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Highlights • This manuscript raises the issue of optimal treatment of isolated visceral metastases in thyroid cancer. • This patient was treated unsuccessfully with multiple bouts of radioiodine before definite successful surgery to resect the metastasis. • This manuscript makes physicians aware that surgery is a viable option in oligometastases of thyroid cancer., Introduction Papillary (PTC) and follicular (FTC) thyroid carcinomas, together known as differentiated thyroid carcinomas (DTC), are among the most curable of cancers. Sites of metastases from FTC are usually osseous and those from PTC are in regional nodal basins and the lungs. Visceral metastases are rare and when they do occur, they tend do so in multiple sites. We present the case of a patient with a follicular variant of PTC and a solitary metastasis to the liver then review the relevant literature. Presentation of case An otherwise healthy 68-year-old woman was diagnosed with follicular variant papillary thyroid cancer in 2003 and subsequently underwent thyroidectomy. The patient’s endocrinologist conducted surveillance of her thyroid cancer. In 2012, due to rise in thyroglobulin, a whole body radioiodine scan was obtained which revealed an iodine-avid left liver lobe mass. Three cycles of radioiodine ablation therapy were unsuccessful and eventually the patient was referred for surgical resection. Metastatic evaluation including a PET scan was negative with the exception of an isolated enhancing 4 cm mass in segment 4B of the liver. Anatomic segmental resection of liver was performed without complications. Intraoperative ultrasonography was used to guide resection of the liver mass. Pathology reports confirmed metastatic follicular variant of PTC. Surgical margins were free of tumor. Patient was discharged home and is doing well one year after surgery. The latest thyroglobulin level was undetectable. Discussion Post-operative surveillance by PCP, endocrinologist or surgeon for patients with thyroid carcinoma should be performed routinely. If identified, a solitary liver metastasis from primary thyroid carcinoma should be considered for surgical resection. Due to sparse data available in literature, collecting more data to establish algorithms for treatment of such rare metastatic cancers may be able to aid physicians to achieve better outcomes. Conclusion Rare distant sites of metastases from DTC include eyes, pharynx, skin, muscle, ovaries, adrenal glands, kidneys, esophagus, pancreas and liver. Isolated, resectable liver metastases from PTC are exceedingly rare. Literature review revealed only 10 reported cases of liver metastases from DTC. As in our patient, solitary liver metastasis from PTC should be considered for surgical resection which offers the best chance for prolonged survival.

Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In radioiodine resistant aggressive papillary thyroid cancers, there remain few effective therapeutic options. A 62-year-old man who underwent multiple operations for papillary thyroid cancer and whose metastases progressed despite standard treatments provided tumor tissue.We analyzed tumor and whole blood DNA by whole genome sequencing, achieving 80× or greater coverage over 94 % of the exome and 90 % of the genome. We determined somatic mutations and structural alterations.We found a total of 57 somatic mutations in 55 genes of the cancer genome. There was notably a lack of mutations in NRAS and BRAF, and no RET/PTC rearrangement. There was a mutation in the TRAPP oncogene and a loss of heterozygosity of the p16, p18, and RB1 tumor suppressor genes. The oncogenic driver for this tumor is a translocation involving the genes for anaplastic lymphoma receptor tyrosine kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4). The EML4-ALK translocation has been reported in approximately 5 % of lung cancers, as well as in pediatric neuroblastoma, and is a therapeutic target for crizotinib.This is the first report of the whole genomic sequencing of a papillary thyroid cancer in which we identified an EML4-ALK translocation of a TRAPP oncogene mutation. These findings suggest that this tumor has a more distinct oncogenesis than BRAF mutant papillary thyroid cancer. Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.

