral mononuclear blood cells (PBMCs) derived from healthy donors were cocultured with melanoma cells at effector:target ratios of 1:1, 1:5, or 1:10, and treated with MCSP-BiTE antibody at doses of 10, 100, or 1000 ng/mL, all MCSP-expressing melanoma cell lines (n=23) were lysed in a dose-dependent and effector:target ratio-dependent manner, whereas there was no cytotoxic activity against MCSP-negative melanoma cell lines (n=2). To investigate whether T cells from melanoma patients could act as effector cells, we cocultured unstimulated PBMCs with allogeneic melanoma cells from 13 patients (4 stage I/II, 3 stage III, and 6 stage IV) or with autologous melanoma cells from 2 patients (stage IV). Although cytotoxic activity varied, all 15 PBMC samples mediated significant redirected lysis by the BiTE antibody. When PBMC or CD8 T cells were prestimulated by anti-CD3 antibody OKT-3 and interleukin-2, the MCSP-BiTE concentrations needed for melanoma cell lysis decreased up to 1000-fold. As MCSP is expressed on most human melanomas, immunotherapy with MCSP/CD3-bispecific antibodies merits clinical investigation.

How important is rigid proctosigmoidoscopy in localizing rectal cancer?

BACKGROUND: Colonoscopic localization of rectal and rectosigmoid tumors may be inaccurate. Rigid proctosigmoidoscopy has been suggested as an adjunctive technique to accurately localize rectal tumors as it may alter treatment options. METHODS: A retrospective review was performed of patients with rectal and rectosigmoid cancer from 2001 to 2006. Patients were stratified into 1 of 4 anatomic regions based on colonoscopic localization of the tumor. The distances of the tumor from the anal verge by colonoscopy were compared with distances obtained via rigid proctosigmoidoscopy. RESULTS: Rigid proctosigmoidoscopy localization likely changed the treatment options in 21% of lower rectal tumors, 14% of middle rectal tumors, 38% of upper rectal tumors, and 29% of rectosigmoid tumors. Overall, this modality impacted 25% of patients. CONCLUSIONS: Rigid proctosigmoidoscopy localization of rectal tumors can significantly change treatment options and should be performed on all patients with colonoscopic localization of a cancer thought to be in the rectosigmoid or rectum.