Intraoperative frozen section analysis of margin status as a quality indicator in gastric cancer surgery.

INTRODUCTION: Positive pathologic margins following gastric cancer (GC) resection carries a poor prognosis. We evaluated intraoperative frozen section (IFS) analysis of resection margins (RMs) as a quality indicator in GC surgery. METHODS: Patients referred to a provincial cancer agency with surgically resected non-metastatic GC between 2004 and 2012 were included. Associations between IFS analysis, other baseline characteristics, RMs, and overall survival (OS) were assessed using logistic regression, Kaplan-Meier analyses, and Cox proportional hazards modeling. RESULTS: Among 377 patients, median age was 67 years, 68% were male, and 16% had +RMs. Thirty-four percent of patients underwent IFS analysis, which protected against +RMs (odds ratio [OR]: 0.34, 95% confidence interval [CI]: 0.16-0.73, p = 0.006) and improved OS (hazards ratio [HR]: 0.72, 95% CI: 0.54-0.98, p = 0.037). OS following re-resection of IFS positive patients was similar to IFS negative patients (69 vs. 54 months, p = 0.317). Stage III disease (OR: 12.8, 95% CI: 3.00-55.0, p = 0.001) and gastroesophageal junction tumors (OR: 2.25, 95% CI: 1.05-4.78, p = 0.036) predicted +RMs. Stage III disease led to worse OS (HR: 2.89, 95% CI: 1.92-4.34, p < 0.001) while intestinal histology improved OS (HR: 0.67, 95% CI: 0.50-0.90, p = 0.007). CONCLUSIONS: IFS analysis reduce +RMs and improve OS and should be incorporated in curative intent GC surgery for patients with locally advanced GC.

Outcomes of Surgical and Chemotherapeutic Treatments of Goblet Cell Carcinoid Tumors of the Appendix.

BACKGROUND: Goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. We examined prognostic clinical and treatment factors in a population-based cohort. METHODS: Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive. RESULTS: Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25-91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I-III patients, and measuring 16.2 months [95% confidence interval (CI) 9.1-29] for stage IV patients. In 67 stage I-III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis, p = 0.02; 45% Tang B vs. 89% Tang A, p < 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4-20.9; p = 0.015). CONCLUSIONS: In this population-based cohort, we demonstrate excellent survival outcomes in stage I-III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.

Prognostic Factors for Locoregional Recurrence in Neuroendocrine Tumors of the Rectum.

BACKGROUND: Optimal management of rectal neuroendocrine tumors is not yet well defined. Various pathologic factors, particularly tumor size, have been proposed as prognostic markers. OBJECTIVE: We characterized sequential patients diagnosed with rectal neuroendocrine tumors in a population-based setting to determine whether tumor size and other pathologic markers could be useful in guiding locoregional management. DESIGN: This study is a retrospective analysis of data from the British Columbia provincial cancer registry. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Sequential patients diagnosed with rectal neuroendocrine tumors between 1999 and 2011 were identified. Neuroendocrine tumors were classified as G1 and G2 tumors with a Ki-67 ≤20% and/or mitotic count ≤20 per high-power field. MAIN OUTCOME MEASURES: Baseline clinicopathologic data including TNM staging, depth of invasion, tumor size, treatment modalities, and outcomes including survival data were measured. RESULTS: Of 91 rectal neuroendocrine tumors, the median patient age was 58 years, and 35 were men. Median tumor size was 6 mm. Median length of follow-up was 58.1 months, with 3 patients presenting with stage IV disease. Treatment included local ablation (n = 5), local excision (n = 79), surgical resection (n = 4), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 cases. Local relapse occurred in 8 cases and 1 relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and Ki-67, mitotic count, grade, and lymphovascular invasion (p < 0.01). Larger tumor size was associated with decreased disease-free survival. LIMITATIONS: Sample size was 91 patients in the whole provincial population over a 13-year time period because of the low incidence of rectal neuroendocrine tumors. CONCLUSIONS: In this population-based cohort, rectal neuroendocrine tumors generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. Pathologic markers play a role in risk stratification and prognostication. See Video Abstract at http://links.lww.com/DCR/A514.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix.

