Survival After Induction Chemotherapy and Chemoradiation Versus Chemoradiation and Adjuvant Chemotherapy for Locally Advanced Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC) patients compared to neoadjuvant chemoradiotherapy alone. The effect of TNT on patient survival has not been fully investigated. MATERIALS AND METHODS: This was a retrospective case series of patients with LARC at a comprehensive cancer center. Three hundred and eleven patients received chemoradiotherapy (chemoRT) as the sole neoadjuvant treatment and planned adjuvant chemotherapy, and 313 received TNT (induction fluorouracil and oxaliplatin-based chemotherapy followed by chemoradiotherapy in the neoadjuvant setting). These patients then underwent total mesorectal excision or were entered in a watch-and-wait protocol. The proportion of patients with complete response (CR) after neoadjuvant therapy (defined as pathological CR or clinical CR sustained for 2 years) was compared by the χ2 test. Disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival were assessed by Kaplan-Meier analysis and log-rank test. Cox regression models were used to further evaluate DFS. RESULTS: The rate of CR was 20% for chemoRT and 27% for TNT (P=.05). DFS, local recurrence-free survival, metastasis-free survival, and overall survival were no different. Disease-free survival was not associated with the type of neoadjuvant treatment (hazard ratio [HR] 1.3; 95% confidence interval [CI] 0.93-1.80; P = .12). CONCLUSIONS: Although TNT does not prolong survival than neoadjuvant chemoradiotherapy plus intended postoperative chemotherapy, the higher response rate associated with TNT may create opportunities to preserve the rectum in more patients with LARC.

Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review.

BACKGROUND: Grade 3 gastroenteropancreatic neuroendocrine neoplasms (G3 GEPNENs) are often aggressive, and the optimal treatment is unclear for this subgroup of neuroendocrine neoplasms (NENs). Temozolomide (TEM)-based regimens have been increasingly used to treat grade 1-2 NENs, but their efficacy in G3 NENs remains undetermined. We aimed to assess the clinical efficacy of TEM-containing regimens in advanced grade 3 GEPNENs. MATERIALS AND METHODS: A multicenter retrospective review (2008-2018) of patients with metastatic/unresectable G3 GEPNENs who received a TEM-containing regimen was undertaken within a North American partnership to pool data. The primary endpoint was time to treatment failure (TTF). Radiologic response was extracted from local reports. RESULTS: One hundred and thirty patients in six high-volume NEN centers were included (median age 55, 64% male, 18% functional, 67% pancreatic NEN). Forty-nine percent were well-differentiated, 35% poorly differentiated, and 15% unknown based on local pathology reports. The regimen used was capecitabine and temozolomide (CAPTEM) in 92% and TEM alone in 8%. Radiological response by local assessment was seen in 36% of patients. Median TTF was 3.6 months and median overall survival (OS) 19.2 months. Six percent of patients required discontinuation of therapy due to adverse events. TTF was longer in first-line treatment (7.8 months vs. 2.9 months; hazard ratio, 1.62; 95% confidence interval, 1.11-2.36; p = .015) and in patients with pancreatic NENs (panNENs) compared with gastrointestinal NENs (5.8 months vs 1.8 months; p = .04). The overall response rate was higher in the first-line setting (51% vs 29%; p = .02) and in panNEN (41% vs 23%; p = .04). CONCLUSION: This is the largest TEM treatment series in G3 NEN, involving collaboration of several major North American NEN centers as a partnership. Thirty-six percent of patients showed some degree of radiographic response, and treatment was generally well tolerated, although the median duration of response was short. Response rates and time to treatment failure were superior in the first-line setting. CAPTEM should be considered a viable treatment option in this setting. Further randomized trials are warranted. IMPLICATIONS FOR PRACTICE: Neuroendocrine neoplasms (NENs) are heterogeneous, and optimal treatment for aggressive grade 3 (G3) NENs remains undetermined. The capecitabine and temozolomide (CAPTEM) regimen has been used in low-grade pancreas NENs but there are few data for its safety and efficacy in the G3 setting. This article reports on the efficacy of temozolomide-containing regimens, particularly CAPTEM, in management of G3 NENs. The good tolerance and response rate show that CAPTEM should be considered a viable regimen in treatment of G3 NENs pending confirmatory prospective studies.