Sensitive and specific biomarkers for pancreatic cancer are currently unavailable. The high mortality associated with adenocarcinoma of the pancreatic epithelium justifies the broadest possible search for new biomarkers that can facilitate early detection or monitor treatment efficacy. Protein glycosylation is altered in many cancers, leading many to propose that glycoproteomic changes may provide suitable biomarkers. In order to assess this possibility for pancreatic cancer, we have performed an in-depth LC-MS/MS analysis of the proteome and MS(n)-based characterization of the N-linked glycome of a small set of pancreatic ductal fluid obtained from normal, pancreatitis, intraductal papillary mucinous neoplasm (IPMN), and pancreatic adenocarcinoma patients. Our results identify a set of seven proteins that were consistently increased in cancer ductal fluid compared to normal (AMYP, PRSS1, GP2-1, CCDC132, REG1A, REG1B, and REG3A) and one protein that was consistently decreased (LIPR2). These proteins are all directly or indirectly associated with the secretory pathway in normal pancreatic cells. Validation of these changes in abundance by Western blotting revealed increased REG protein glycoform diversity in cancer. Characterization of the total N-linked glycome of normal, IPMN, and adenocarcinoma ductal fluid clustered samples into three discrete groups based on the prevalence of six dominant glycans. Within each group, the profiles of less prevalent glycans were able to distinguish normal from cancer on this small set of samples. Our results emphasize that individual variation in protein glycosylation must be considered when assessing the value of a glycoproteomic marker, but also indicate that glycosylation diversity across human subjects can be reduced to simpler clusters of individuals whose N-linked glycans share structural features.

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here, we describe a novel tumor–stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of hypoxia-inducible factor-1α (HIF-1α) by tumor hypoxia strongly activates secretion of the sonic hedgehog (SHH) ligand by cancer cells, which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and hedgehog signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. Our findings strengthen the rationale for testing HIF inhibitors and may therefore represent a novel therapeutic option for pancreatic cancer. Cancer Res; 73(11); 3235–47. ©2013 AACR.

The development of DNA microarray and quantitative real-time polymerase chain reaction technologies has allowed for precise quantitation of RNA expression of hundreds to thousands of genes. These technologies have significantly impacted the study and understanding of cancer in terms of its molecular and genetic characteristics. In this review article, breast cancer, colon cancer, and adrenal carcinoma have been chosen to illustrate the principle and techniques of genomic profiling and to illustrate how such methods may be used to develop genomic signatures for personalized risk assessment and to individualize patient treatment. J. Surg. Oncol. 2011;103:563–573. © 2011 Wiley-Liss, Inc.

Purpose of review Adrenocortical carcinoma is an aggressive, lethal malignancy of the adrenal cortex. The rarity of the disease has stymied therapeutic development. Recent work toward understanding the molecular pathogenesis of the disease has identified several potential new diagnostic and therapeutic targets. Recent findings The molecular characterization of adrenocortical carcinoma has identified dysregulation of the Gap 2/mitosis transition and the insulin-like growth factor 1 receptor signaling cascade as two major pathways for therapeutic development. These studies have also highlighted an unappreciated heterogeneity of the disease at the gene level that nevertheless seems to converge onto common cellular pathways. Additionally, the characterization of Wnt signaling through β-catenin in adrenal development, the demonstration of the involvement of BMP signaling in adrenocortical carcinoma growth regulation, and the discovery that ERCC1 expression levels can predict therapeutic response to platinum are just a few of the recent advances that promise to shed light on adrenocortical carcinoma biology. Summary Short-term, therapeutic development should target the Gap 2/mitosis transition and the downstream signaling of the insulin-like growth factor 1 receptor receptor. Long-term, additional characterization of patient samples, particularly at the sequence level, is required to fully understand adrenocortical carcinoma biology and apply that knowledge to clinical practice.