BACKGROUND: The debate remains whether appendiceal goblet cell cancers behave as classical carcinoid or adenocarcinoma. Treatment options are unclear and reports of outcomes are scarce. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) is considered optimal treatment for peritoneal involvement of other epithelial appendiceal tumors. METHODS: Prospective cohorts of patients treated for advanced appendiceal tumors from three peritoneal malignancy centres were collected (1994-2011). All patients underwent complete CRS+HIPEC, when possible, or tumor debulking. Demographic and outcome data for patients with goblet cell cancers were compared to patients with low- or high-grade epithelial appendiceal tumors treated during the same time period. RESULTS: Details on 45 goblet cell cancer patients were compared to 708 patients with epithelial appendix lesions. In the goblet cell group, 57.8 % were female, median age was 53 years, median peritoneal cancer index (PCI) was 24, and CRS+HIPEC was achieved in 71.1 %. These details were similar in patients with low- or high-grade epithelial tumors. Lymph nodes were involved in 52 % of goblet cell patients, similar to rates in high-grade cancers, but significantly higher than in low-grade lesions (6.4 %; p < 0.001). At 3 years, overall survival (OS) was 63.4 % for goblet cell patients, intermediate between that for high-grade (40.4-52.2 %) and low-grade (80.6 %) tumors. On multivariate analysis, tumor histology, PCI, and achievement of CRS+HIPEC were independently associated with OS. CONCLUSIONS: This data supports the concept that appendiceal goblet cell cancers behave more as high-grade adenocarcinomas than as low-grade lesions. These patients have reasonable long-term survival when treated using CRS+HIPEC, and this strategy should be considered.

Cytoreduction and heated intraperitoneal chemotherapy for colorectal cancer: are we excluding patients who may benefit?

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are increasingly used to treat peritoneal carcinomatosis from colorectal cancer. It is still relatively unknown which poor prognostic factors to avoid in order to optimize patient selection for CRS + HIPEC. METHODS: Between February 2003 and October 2011, 68 consecutive colorectal cancer patients who underwent CRS + HIPEC with a complete cytoreduction were identified from a prospective database. Survival analysis was performed using the Kaplan-Meier method, with log rank testing of differences between groups. Multivariate analysis was conducted using Cox proportional hazard regression. RESULTS: Median follow-up was 30.3 (range, 2-88) months amongst survivors. Patients with a peritoneal cancer index (PCI) of 10 or less showed improved survival over those with a PCI of 11 or higher (P = 0.03). No difference in survival was seen for the other potentially poor prognostic variables including lymph node status, synchronous peritoneal disease, peri-operative systemic chemotherapy, and rectal cancer primary. CONCLUSIONS: A low PCI was associated with improved survival. Complete CRS + HIPEC appears to result in similar survival outcomes regardless of delivery of peri-operative systemic chemotherapy. Rectal origin, lymph node status, and synchronous peritoneal disease should not be used as an absolute exclusion criteria for CRS + HIPEC based on current data.

Appendiceal goblet cell carcinoid and mucinous neoplasms are closely associated tumors: lessons from their coexistence in primary tumors and concurrence in peritoneal dissemination.

BACKGROUND: Goblet cell carcinoid (GCC) and appendiceal mucinous neoplasms (AMNs) are considered as different appendiceal tumors. Coexistence of both tumors was occasionally noted. We further observed the concurrence in both primary tumors and their peritoneal dissemination, that is, peritoneal carcinomatosis (PC) including pseudomyxoma peritonei (PMP). METHODS: Review of our 10-year file identified two subgroups of cases with such concurrence. Group 1 is 14 cases of PC/PMP treated by surgical cytoreduction. Morphologic components of GCC, low-grade mucinous neoplasm (LMN), mucinous adenocarcinoma (MCA), and non-mucinous adenocarcinoma (NMCA) were identified separately in different organs/tissues. Group 2 is eight cases of localized primary tumors of appendix and ileocecal junction. RESULTS: In Group 1, primary tumors (11 GCC, 1 GCC + LMN, 1 MCA, 1 NMCA) were identified in appendix (13) and in rectum (1). Further review identified mixed morphologic components in 7/12 GCC cases, including GCC + LMN (2), GCC + MCA (2), GCC + NMCA (1), and GCC + MCA + NMCA (2). Over peritoneal dissemination, GCC and/or other components were coexistent at different sites and in variable combinations. In Group 2, primary tumors were initially diagnosed as GCC (7) and MCA (1). Further review identified mixed components in all cases, including GCC + LMN (3), GCC + LMN + MCA (3), GCC + MCA + NMCA (2). CONCLUSIONS: GCC may present as a component mixed with AMNs and even with conventional adenocarcinoma in both primary tumors and metastatic lesions. AMN in any given single case may show a wide morphologic spectrum. GCC and AMN may share a common tumor stem cell with potential of multiple lineage differentiations.