Clinical and genetic determinants of ovarian metastases from colorectal cancer.

BACKGROUND: Ovarian metastases from colorectal cancer (OM-CRC) often are unresponsive to chemotherapy and are associated with poor survival. To the authors' knowledge, the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear. METHODS: Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified. Next-generation somatic mutation profiling (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]) was performed on 38 OM-CRC cases, including 21 matched tumor pairs/trios. Regression models were used to analyze variables associated with progression-free survival and overall survival (OS). RESULTS: Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), SMAD family member 4 (SMAD4), and neurotrophic receptor tyrosine kinase 1 (NTRK1) mutations were more frequent in cases of OM-CRC than in instances of CRC occurring without OM. SMAD4 and lysine methyltransferase 2D (KMT2D) mutations were associated with reduced OS. Matched multisite tumor sequencing did not identify OM-specific genomic alterations. Of the 195 patients who underwent oophorectomy for OM-CRC (median age, 49 years with a progression-free survival of 9.4 months and an OS of 23 months from oophorectomy), 76% had extraovarian metastasis (EOM). In multivariable analysis, residual disease after surgery (R2 resection) was associated with worse survival. Patients with EOM were less likely to achieve R0/R1 surgical resection status (complete macroscopic resection without clinical/radiological evidence of disease) (48% vs 94%). However, if R0/R1 resection status was achieved, both patients with (35.9 months vs 12 months) and without (43.2 months vs 14.5 months) EOM were found to have better OS. Among 114 patients with R0/R1 resection status, 23 (20%) had no disease recurrence, including 10 patients (9%) with > 3 years of follow-up. CONCLUSIONS: Loss-of-function alterations in SMAD4 are frequent and predictive of worse survival in patients with OM-CRC. Similar to oligometastatic CRC to the lung or liver, surgical resection of OM-CRC is associated with a better outcome only if all macroscopic metastatic disease is resected. Cancer 2017;123:1134-1143. © 2016 American Cancer Society.

Chemotherapy and intensity-modulated radiation therapy for locally advanced pancreatic cancer achieves a high rate of R0 resection.

BACKGROUND: To assess local control, survival and conversion to resectability among locally advanced pancreatic cancer (LAPC) patients treated with induction chemotherapy (ICT) followed by chemoradiotherapy treatment using intensity-modulated radiation therapy (IMRT). MATERIAL AND METHODS: Between 2007 and 2012, 134 LAPC patients were treated with ICT followed by IMRT. After chemoradiotherapy, 40 patients received maintenance chemotherapy. RESULTS: With a median follow-up of 20 months, median overall survival (OS) was 23 months. One- and two-year OS was 85% and 47%, respectively. On multivariate analysis, progression of disease after IMRT was associated with worse OS. Cumulative incidence of local failure was 10% at one year and 36% at two years. Twenty-six patients (19%) underwent resection after chemoradiotherapy including 22 patients (85%) with negative margins. On multivariate analysis, response to IMRT was associated with surgery (p = .01). Acute grade 3-4 hematologic and non-hematologic toxicity rates were 26% and 4.5%, respectively. CONCLUSION: IMRT is safe in patients with LAPC. Patients with non-progressive LAPC after ICT and who received IMRT had high rates of local control and prolonged survival.