Growing tumors are hypoxic and respond to microenvironmental stress through increased expression of the hypoxia inducible factor-1α (HIF-1α) transcription factor, resulting in an adaptive switch to glycolytic metabolism, angiogenic signaling, survival, and metastasis. HIF-1α expression is associated with tumor resistance to cytotoxic therapy and inferior patient outcomes. Pancreatic cancer is the most hypoxic of all solid tumors and remains refractory to current chemoradiotherapy. We have seen nuclear HIF-1α in 88% of human pancreatic ductal carcinoma but in only 16% of normal pancreas. Stroma adjacent to the pancreatic ductal carcinoma also showed HIF-1α in 43% of cases. We investigated the novel selective HIF-1α inhibitor PX-478 on in vitro and in vivo radiation response of human pancreatic cancer models. Inhibition of HIF-1α by PX-478 increased cell killing by radiation. In mice with Panc-1, CF-PAC-1, or SU.86.86 pancreatic xenografts, concurrent administration of PX-478 potentiated the antitumor effects of fractionated radiation, with or without combined treatment with 5-fluorouracil or gemcitabine. Alternative sequencing of PX-478 with fractionated radiotherapy suggests optimal radiosensitization with concurrent or neoadjuvant administration of drug. Early tumor responses to combined PX-478/radiation treatment could be rapidly and repeatedly quantified by vascular imaging biomarkers. Dual-tracer dynamic contrast enhanced–magnetic resonance imaging and ultrasound imaging discriminated response to combined treatment prior to detection of differences in anatomic tumor size at 10 days posttreatment. Therefore, PX-478 is a mechanistically appealing and potentially clinically relevant enhancer of pancreatic cancer radiosensitivity, inhibiting tumor and stromal HIF-1 proangiogenic signaling and reducing the innate radiation resistance of hypoxic tumor cells. Mol Cancer Ther; 9(7); 2057–67. ©2010 AACR.

6539Background: Precision medicine (PM) molecular panel (MP) testing report actionable findings with associated targeted therapies (including immunotherapies). However, these actionable findings “r...

People want personalized medical care. I would like to think that we doctors have always treated our patients based on their individual health status, including factors such as their medical history, family history, laboratory data, results of imaging, and patient wishes. Personalized medicine, as a term, has evolved to indicate that the results of various forms of genomic analysis are applied to tailor an individual patient’s medical care. Patients don’t know, and indeed, most doctors don’t understand the future that the emerging molecular technologies can bring to the practice of medicine. Still, there are clear advantages that supplement but do not replace traditional clinical medicine. These advantages include the potential for predicting susceptibility to disease and as a result, more detailed screening or prophylactic preventive treatment. Personalized medicine also offers the potential for the diagnosis of disease at an early and more effectively treated time when the sequelae of the disease may be ameliorated. This is particularly true in the cancer field, where we work. Potential beneficiaries of the novel technologies will primarily be our patients but those who pay for medical care will also benefit. There are immense business opportunities for companies that develop diagnostics, drugs, or methods for data analysis. My message today is to focus on how we as surgeons have an opportunity and a responsibility to become involved and influence the development of personalized medicine as a field of discipline. Already several medical schools have developed institutes, programs, or curriculum focused on personalized medicine. Companies have been formed marketing individual analyses that purport to predict one’s risk of the development of a myriad of diseases ranging from Alzheimer’s disease or diabetes to male pattern baldness. In my address, I plan to review the current state of the field as it relates to our practice as endocrine surgeons.

Adrenocortical carcinoma (ACC) is an aggressive endocrine tumor with a poor 5-year survival rate of 10–20%. Current therapy is often ineffective and may be associated with intolerable side effects. Although ACC is extremely rare, recent advances in genomic and expression profiling, coupled with knowledge gained from the study of the inherited syndromes that increase ACC risk, are beginning to bring together a picture of a tumor type dependent on p53, the G2/M cell cycle transition and IGF2 stimulation. Nevertheless, ACC remains a heterogeneous disease. Only recently have sufficient tumors been characterized and results published to permit an exploration of this diversity. Advances in treatment will depend on exploiting those pathways already implicated in ACC, along with those yet to be identified, and testing those treatments in better models of the disease than the three cell lines that currently exist and are widely available to the community.

