Kerrington D. Smith

Effect of initiating a multidisciplinary care clinic on access and time to treatment in patients with pancreatic adenocarcinoma.

PURPOSE Neoadjuvant therapy for pancreatic adenocarcinoma requires referral to multiple specialists before initiating therapy. We evaluated the effect of establishing a multidisciplinary clinic (MDC) for patients with newly diagnosed pancreatic adenocarcinoma on treatment access and time to therapy. METHODS Patients with newly diagnosed pancreatic adenocarcinoma diagnosed and treated at our center were included. Two patient groups were defined: preclinic represented those patients diagnosed before 2008 and MDC represented those patients diagnosed since 2009 who were treated in the newly created MDC and were initially candidates for neoadjuvant therapy. The primary outcomes were days from diagnosis to first treatment (initiation of chemotherapy or external beam radiation), days to completion of all required consultations, and number of visits needed before initiation of therapy. RESULTS Ninety-seven patients were diagnosed and treated at our medical center from 2003 to 2008; 22 were treated in 2009 after the implementation of the MDC. Compared with the preclinic group, patients treated in the MDC had shorter times from biopsy to treatment (7.7 days v 29.5 days, P < .001), shorter time to completion of all required pretreatment consultations (7.1 days v 13.9 days, P < .001), and fewer visits to complete all consultations (1.1 v 4.3, P < .001). Thirty-three percent of patients seen in the MDC enrolled onto clinical research trials. CONCLUSION In patients with pancreatic adenocarcinoma undergoing neoadjuvant therapy, the establishment of a multidisciplinary pancreas tumor clinic led to improved patient access to consultations and shorter time to initial treatment.

Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

BACKGROUND Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. METHODS Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. RESULTS A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. CONCLUSIONS Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies.

Adjuvant and neoadjuvant therapy for primary GIST

Adjuvant therapy for primary GIST has proven benefit in extending disease free survival. Defined risk factors for recurrent disease are based on GIST size, location, and mitotic rate and provide useful guidelines for selecting patients for adjuvant therapy considerations. Neoadjuvant therapy with tyrosine kinase inhibition has potential usefulness in primary GIST, although not yet as standard of care. Advantages can include tumor downsizing to provide opportunity for less morbid surgical resection as well as to decrease risk of intra-op tumor rupture. These theoretical considerations have not been evaluated in large clinical studies.

Role of Surgery in Familial Adenomatous Polyposis and Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome)

Surgery remains the mainstay of treatment for patients who develop colorectal cancer (CRC) in the setting of a hereditary CRC syndrome. In patients with a hereditary CRC syndrome, surgery can be prophylactic, therapeutic with curative intent, and, in some cases, palliative. The type and extent of surgical resection in familial adenomatous polyposis (FAP) and in the Lynch syndrome is influenced by differences in the natural history of carcinogenesis between the two syndromes and by the effectiveness of and patient compliance with available surveillance strategies. In this article, the surgical options for the management of patients with FAP and Lynch syndrome are discussed.

Genomic characterization of patient-derived xenograft models established from fine needle aspirate biopsies of a primary pancreatic ductal adenocarcinoma and from patient-matched metastatic sites

N-of-1 trials target actionable mutations, yet such approaches do not test genomically-informed therapies in patient tumor models prior to patient treatment. To address this, we developed patient-derived xenograft (PDX) models from fine needle aspiration (FNA) biopsies (FNA-PDX) obtained from primary pancreatic ductal adenocarcinoma (PDAC) at the time of diagnosis. Here, we characterize PDX models established from one primary and two metastatic sites of one patient. We identified an activating KRAS G12R mutation among other mutations in these models. In explant cells derived from these PDX tumor models with a KRAS G12R mutation, treatment with inhibitors of CDKs (including CDK9) reduced phosphorylation of a marker of CDK9 activity (phospho-RNAPII CTD Ser2/5) and reduced viability/growth of explant cells derived from PDAC PDX models. Similarly, a CDK inhibitor reduced phospho-RNAPII CTD Ser2/5, increased apoptosis, and inhibited tumor growth in FNA-PDX and patient-matched metastatic-PDX models. In summary, PDX models can be constructed from FNA biopsies of PDAC which in turn can enable genomic characterization and identification of potential therapies.

Pancreatic PEComa is a novel member of the family of tuberous sclerosis complex-associated tumors: case report and review of the literature

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with variable penetrance and a wide spectrum of disease manifestations even within the same family. Major diagnostic criteria for TSC include several distinct neoplasms, including facial angiofibroma, cardiac rhabdomyoma, lymphangioleiomyomatosis, subependymal giant cell astrocytoma, and renal angiomyolipoma. Germline mutations in either of two genes, TSC1 and TSC2, which code for hamartin and tuberin, respectively, cause TSC. Hamartin and tuberin, along with a third protein, TBC1D7, function as a heterocomplex to regulate activation of mTOR complex 1 (mTORC1) through regulation of the rheb GTPase. [5] Loss-of-function mutations in the TSC1 or TSC2 gene lead to activation of mTORC1, which is a direct contributor to the growth of these tumors, and this abnormal activation can be therapeutically blocked by rapamycin and its analogs, such as everolimus. [3] Although not completely separable clinically, TSC1 mutations are associated with overall milder disease severity than TSC2 mutations. The spectrum of clinical features of TSC continues to evolve. More recently, liver angiomyolipomas and pancreatic neuroendocrine tumors (NETs) have been described as manifestations of TSC. [4], [8] Little is known about other types of pancreatic neoplasms associated with TSC. Here, we describe multiple perivascular epithelioid cell tumors (PEComas) in the pancreas of a patient with TSC and provide proof of TSCrelated origin of these PEComas.

Total Pancreatectomy and Islet Autotransplant in the Treatment of Chronic Pancreatitis: Tread Very, Very Carefully

Total Pancreatectomy and Islet Autotransplant in the Treatment of Chronic Pancreatitis: Tread Very, Very Carefully

Staging Diagnostic Laparoscopy for Localized Pancreatic Cancer

This chapter will review the utility of staging laparoscopy in the setting of localized pancreatic cancer, including its benefits in detecting radiographic occult metastatic disease and cost-effectiveness of this diagnostic tool.

Pancreatectomy with Islet Autotransplant

Total pancreatectomy with islet autotransplant is a novel procedure for the treatment of pancreatitis, particularly in patients with diffuse disease unresponsive to medical therapy. Strict patient selection criteria are necessary to optimize outcomes. Postoperatively patients require careful glucose monitoring and nutritional support.

Drainage and Resection Surgery for Pancreatitis

Several surgical options exist for treatment of pancreatitis; these can be broadly categorized into drainage or resection procedures. The Puestow operation is a drainage procedure involving a longitudinal pancreatic ductotomy with anastomosis to jejunum and provides decompression for patients with significant ductal obstruction. Potential drawbacks of pancreatic resection surgery include persistent pain and development of surgical diabetes.