Identification of germline genetic mutations in patients with pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PAC) is part of several cancer predisposition syndromes; however, indications for genetic counseling/testing are not well-defined. In the current study, the authors sought to determine mutation prevalence and characteristics that are predictive of an inherited predisposition for PAC. METHODS: A total of 175 consecutive patients with PAC who underwent clinical genetics assessment at Memorial Sloan Kettering Cancer Center between 2011 and 2014 were identified. Clinical data, family history, and germline results were evaluated. RESULTS: Among 159 patients with PAC who pursued genetic testing, 24 pathogenic mutations were identified (15.1%; 95% confidence interval, 9.5%-20.7%), including BRCA2 (13 mutations), BRCA1 (4 mutations), p16 (2 mutations), PALB2 (1 mutation), and Lynch syndrome (4 mutations). BRCA1/BRCA2 prevalence was 13.7% in Ashkenazi Jewish (AJ) patients (95 patients) and 7.1% in non-AJ patients (56 patients). In AJ patients with a strong, weak, or absent family history of BRCA-associated cancers, the mutation prevalence was 16.7%, 15.8%, and 7.4%, respectively. The mean age at the time of diagnosis in all mutation carriers was 58.5 years (range, 45-75 years) compared with 64 years (range, 27-87 years) in those not carrying a mutation (P = .02). Although BRCA2 was the most common mutation identified, no patients with early-onset PAC (diagnosed at age ≤ 50 years) harbored a BRCA2 mutation and the mean age at diagnosis in BRCA2 carriers was equivalent to that of individuals who were not mutation carriers (P = .34). Mutation prevalence in patients with early-onset disease (21 patients) was 28.6%, including BRCA1 (2 mutations), p16 (2 mutations), MSH2 (1 mutation), and MLH1 (1 mutation). CONCLUSIONS: Mutations in BRCA2 account for > 50% of patients with PAC with an identified susceptibility syndrome. AJ patients were found to have high BRCA1/BRCA2 prevalence regardless of personal/family history, suggesting that ancestry alone indicates a need for genetic evaluation. With the exception of BRCA2-associated PAC, an inherited predisposition for PAC is associated with an earlier age at PAC diagnosis, suggesting that this subset of patients may also represent a population warranting further evaluation.

A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma.

BACKGROUND: The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined. OBJECTIVE: We evaluated the efficacy of gemcitabine and oxaliplatin administered as preoperative therapy in patients with resectable pancreas adenocarcinoma. METHODS: Eligible patients were screened using computed tomography-pancreas angiography, laparoscopy, endoscopic ultrasonography, and fine-needle aspiration cytology to identify 38 patients who received 4 cycles of neoadjuvant gemcitabine 1000 mg/m intravenously over 100 minutes and oxaliplatin 80 mg/m intravenously over 2 hours, every 2 weeks. Patients whose tumors remained resectable at restaging proceeded to operation and subsequently received 5 cycles of adjuvant gemcitabine (1000 mg/m intravenously over 30 minutes days 1, 8, and 15 every 4 weeks). The primary endpoint was 18-month overall survival and secondary endpoints included radiological, tumor marker and pathological response to neoadjuvant therapy, time to recurrence, patterns of failure, and feasibility of obtaining preoperative core biopsies. RESULTS: Thirty-five of 38 patients (92%) completed neoadjuvant therapy. Twenty-seven patients underwent tumor resection (resectability rate 71%), of which 26 initiated adjuvant therapy for a total of 23 patients (60.5%) who completed all planned therapy. The 18-month survival was 63% (24 patients alive). The median overall survival for all 38 patients was 27.2 months (95% confidence interval: 17-NA) and the median disease-specific survival was 30.6 months (95% confidence interval: 19-NA). CONCLUSIONS: This study met its endpoint and provided a signal suggesting that exploration of neoadjuvant systemic therapy is worthy of further investigation in resectable pancreas adenocarcinoma. Improved patient selection and more active systemic regimens are key. Clinical trials identification: NCT00536874.

A retrospective review of 126 high-grade neuroendocrine carcinomas of the colon and rectum.