How often do level III nodes bear melanoma metastases and does it affect patient outcomes?

BACKGROUND: Limited data exist regarding the necessity of resecting level three nodes as part of an axillary dissection for melanoma. The objective of this study was to determine how often level III nodes have metastases, in patients with sentinel lymph node (SLN) positive, palpable and bulky axillary disease, and to determine patient outcomes. METHODS: A retrospective chart review was completed at two tertiary care centers of patients with melanoma that had level three axillary dissections. At the time of surgery, the level III nodes were sent as a separate specimen. Bulky disease was defined as a large mass in all three levels that could not be separated. RESULTS: A total of 117 patients were identified. Three percent and 18 % of patients with SLN+ and palpable disease, respectively, had further disease in their level III nodes. All bulky patients had level III disease. Those with level III disease had a worse 3-year overall survival than those who did not (15.2 vs. 61.1 %, p < 0.001). For patients with palpable and bulky disease, systemic recurrence rate was 65 and 88 %, with a median time to metastases of 13.6 and 2 months, respectively. CONCLUSIONS: Patients with SLN+ disease rarely have positive level III nodes, questioning the need for routine removal of these nodes. Patients with palpable and bulky lymph node disease have implied occult distant metastases at the time of diagnosis and treatment. With the advent of improved targeted therapies for melanoma, clinical trials evaluating their role in patients with stage III disease may be warranted to improve patient outcomes.

HIPEC + EPIC versus HIPEC-alone: differences in major complications following cytoreduction surgery for peritoneal malignancy.

INTRODUCTION: Peritoneal metastases (PM) can be treated with cytoreduction surgery (CRS) with intraoperative heated intraperitoneal chemotherapy (HIPEC) plus or minus early postoperative intraperitoneal chemotherapy (EPIC). HIPEC + EPIC may be associated with more complications than HIPEC alone. METHODS: A prospective database of consecutive patients undergoing CRS + HIPEC ± EPIC at the University of Calgary between February 2000 and May 2011 was reviewed. Patient, tumor, and perioperative variables included peritoneal cancer index (PCI), completeness of cytoreduction (CCR) score, HIPEC ± EPIC type, and grade III/IV complications. RESULTS: 198 patients had a CCR score of 0/1 and received: (1) HIPEC mitomycin C + EPIC 5-fluorouracil for 5 days (n = 85; February 2000-January 2008); or (2) HIPEC oxaliplatin with IV 5-fluorouracil + no EPIC (n = 113; February 2008-May 2011). Clinicodemographics were similar except PCI was higher in the HIPEC-alone group (mean PCI 22 vs. 17; P = 0.02). The rate of grade III/IV complications was higher in the HIPEC + EPIC group (44.7% vs. 31.0%; P = 0.05). On multivariate logistic regression only HIPEC + EPIC and PCI > 26 were associated with an increased rate of complications. CONCLUSION: In patients with PM, the use of EPIC, in combination with CRS and HIPEC, is associated with an increased rate of complications. Surgeons should consider using HIPEC only (without EPIC).

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal carcinomatosis arising from colorectal cancer.

BACKGROUND: Peritoneal carcinomatosis (PC) from colorectal cancer is associated with a poor prognosis. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) have improved survival compared to systemic chemotherapy. We evaluate the results of this treatment in our institution. METHODS: Treatment consisted of complete CRS followed by HIPEC with oxaliplatin (460 mg/m(2) ) in 2 L/m(2) of D5W at 42°C during 30 min. RESULTS: From 2004 to 2011, 40 patients with PC from colorectal cancer were included and 25 CRS + HIPEC were performed. Six patients had a negative second-look surgery and nine had unresectable disease. Median follow-up was 22.8 months. Overall 3- and 5-year survival rates for the cohort were 56% and 33%. The 3- and 5-year overall survival rates were 61% and 36% for HIPEC group, 82% and 67% for patients with negative second-look, and 22% and 0% for the unresectable group (P = 0.0087). 3-year disease-free survival for HIPEC group was 22%. Major complication and mortality rate for HIPEC group were 20% and 4%. Peritoneal carcinomatosis index (P = 0.0374) and lymph node status (P = 0.027) were prognostic indicators. CONCLUSIONS: CRS + HIPEC with oxaliplatin for PC from colorectal cancer is an effective treatment with encouraging survival results.