The PRL phosphatases have been implicated in cancer cell growth and metastasis in a variety of tumor types. Using cDNA microarray, we previously identified and reported PRL-1 as being highly up-regulated in pancreatic cancer cell lines. In this study, we sought to further evaluate the expression of all three PRL phosphatases in pancreatic cancer cell lines and extend our findings to in situ analysis of primary pancreatic tumors taken directly from patients. Additionally, we determine if small interfering RNA-mediated knockdown of relevant PRLs confers antitumor effects in pancreatic cancer cells. Using oligonucleotide expression arrays, mRNA levels of PRL-1 and PRL-2 but not PRL-3 were identified as up-regulated in pancreatic cancer cell lines and tumor samples taken directly from patients compared with those of normal pancreas. Focusing on PRL-1 and PRL-2, high levels of both proteins were detected in a subset of pancreatic cancer cell lines and tumor samples using Western blotting and immunohistochemistry, respectively. Small interfering RNA-mediated knockdown of PRL-1 and PRL-2 in combination resulted in a moderate reduction of cellular growth and migration in MIA PaCa-2 and PANC-1 cells. More importantly, knockdown of both PRL-1 and PRL-2 significantly inhibited colony formation of these cells in soft agar as well as serum-induced Akt phosphorylation. These data support the hypothesis that PRL phosphatases regulate key pathways involved in tumorigenesis and metastasis and that knockdown of both PRL-1 and PRL-2 is required to disrupt PRL phosphatase function in pancreatic cancer cells. [Mol Cancer Ther 2008;7(1):202–10]

Background Adrenocortical carcinoma (ACC) is an aggressive cancer with a 5 year survival rate of 20–30 %. Various factors have been implicated in the pathogenesis of ACC including dysregulation of the G2/M transition and aberrant activity of p53 and MDM2. Polo-like kinase 1 (PLK-1) negatively modulates p53 functioning, promotes MDM2 activity through its phosphorylation, and is involved in the G2/M transition. Gene expression profiling of 44 ACC samples showed that increased expression of PLK-1 in 29 % of ACC. Consequently, we examined PLK-1’s role in the modulation of the p53 signaling pathway in adrenocortical cancer. Methods We used siRNA knock down PLK-1 and pharmacological inhibition of PLK-1 and MDM2 ACC cell lines SW-13 and H295R. We examined viability, protein expression, p53 transactivation, and induction of apoptosis. Results Knocking down expression of PLK-1 with siRNA or inhibition of PLK-1 by a small molecule inhibitor, BI-2536, resulted in a loss of viability of up to 70 % in the ACC cell lines H295R and SW-13. In xenograft models, BI-2536 demonstrated marked inhibition of growth of SW-13 with less inhibition of H295R. BI-2536 treatment resulted in a decrease in mutant p53 protein in SW-13 cells but had no effect on wild-type p53 protein levels in H295R cells. Additionally, inhibition of PLK-1 restored wild-type p53’s transactivation and apoptotic functions in H295R cells, while these functions of mutant p53 were restored only to a smaller extent. Furthermore, inhibition of MDM2 with nutlin-3 reduced the viability of both the ACC cells and also reactivated wild-type p53′s apoptotic function. Inhibition of PLK-1 sensitized the ACC cell lines to MDM2 inhibition and this dual inhibition resulted in an additive apoptotic response in H295R cells with wild-type p53. Conclusions These preclinical studies suggest that targeting p53 through PLK-1 is an attractive chemotherapy strategy warranting further investigation in adrenocortical cancer. Electronic supplementary material The online version of this article (doi:10.1186/s40169-015-0080-3) contains supplementary material, which is available to authorized users.

Context Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five-year survival rate and limited treatment options. Objective Understanding of the molecular pathogenesis of this disease has been aided by genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC. Design In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors. Results This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC. Conclusions DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors.