BACKGROUND: High-grade neuroendocrine carcinomas (HGNECs) of the colon and rectum are rare, constituting less than 1 % of colorectal cancers. The purpose of this study was to identify the natural history and oncologic outcomes of this disease, describe the use of surgery, and determine the clinical and pathological factors associated with outcomes. METHODS: Following Institutional Review Board approval, patients with HGNEC were identified from our institutional database. Patient charts and pathology reports were analyzed retrospectively for clinical and pathological factors. RESULTS: A total of 126 patients with a median follow-up of 9 months were identified. Median survival was 13.2 months, and 85 (67 %) patients had metastatic disease at diagnosis. Three-year overall survival (OS) was 5 and 18 % for patients with and without metastatic disease, respectively. Factors associated with improved OS on multivariable analysis were absence of metastatic disease and presence of an adenocarcinoma component within the tumor. In patients with metastatic disease, response to chemotherapy was the only factor associated with survival. In patients with localized disease, an adenocarcinoma component within the tumor was the only factor associated with survival. Resection of tumor was not associated with survival in either localized or metastatic disease. CONCLUSION: High-grade colorectal NECs are extremely aggressive tumors with poor prognosis. Patients appear to have a marginally better prognosis if they present without metastatic disease, have an adenocarcinoma component within their tumor, or respond to chemotherapy. Surgery, particularly in the presence of metastatic disease, may not offer a survival benefit for the majority of patients.

Pancreatic neuroendocrine paraneoplastic optic neuropathy: confirmation with antibody to optic nerve and hepatic metastasis.

A 68-year-old woman presented with bilateral visual loss as the only clinical manifestation of an occult pancreatic nonsecretory neuroendocrine tumor (NET). The suspected diagnosis of paraneoplastic optic neuropathy was confirmed using immunofluorescence assays to demonstrate the presence of antibodies in the patient's serum that reacted with antigen(s) in the optic nerve and in the pancreatic NET hepatic metastasis. Treatment of the underlying cancer was followed by marked improvement in visual function.

Quantitative Computed Tomography Image Analysis to Predict Pancreatic Neuroendocrine Tumor Grade.

PURPOSE: The therapeutic management of pancreatic neuroendocrine tumors (PanNETs) is based on pathological tumor grade assessment. A noninvasive imaging method to grade tumors would facilitate treatment selection. This study evaluated the ability of quantitative image analysis derived from computed tomography (CT) images to predict PanNET grade. METHODS: Institutional database was queried for resected PanNET (2000-2017) with a preoperative arterial phase CT scan. Radiomic features were extracted from the primary tumor on the CT scan using quantitative image analysis, and qualitative radiographic descriptors were assessed by two radiologists. Significant features were identified by univariable analysis and used to build multivariable models to predict PanNET grade. RESULTS: Overall, 150 patients were included. The performance of models based on qualitative radiographic descriptors varied between the two radiologists (reader 1: sensitivity, 33%; specificity, 66%; negative predictive value [NPV], 63%; and positive predictive value [PPV], 37%; reader 2: sensitivity, 45%; specificity, 70%; NPV, 72%; and PPV, 47%). The model based on radiomics had a better performance predicting the tumor grade with a sensitivity of 54%, a specificity of 80%, an NPV of 81%, and a PPV of 54%. The inclusion of radiomics in the radiographic descriptor models improved both the radiologists' performance. CONCLUSION: CT quantitative image analysis of PanNETs helps predict tumor grade from routinely acquired scans and should be investigated in future prospective studies.

Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors.

Well-differentiated neuroendocrine tumors (NETs), which are also referred to as well-differentiated endocrine carcinoma according to WHO terminology, are usually slow-growing cancers, even when they exhibit gross local invasion and/or metastases. The survival of patients with metastatic NET is often measured in years to decades. Once NET progresses or becomes symptomatic the patient's prognosis is poor. An important challenge for clinicians is to distinguish at an early stage those patients who will die with the disease, from those who will succumb because of it, so that the appropriate level of care can be administered. Reliable genomic predictors could provide substantial advancements in prognosis and, possibly, treatment; however, such markers are currently unavailable. Early literature on the treatment of NETs is confounded by a lack of formal objective response criteria. Somatostatin analogs can control symptoms and can stabilize some slow-growing tumors, but rarely result in tumor regression. Surgery is curative in only a minority of patients, and systemic chemotherapy is minimally effective. Advances in the understanding of tumor biology have led to the identification of important cellular processes involved in the pathogenesis of NETs, and agents that target these processes have now entered clinical trials. We will discuss the data on therapies currently used to treat well-differentiated NETs, and the strategies being used in clinical trials.