Malignant triton tumors--complete surgical resection and adjuvant radiotherapy associated with improved survival.

BACKGROUND: Malignant triton tumors (MTT) are a rare form of peripheral nerve sheath tumors that follows a particularly aggressive course. Given its rarity, only case reports and small series of patients have been published. METHODS: A Pubmed search was conducted (1966-2009) using the terms "triton tumor," "rhabdomyosarcoma," and "malignant peripheral nerve sheath tumor." The reference lists of retrieved articles were searched. Cases were included when the diagnosis was clear, the patient underwent surgery, and follow-up data were available. Univariate and multivariate analyses were conducted for predictors of positive resection margin, local recurrence/progression, development of metastases, and mortality. RESULTS: A total of 124 cases were included. The overall 5-year survival was 14% and the median time to death was 13 months. The overall local recurrence/progression rate was 50% and the median time to recurrence/progression was 6 months. On multivariate Cox proportional hazards analysis, positive margin status (HR 2.2, P = 0.01), local recurrence/progression (HR 3.1, P = 0.003), and development of metastases (HR 2.6, P = 0.003) were associated with mortality. Adjuvant radiotherapy was associated with improved survival (HR 0.4, P = 0.005). CONCLUSION: Complete surgical resection and adjuvant radiotherapy should be the cornerstones of treatment for MTT.

Timely access and quality of care in colorectal cancer: are they related?

OBJECTIVE: Colorectal cancer patients want both timely access and high-quality care. The objective of this study was to explore relationships between quality indicators and access time intervals specific to colorectal cancer patients. DESIGN: Prospective consecutive cohort study. SETTING: Single health district. PARTICIPANTS: Between February 2002 and February 2004, all patients undergoing non-emergent surgery for primary colorectal cancer were enrolled. INTERVENTION: A standardized method was used to collect clinicodemographic, diagnostic and treatment event data. MAIN OUTCOME MEASURES: Associations between accepted colorectal cancer-specific quality indicators and benchmarked access time intervals for diagnosis, surgery and adjuvant therapy were examined using multivariate logistic regression, controlling for clinicodemographic factors. RESULTS: Among the 392 patients in the study cohort, 9.9% were diagnosed on screening examination, 53.1% underwent preoperative staging imaging and 74.5% underwent full preoperative colonic examination. On multivariate logistic regression, patients presenting via screening were more likely to move from presentation to diagnosis within the 4-week benchmark for this access time interval, compared with symptomatic patients (RR 8.1, P < 0.001). The absence of preoperative staging imaging was associated with achievement of the 4-week benchmark for the access time interval from diagnosis to surgery (RR 2.5, P < 0.001). Similarly, an absence of complete preoperative colonic examination was associated with achievement of the 8-week benchmark for the access time interval from surgery to adjuvant therapy (RR 6.6, P = 0.008). CONCLUSIONS: Although several associations between quality indicators and benchmarked access time intervals for colorectal cancer patients were identified, the relationship between quality and access is complex and far from universal. It is therefore clear that quality care and timely access are not synonymous, and that both must be studied to improve colorectal cancer care.

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.

BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. RESULTS: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT'nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. CONCLUSIONS: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.

Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours.

BACKGROUND: Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells). METHODS: The expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray. RESULTS: CCT showed reduced Hes1/Elf3 and Sox9/Klf4 coupled with elevated Math1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higher Klf4 and similar Ngn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed a Notch signalling similar to adenocarcinoma. Mucinous tumours showed lower Elf3 than normal appendiceal epithelium and higher Math1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showed Notch signalling similar to other glandular tumours, but lower Klf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation. CONCLUSIONS: Wnt/secretory lineage protein and Notch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours.

Performance of variable selection methods using stability-based selection.