Mitotane (2-[o-chlorophenyl]-2-[p-chloro phenyl]-1,1-dichloroethane or o,p´-DDD), an isomer of the banned pesticide 1,1,1-trichloro2,2-di(4-chlorophenyl)ethane (DDT), is the current standard of care for patients presenting with advanced and metastatic adrenocortical carcinoma (ACC) [1–3]. Mitotane or combinations containing mitotane have remained the standard of care for patients with ACC for over 30 years despite a lack of understanding regarding its mechanism of action or interactions with other agents and a suboptimal effectiveness. The results from the recently reported FIRM-ACT trial [4] and evidence from a study of urine steroid profiles of patients with ACC cast further doubt on the broad use of mitotane in treating ACC patients [5]. These studies highlight a need to identify markers of mitotane resistance and put significant effort into the development of new treatments, and possibly treatment paradigms, in order to improve outcomes for patients with ACC. Why mitotane is the standard of care for the treatment of ACC ACC is an aggressive cancer of the adrenal cortex. The outcome for patients with ACC has remained unchanged in the past 25 years, with the overall 5-year survival of patients undergoing surgical resection being approximately 40% [6]. The disease may have a variable course. Certain patients generally fare better, including those with stage II disease whose 5-year survival rates approach 60%, and improve to greater than 95% if their tumor does not recur within 16 months [7]. However, patients who present with large, locally invasive tumors, have involved surgical margins or present with metastatic disease fare considerably worse with 5-year survival rates of 10–20% [6]. The rationale for using mitotane as treatment for ACC stems from early observations of the adrenolytic effect of the pesticide DDT

Doctors John Verner Jr. and Ashton B. Morrison happened to be sitting next to each other at a case presentation of a patient who died with profuse watery diarrhea attributed to chronic laxative abuse. The autopsy report noted the presence of a benign islet cell that was felt to be of no clinical significance. These two astute physicians realized that more was afoot, and when a second patient with a similar presentation was found, they realized they were on to a new clinical entity. Verner was an endocrinologist with an interest in hypokalemia and Morrison was a pathologist whose primary research interest was in chronic renal insufficiency. They partnered to make a seminal discovery in endocrine surgery by describing the syndrome of watery diarrhea, hypokalemia, and achlorhydria that bears their monikers. This chapter details the backgrounds, careers, and personal perspectives on their important contribution.

Summary Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma. Methods In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989. Findings Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256–507] vs 356 days [249–556]; hazard ratio 0·94 [95% CI 0·61–1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related. Interpretation Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma. Funding Astellas.

We examined the influence of gender and climacteric status, two coronary risk factors, on bradykinin (BK)-induced dilation in adipose arterioles from men and women of different ages [premenopausal women (Pre-W), postmenopausal women (Post-W), and similar aged men (Y-M and O-M), respectively]. We examined the responses from both omental (more closely associated with coronary disease) and subcutaneous fat. Tissues were obtained at surgery and cannulated (60 mmHg) for measurement of internal diameter. In vessels from omental tissue, dilation to BK was more sensitive in Pre-W than other groups, whereas in vessels from subcutaneous tissue, sensitivity to BK was greater in both Pre-W and Post-W compared with Y-M and O-M. Maximal dilation was similar among groups. Indomethacin (Indo; 10−5 M) alone had no effect on dilation to BK in any groups, but Indo and N ω-nitro-l-arginine methyl ester (l-NAME; 10−4 M) reduced dilation to BK in Pre-W more than in Y-M. l-NAME increased dilation to BK in subcutaneous fat from Y-M but had no effect in Post-W and O-M. Indo- and l-NAME-resistant dilation in all vessels was markedly reduced by 30 mM KCl. There was no difference in sodium nitroprusside-induced dilation among groups. We conclude that gender and climacteric state contribute to mechanisms of microvascular regulation in humans. Functional vascular differences in visceral and subcutaneous fat may underlie the proposed differential influence of these tissues on cardiovascular risk.