Giving Voice to Patient Values Throughout Cancer: A Novel Nurse-Led Intervention.

CONTEXT: Optimal advance care planning allows patients to articulate their values as a touchstone for medical decision making. Ideally, this occurs when patients are clinically stable, and with opportunities for iteration as the clinical situation unfolds. OBJECTIVES: Testing feasibility and acceptability in busy outpatient oncology clinics of a novel program of systematic, oncology nurse-led values discussions with all new cancer patients. METHODS: Within an institutional initiative integrating primary and specialist palliative care from diagnosis for all cancer patients, oncology nurses were trained to use specific questions and an empathic communication framework to discuss health-related values during outpatient clinic visits. Nurses summarized discussions on a template for patient verification, oncologist review, and electronic medical record documentation. Summaries were reviewed with the patient at least quarterly. Feasibility and acceptability were evaluated in three clinics for patients with hematologic or gastrointestinal malignancies. RESULTS: Oncology nurses conducted 177 total discussions with 67 newly diagnosed cancer patients (17 with hematologic and 50 with gastrointestinal malignancies) over two years. No patient declined participation. Discussions averaged eight minutes, and all patients verified values summaries. Clinic patient volume was maintained. Of 31 patients surveyed, 30 (97%) reported feeling comfortable with the process, considered it helpful, and would recommend it to others. Clinicians strongly endorsed the values discussion process. CONCLUSION: Nurse-led discussions of patient values soon after diagnosis are feasible and acceptable in busy oncology clinics. Further research will evaluate the impact of this novel approach on additional patient-oriented outcomes after broader dissemination of this initiative throughout our institution.

Brain Metastases in Pancreatic Ductal Adenocarcinoma: Assessment of Molecular Genotype-Phenotype Features-An Entity With an Increasing Incidence?

PURPOSE: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel). Overall survival was calculated from date of diagnosis to either date of last follow-up or death. Survival after BM was calculated from date of diagnosis of BM by radiology or pathology to either date of last follow-up or death. RESULTS: From a total of 5824 patients with PDAC identified from January 2000 to January 2016, twenty-five patients (0.4%) had BM. Median age at PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (range, 0-79 months). Median overall survival after BM diagnosis was 1.5 months (range, 1-31 months). Overall survival for patients who had craniotomy (n = 4) was 11 months (range, 1-31 months), with 2 long-term survivors at 21 and 31 months, respectively. Four patients had leptomeningeal disease. Six of 25 patients had germ-line testing, and 3 had BRCA mutations (2 BRCA1 and 1 BRCA2). Somatic profiling identified KRAS mutations in 100% (4 G12D, 2 G12V, and 1 Q61K). CONCLUSION: BM from PDAC is a rare event. We identified a speculative association of germ-line BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival after BM development is poor; prolonged survival occurred in selected patients via a multidisciplinary approach.

Misery Loves Company: Presenting Symptom Clusters to Urgent Care by Patients Receiving Antineoplastic Therapy.

PURPOSE: The Centers for Medicare & Medicaid Services (CMS) identifies suboptimal management of treatment toxicities as a care gap and proposes the measurement of hospital performance on the basis of emergency department visits for 10 common symptoms. Current management strategies do not address symptom co-occurrence. METHODS: We evaluated symptom co-occurrence in three patient cohorts that presented to a cancer hospital urgent care center in 2016. We examined both the CMS-identified symptoms and an expanded clinician-identified set defined as symptoms that could be safely managed in the outpatient setting if identified early and managed proactively. The cohorts included patients who presented with a CMS-defined symptom within 30 days of treatment, patients who presented within 30 days of treatment with a symptom from the expanded set, and patients who presented with a symptom from the expanded set within 30 days of treatment start. Symptom co-occurrence was measured by Jaccard index. A community detection algorithm was used to identify symptom clusters on the basis of a random walk process, and network visualizations were used to illustrate symptom dynamics. RESULTS: There were 6,429 presentations in the CMS symptom-defined cohort. The network analysis identified two distinct symptom clusters centered around pain and fever. In the expanded symptom cohort, there were 5,731 visits and six symptom clusters centered around fever, emesis/nausea, fatigue, deep vein thrombosis, pain, and ascites. For patients who newly initiated treatment, there were 1,154 visits and four symptom clusters centered around fever, nausea/emesis, fatigue, and deep vein thrombosis. CONCLUSION: Uncontrolled symptoms are associated with unplanned acute care. Recognition of the complexity of symptom co-occurrence can drive improved management strategies.

Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

Importance: Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases. Objective: To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC. Design, Setting, and Participants: A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified. Exposures: Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT). Main Outcomes and Measures: Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK. Results: Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort. Conclusions and Relevance: Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.

Malignant transformation of glucagonoma with SPECT/CT In-111 OctreoScan features: A case report.

RATIONALE: Glucagonoma is an uncommon disease but it has been associated with a pattern of symptoms defined as glucagonoma syndrome. These symptoms, if promptly recognized, could help to speed up the diagnosing process. PATIENT CONCERNS: We report a case of a 68-year-old woman with a pancreatic glucagonoma. Her symptoms at the onset were typical of the glucagonoma syndrome. DIAGNOSES: After a significant weight loss, she underwent a computer tomography scan of the abdomen, which showed a hypervascular lesion of the tail of the pancreas and hypervascular lesions of the liver. An ultrasound guided biopsy was performed and pathology was consistent with glucagonoma. Her blood glucagon levels were elevated. OUTCOMES: She was treated with chemotherapy and somatostatin analogs. After 4 years, the disease had a malignant transformation, and metastases suddenly started to grow up. She stopped being responsive to treatment and eventually passed away. LESSONS: Due to its rarity, clinical diagnosis is challenging and generally it comes after a long interval since the onset of symptoms. Awareness of physicians and dermatologists of the characteristic necrolytic migratory erythema, and of the other symptoms, often leads to early diagnosis.

Capecitabine With Mitomycin Reduces Acute Hematologic Toxicity and Treatment Delays in Patients Undergoing Definitive Chemoradiation Using Intensity Modulated Radiation Therapy for Anal Cancer.

PURPOSE: To assess the impact on acute toxicity of replacing 5-fluorouracil (5-FU) with capecitabine in definitive chemoradiation for patients with anal squamous cell carcinoma (ASCC). METHODS AND MATERIALS: We retrospectively reviewed the records of 107 consecutive patients with nonmetastatic ASCC treated with definitive chemoradiation from January 2009 to May 2014. In 2011, based on the noninferiority of capecitabine versus 5-FU, our institutional practice shifted to use capecitabine instead of 5-FU for ASCC. Of 107 patients, 63 were treated with infusional 5-FU (1000 mg/m2/day for 4 days) and mitomycin C (MMC) (10 mg/m2) during weeks 1 and 5, and 44 patients were treated with capecitabine (825 mg/m2 twice daily) Monday through Friday throughout radiation therapy (RT) and MMC (10 mg/m2) during weeks 1 and 5. The incidence of grade 3 to 4 acute toxicity was compared between the 2 groups. RESULTS: The median age at diagnosis was 59 years, and 78 patients (73%) were female. The patient characteristics were similar between the 2 treatment groups. All patients in both groups were treated with intensity modulated RT (median dose, 56 Gy). In the 5-FU group, 52% experienced grade 3 to 4 neutropenia compared with 20% in the capecitabine group (P=.001). Treatment breaks resulting from toxicity, primarily related to grade 3+ hematologic toxicity, were necessary for 42% of patients treated with 5-FU versus 16% of those treated with capecitabine (P=.006). CONCLUSIONS: Pelvic radiation therapy with MMC plus capecitabine was well tolerated and appeared to have less grade 3+ acute hematologic toxicity and fewer treatment interruptions than in a population of ASCC patients undergoing definitive chemoradiation with MMC and 5-FU.

Well-Differentiated Neuroendocrine Tumors with a Morphologically Apparent High-Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas.