BACKGROUND: Variable selection is frequently carried out during the analysis of many types of high-dimensional data, including those in metabolomics. This study compared the predictive performance of four variable selection methods using stability-based selection, a new secondary selection method that is implemented in the R package BioMark. Two of these methods were evaluated using the more well-known false discovery rate (FDR) as well. RESULTS: Simulation studies varied factors relevant to biological data studies, with results based on the median values of 200 partial area under the receiver operating characteristic curve. There was no single top performing method across all factor settings, but the student t test based on stability selection or with FDR adjustment and the variable importance in projection (VIP) scores from partial least squares regression models obtained using a stability-based approach tended to perform well in most settings. Similar results were found with a real spiked-in metabolomics dataset. Group sample size, group effect size, number of significant variables and correlation structure were the most important factors whereas the percentage of significant variables was the least important. CONCLUSIONS: Researchers can improve prediction scores for their study data by choosing VIP scores based on stability variable selection over the other approaches when the number of variables is small to modest and by increasing the number of samples even moderately. When the number of variables is high and there is block correlation amongst the significant variables (i.e., true biomarkers), the FDR-adjusted student t test performed best. The R package BioMark is an easy-to-use open-source program for variable selection that had excellent performance characteristics for the purposes of this study.

Distinguishing Benign from Malignant Pancreatic and Periampullary Lesions Using Combined Use of ¹H-NMR Spectroscopy and Gas Chromatography-Mass Spectrometry.

Previous work demonstrated that serum metabolomics can distinguish pancreatic cancer from benign disease. However, in the clinic, non-pancreatic periampullary cancers are difficult to distinguish from pancreatic cancer. Therefore, to test the clinical utility of this technology, we determined whether any pancreatic and periampullary adenocarcinoma could be distinguished from benign masses and biliary strictures. Sera from 157 patients with malignant and benign pancreatic and periampullary lesions were analyzed using proton nuclear magnetic resonance (¹H-NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS). Multivariate projection modeling using SIMCA-P+ software in training datasets (n = 80) was used to generate the best models to differentiate disease states. Models were validated in test datasets (n = 77). The final ¹H-NMR spectroscopy and GC-MS metabolomic profiles consisted of 14 and 18 compounds, with AUROC values of 0.74 (SE 0.06) and 0.62 (SE 0.08), respectively. The combination of ¹H-NMR spectroscopy and GC-MS metabolites did not substantially improve this performance (AUROC 0.66, SE 0.08). In patients with adenocarcinoma, glutamate levels were consistently higher, while glutamine and alanine levels were consistently lower. Pancreatic and periampullary adenocarcinomas can be distinguished from benign lesions. To further enhance the discriminatory power of metabolomics in this setting, it will be important to identify the metabolomic changes that characterize each of the subclasses of this heterogeneous group of cancers.

Surgical management of rectal carcinoids: trends and outcomes from the Surveillance, Epidemiology, and End Results database (1988 to 2012).

BACKGROUND: Local excision of small (<10 mm) rectal carcinoids is a standard treatment. Actual patterns of care and outcomes are understudied because of the rarity of this tumor. METHODS: Surveillance, Epidemiology, and End Results database (1988 to 2012) was interrogated for rectal carcinoid patients. Chi-square testing and Kaplan-Meier survival analysis were used to compare survival outcomes. RESULTS: Of all, 11,329 patients were identified-9,605 with only localized disease. The majority (77%) underwent local excision only. Full rectal resection was performed more frequently for tumors greater than 10 mm (11.7% to 12.2%) than for tumors less than 10 mm (4.5% to 4.9%, P < .001), and for higher T stage (T1: 4.0%, T2: 11.4%, T3/4:30.4%, P < .001). Nonoperative management was more common after year 2000 (11.2% to 13.7%) than prior (7.4% to 8.5%, P < .001). Cancer-specific survival improved across time periods but did not differ between nonoperative, local excision, or surgical resection. CONCLUSIONS: Nonexcisional management of small, localized rectal carcinoids is becoming more common and may offer equivalent survival to excision or resection.

Intensity-Modulated Radiotherapy (IMRT) vs Helical Tomotherapy (HT) in Concurrent Chemoradiotherapy (CRT) for Patients with Anal Canal Carcinoma (ACC): an analysis of dose distribution and toxicities.