Pancreatic neuroendocrine tumors rarely undergo cystic degeneration leading to a radiologic appearance, which is often interpreted as a pancreatic mucinous cystadenoma or pseudocyst. We reviewed our experience with 38 neuroendocrine tumors, four of which were cystic, and 24 other cystic pancreatic tumors (mucinous cystadenoma [n = 5], cystadenocarcinoma [n = 6], serous cystadenoma [n = 3], solid/cystic papillary neoplasm [n = 3], intraductal papillary mucinous tumor [n = 6], and mucinous adenocarcinoma [n = 1]) managed operatively between 1990 and 2000. This review was undertaken to identify clinical and pathologic features useful for preoperative diagnosis of cystic neuroendocrine tumors. Two of the four patients with cystic neuroendocrine tumors presented with abdominal pain, one patient was asymptomatic, and one patient had hypoglycemia. Three of the four cystic neuroendocrine tumors were identified by CT scan, and none were biopsied preoperatively. Preoperative diagnoses included mucinous cystadenoma in two patients (n = 2), pancreatic cystic neoplasm in one patient, (n = 1) and insulinoma in one patient (n = 1). All four cystic neuroendocrine tumors were benign and were completely resected (distal pancreatectomy [n = 2], enucleation [n = 2]). Cystic neuroendocrine tumors are difficult to diagnose preoperatively because the majority of these tumors are nonfunctional, and CT does not differentiate these tumors from other cystic neoplasms. Cystic neuroendocrine tumors represent a subgroup of pancreatic cystic and neuroendocrine tumors with malignant potential. Their high resectability rate further supports the role of surgical exploration and resection in the treatment of pancreatic cystic neoplasms.

Background Several members of the zinc finger protein family have been recently shown to have a role in cancer initiation and progression. Zinc finger protein 367 (ZNF367) is a member of the zinc finger protein family and is expressed in embryonic or fetal erythroid tissue but is absent in normal adult tissue. Methodology/Principal Findings We show that ZNF367 is overexpressed in adrenocortical carcinoma, malignant pheochromocytoma/paraganglioma and thyroid cancer as compared to normal tissue and benign tumors. Using both functional knockdown and ectopic overexpression in multiple cell lines, we show that ZNF367 inhibits cellular proliferation, invasion, migration, and adhesion to extracellular proteins in vitro and in vivo. Integrated gene and microRNA expression analyses showed an inverse correlation between ZNF367 and miR-195 expression. Luciferase assays demonstrated that miR-195 directly regulates ZNF367 expression and that miR-195 regulates cellular invasion. Moreover, integrin alpha 3 (ITGA3) expression was regulated by ZNF367. Conclusions/Significance Our findings taken together suggest that ZNF367 regulates cancer progression.

ver the past several years, mucinproducing pancreatic tumors have become a much more widely recognized entity. With increasing awareness has also come an evolution of concepts and nomenclatures regarding this set of pancreatic neoplasms. Understandably, this maturation process has led to confusion over categorization, management, and prognosis. This article will propose a unifying view of these mucinproducing tumors and provide imaging examples for illustrations. Mucin-producing pancreatic tumors should be considered when cystic lesions of the pancreas are found. Most pancreatic “cysts” are nonneoplastic, usually inflammatory pseudocysts. Approximately 5‐15% of these cystic masses will be neoplastic [1]. Until 1978, the term “cystadenoma” was used to describe cystic neoplasms of the pancreas [2, 3]. At that time, the mucinous tumors were subdivided from the serous cystadenoma. More recently, the mucinous tumors have been further subclassified into two major groups: intraductal papillary mucinous neoplasm and mucinous cystic neoplasm. These two entities share a common array of epithelia that ranges from adenomatous, to proliferative ductal epithelium, to invasive carcinoma. These different epithelia may be present within a single tumor or may evolve toward the more aggressive form, similar to that of colon carcinoma [4]. Most consider both mucinous lesions as at least premalignant if not a low-grade malignancy [5]. In general, both lesions are associated with a better prognosis than the more common ductal carcinoma. However, the intraductal papillary mucinous neoplasm and mucinous cystic neoplasm differ sufficiently in clinical presentation, anatomic location, radiographic appearance, and patient demographics (Table 1) to justify their division. Intraductal Papillary Mucinous Neoplasm