PURPOSE: Most well-differentiated neuroendocrine tumors (WD-NET) of the enteropancreatic system are low-intermediate grade (G1, G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki-67 index (>20%) defines a group of aggressive neoplasms designated as high-grade (G3) neuroendocrine carcinoma (NEC). High-grade NEC is equated with poorly differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high-grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized. EXPERIMENTAL DESIGN: We investigated 31 cases of WD-NETs with evidence of a component of a high-grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected IHC and gene mutation analyses performed. RESULTS: The high-grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high-grade component remained akin to those of G1-G2 WD-NETs. The median disease-specific survival (DSS) was 55 months (16-119 months), and 2-year and 5-year DSS was 88% and 49%, respectively-significantly better than that of a comparison group of true PD-NEC (DSS 11 months). CONCLUSIONS: Mixed grades can occur in WD-NETs, which are distinguished from PD-NECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PD-NECs.

Simultaneous segmentation and iterative registration method for computing ADC with reduced artifacts from DW-MRI.

PURPOSE: Apparent diffusion coefficient (ADC), derived from diffusion-weighted magnetic resonance images (DW-MRI), measures the motion of water molecules in vivo and can be used to quantify tumor response to therapy. The accurate measurement of ADC can be adversely affected by organ motion and imaging artifacts. In this paper, the authors' goal was to develop an automated method for reducing artifacts and thereby improve the accuracy of ADC measurements in moving organs such as liver. METHODS: The authors developed a novel method of computing ADC with fewer artifacts, through simultaneous image segmentation and iterative registration (SSIR) of multiple b-value DW-MRI. The authors' approach reduces artifacts by automatically finding the best possible alignment between the individual b-value images and a reference DW image using a sequence of transformations. It selects such a sequence by an iterative choice of b-value DW images based on the accuracy of their alignment with the reference DW image. The authors' approach quantifies the accuracy of alignment between a pair of images using modified Hausdroff distance computed between the structures of interest. The structures of interest are identified by a user through strokes drawn in one or more slices in the reference DW image, which are then volumetrically segmented using GrowCut. The same structures are segmented in the remaining b-value images by transforming the user-drawn strokes through registration. The ADC values are computed from all the aligned b-value images. The images are aligned by using affine registration followed by deformable B-spline registration with cubic B-spline resampling. RESULTS: The authors compared the results of ADC computed using their approach with ADC computed (a) without registration and (b) with basic affine registration of all b-value images to a chosen reference. The authors' approach was the most effective in reducing artifacts compared to the other two methods. It resulted in a mean artifact ratio (fraction of voxels in a structure with negative ADC over total number of voxels in the structure) of 2.7% versus 5.4% for affine registration and 32% for no registration for >200 tumors. The authors' approach also resulted in the lowest median standard deviation in the computed mean ADC for all tumors [0.05,0.09,0.07,0.58] compared to those from affine image registration [0.02, 0.14, 0.58, 0.79] and no image registration [0.64, 0.83, 0.83, 1.09] on tests where random displacement [8,10,12,16] pixels were introduced in multiple trials in the b-value images. CONCLUSIONS: The authors developed a novel approach for reducing artifacts in ADC maps through simultaneous registration and segmentation of multiple b-value DW images. The authors' method explicitly employs a registration quality metric to align images. When compared to basic affine and no image registrations, the authors' approach produces registrations of greater accuracy with lowest artifact ratio and median standard deviation of the computed mean ADC values for a wide range of displacements.

Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.

PURPOSE: BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC. EXPERIMENTAL DESIGN: We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib. RESULTS: Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients. CONCLUSIONS: Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC.

Successful control of liver metastases from pancreatic solid-pseudopapillary neoplasm (SPN) using hepatic arterial embolization.

No systemic agents that are known to be effective for the treatment of solid-pseudopapillary neoplasm (SPN) are available. We report the prolonged and sustained control of metastatic pancreatic SPN to the liver using hepatic arterial embolization (HAE), where a total of 13 HAE sessions were performed over a 6-year period.