PURPOSE: Intensity-modulated radiotherapy (IMRT) and helical tomotherapy (HT) have been adopted for radiotherapy treatment of anal canal carcinoma (ACC) due to better conformality, dose homogeneity and normal-tissue sparing compared to 3D-CRT. To date, only one published study compares dosimetric parameters of IMRT vs HT in ACC, but there are no published data comparing toxicities. Our objectives were to compare dosimetry and toxicities between these modalities. METHODS AND MATERIALS: This is a retrospective study of 35 ACC patients treated with radical chemoradiotherapy at two tertiary cancer institutions from 2008-2010. The use of IMRT vs HT was primarily based on center availability. The majority of patients received fluorouracil (5-FU) and 1-2 cycles of mitomycin C (MMC); 2 received 5-FU and cisplatin. Primary tumor and elective nodes were prescribed to ≥54Gy and ≥45Gy, respectively. Patients were grouped into two cohorts: IMRT vs HT. The primary endpoint was a dosimetric comparison between the cohorts; the secondary endpoint was comparison of toxicities. RESULTS: 18 patients were treated with IMRT and 17 with HT. Most IMRT patients received 5-FU and 1 MMC cycle, while most HT patients received 2 MMC cycles (p<0.01), based on center policy. HT achieved more homogenous coverage of the primary tumor (HT homogeneity and uniformity index 0.14 and 1.02 vs 0.29 and 1.06 for IMRT, p=0.01 and p<0.01). Elective nodal coverage did not differ. IMRT achieved better bladder, femoral head and peritoneal space sparing (V30 and V40, p ≤ 0.01), and lower mean skin dose (p<0.01). HT delivered lower bone marrow (V10, p<0.01) and external genitalia dose (V20 and V30, p<0.01). Grade 2+ hematological and non-hematological toxicities were similar. Febrile neutropenia and unscheduled treatment breaks did not differ (both p=0.13), nor did 3-year overall and disease-free survival (p=0.13, p=0.68). CONCLUSIONS: Chemoradiotherapy treatment of ACC using IMRT vs HT results in differences in dose homogenity and normal-tissue sparing, but no significant differences in toxicities.

Hyperthermic intraperitoneal chemotherapy + early postoperative intraperitoneal chemotherapy versus hyperthermic intraperitoneal chemotherapy alone: assessment of survival outcomes for colorectal and high-grade appendiceal peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved survival for colorectal and high-grade appendiceal carcinomatosis. We compared the overall and recurrence-free survival (OS and RFS) of patients treated with HIPEC with mitomycin c and early postoperative intraperitoneal chemotherapy (EPIC) with fluorouracil versus HIPEC alone using oxaliplatin and simultaneous IV infusion of fluorouracil. METHODS: Ninety-three patients with colorectal or high-grade appendiceal carcinomatosis were treated with CRS and HIPEC + EPIC or HIPEC alone. OS and RFS were analyzed using Kaplan-Meier curves and log-rank testing. RESULTS: Survival did not differ between HIPEC regimens. The 3-year OS and RFS rates were 50% and 21% for HIPEC + EPIC and 46% and 6% for HIPEC alone (P = .72 and P = .89, respectively). HIPEC + EPIC patients experienced more grade III/IV complications (43.2% vs 19.6%, P = .01). CONCLUSIONS: There was no difference in OS and RFS between colorectal and high-grade appendiceal adenocarcinoma patients treated with CRS and HIPEC + EPIC versus HIPEC alone. However, HIPEC + EPIC patients suffered greater morbidity, making HIPEC alone the preferable regimen.

Simplified 2-tier histologic grading system accurately predicts outcomes in goblet cell carcinoid of the appendix.

Goblet cell carcinoid (GCC) is a rare appendiceal malignancy with both neuroendocrine and glandular features. Clinical outcomes of patients with GCC vary widely and a histology-based 3-tiered prognostic scheme has been previously suggested; however, this scheme is subjective and challenging to apply in day-to-day practice. We sought to construct a simplified and prognostic grading system based on objective histologic features with specific criteria. A continuous population-based cohort of GCC with clinical outcome data and archival tissue available for review was extracted from regional databases. For the 78 patients with confirmed appendiceal GCC, specific histologic features, including cytologic atypia, peritumoral stromal desmoplasia, and solid growth pattern, were recorded, and a scoring system was devised, which separates patients with GCC into low-grade (n = 55; 71%) or high-grade (n = 23; 29%) histology. Correspondingly, clinical follow-up data show good prognosis in those with low-grade histology with median and 10-year overall survival of 51.0 months and 80.5%, respectively, whereas those with high-grade histology have a poor prognosis with median and 10-year overall survival of 16.5 months (P = .006) and 0% (P < .001), respectively. Multivariate Cox proportional hazard modeling demonstrates that this 2-tier histologic system remains predictive of overall survival when controlled for TNM clinicopathological stage. These data show that a simple and objective histologic scoring system separates GCC into low- and high-grade histology with divergent clinical outcomes.

Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing.

Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes NF2, CDKN2A, LATS2, amongst others, were identified. Activation of MET-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.