To study the effect of barium sulfate on wound healing in the gastrointestinal tract of the rat.Sixty rats weighing approximately 320 g were divided into four groups: Fifteen control rats had gastric, small-bowel, and colonic incisions; 15 rats had gastric incision; 15 rats had small-bowel incision; and 15 rats had colonic incision. Barium sulfate was placed into the incision before closure in all rats except those in the control group, and the effects were documented clinically and histopathologically for 3 months. Autopsy was performed in five rats from each group at 1, 4, and 12 weeks. The incisions in the rats receiving barium sulfate were compared with those in the control rats.There was no difference in the clinical course (weight gain, activity, and viability) between the control and experimental groups. Early and late autopsy findings and histopathologic grading of healing and inflammatory response were similar for both the control and experimental groups.Under the conditions of this study, the effect of barium sulfate on visceral transmural wound healing in the gastrointestinal tract of the rat was minimal.

BACKGROUND In the absence of metastases, there are no reliable microscopic features that distinguish malignant from benign pheochromocytomas. Because a common feature of malignancy is the loss of cell cycle regulation and normal growth arrest, the authors hypothesized that analysis of the cell cycle could be used to aid in the diagnosis of malignant pheochromocytoma. METHODS Cell cycle analysis of archival samples of 51 pheochromocytomas (40 sporadic, 11 familial) from 45 patients, including 6 malignant and 45 benign tumors, was conducted. Flow cytometry data and immunohistochemistry for markers of cell proliferation (proliferating cell nuclear antigen [PCNA] and MIB-1 [Ki-67]) were correlated with the authors' clinical data base records, with a mean follow-up of 66 months. RESULTS No correlation of DNA ploidy, S-phase fraction by flow cytometry, or PCNA with malignancy was observed. Staining for the MIB-1 nuclear proliferation marker was positive in 3 of 6 (50%) of the malignant pheochromocytomas and negative in all 45 benign tumors (P< 0.01). CONCLUSIONS Contrary to some previous reports, a diploid DNA pattern does not necessarily predict benign behavior of pheochromocytoma. In this study, cell cycle analysis and, in particular, assessment of the MIB-1 nuclear proliferation marker was useful in the histologic evaluation of pheochromocytoma, as MIB-1 was expressed only in malignant tumors. Cancer 1999;86:1583–9. © 1999 American Cancer Society.

Adrenocortical cancers are relatively rare endocrine tumors that usually present when hormonally active or after they have become large and metastasis has occurred. Consequently, the 5-year survival rate is 20% to 35%. Surgical removal remains the only form of therapy proven to prolong survival. Mitotane is the most accepted form of chemotherapy. For the approximately 20% to 25% of patients whose tumors respond to mitotane, survival is prolonged.

Reports of improved survival rates for patients with resected adenocarcinoma of the pancreas coincide with the adoption of adjuvant chemoradiation protocols. The impact of nodal micrometastases demonstrated by molecular assays and adjuvant therapy on survival of patients with stage I pancreatic cancer has not been adequately assessed.A retrospective analysis of postoperative chemoradiation on survival in 61 patients undergoing resection of pancreatic adenocarcinomas from 1984 to 1997 was performed. Archival tumors and regional nodes from 25 patients with stage I cancers were tested for a Kiras oncogene mutation using polymerase chain reaction and analysis for restriction fragment length polymorphisms (PCR/RFLP).Adjuvant chemoradiation was associated with improved survival for stage I (P.01), but not stage III, disease. Seventeen (68%) of 25 patients with stage I disease tested had evidence of mutant Kiras in one or more regional nodes. Survival did not differ for patients with molecular micrometastases. Six of 17 (35%) patients with micrometastases received adjuvant chemoradiation and had improved survival (P.05).The majority of patients with stage I pancreatic cancer have PCR/RFLP evidence of lymph node micrometastases. Adjuvant chemoradiation improves survival in these patients by treating micrometastases not detected by histology. Adjuvant chemoradiation should be used for patients with stage I pancreatic cancers.

BACKGROUND Stage I (T1-2N0M0) adenocarcinoma of the pancreas is associated with a 5-year survival rate of 15-25%. Despite apparently curative resection and pathologic staging indicating localized disease, these cancers recur. The authors hypothesized that there exists microscopic regional disease that is not detected by surgical exploration or routine histopathology. METHODS Because 90-95% of pancreatic cancers exhibit codon 12 K-ras mutations, the authors examined regional lymph nodes for mutated K-ras as a marker of metastasis. DNA was extracted from paraffin embedded archival specimens (primary tumors and histologically negative lymph nodes) of patients with Stage I pancreatic adenocarcinoma. The target region of K-ras was amplified by polymerase chain reaction (PCR) and tested for codon 12 mutation by BstN1 restriction digestion (restriction fragment length polymorphism [RFLP]) that recognized normal but not mutated sequences. Cell lines that harbored normal or mutated K-ras and resected jejunum or gallbladder were used as controls. The regional lymph nodes of 22 patients whose tumors harbored mutated K-ras were tested. RESULTS Dilution experiments with normal and mutant control cell line DNA demonstrated an assay sensitivity for mutated K-ras of 0.1%. Mutated K-ras was found in at least 1 regional lymph node in 16 (73%) of 22 patients with pathologic Stage I pancreatic adenocarcinoma, which suggested metastases not detected by routine histopathology. DNA sequence analysis was performed in four patients and confirmed identical point mutations in the primary tumor and accompanying PCR/RFLP positive lymph nodes. CONCLUSIONS Pathologic examination of regional lymph nodes in pancreatic adenocarcinoma specimens fails to detect metastases in many patients. Lymph node micrometastasis is one reason for the poor survival rates observed among patients with Stage I cancers. PCR/RFLP may have a role in staging early pancreatic cancers. Cancer 1998;83:1328-1334. © 1998 American Cancer Society.

Pheochromocytomas are a rare cause of hypertension in pregnancy. Laparoscopic adrenalectomy has been used effectively and safely in nonpregnant patients with pheochromocytoma, with the resultant benefits to the patients of less postoperative pain, shorter hospital stay, and quicker return to normal activities than is associated with open techniques. This represents the first report of a laparoscopic adrenalectomy for pheochromocytoma in a pregnant woman. Issues that are unique to laparoscopic surgery in pregnant patients are discussed.

Background The field of cancer genomics has rapidly adopted next-generation sequencing (NGS) in order to study and characterize malignant tumors with unprecedented resolution. In particular for cancer, one is often trying to identify somatic mutations – changes specific to a tumor and not within an individual’s germline. However, false positive and false negative detections often result from lack of sufficient variant evidence, contamination of the biopsy by stromal tissue, sequencing errors, and the erroneous classification of germline variation as tumor-specific. Results We have developed a generalized Bayesian analysis framework for matched tumor/normal samples with the purpose of identifying tumor-specific alterations such as single nucleotide mutations, small insertions/deletions, and structural variation. We describe our methodology, and discuss its application to other types of paired-tissue analysis such as the detection of loss of heterozygosity as well as allelic imbalance. We also demonstrate the high level of sensitivity and specificity in discovering simulated somatic mutations, for various combinations of a) genomic coverage and b) emulated heterogeneity. Conclusion We present a Java-based implementation of our methods named Seurat, which is made available for free academic use. We have demonstrated and reported on the discovery of different types of somatic change by applying Seurat to an experimentally-derived cancer dataset using our methods; and have discussed considerations and practices regarding the accurate detection of somatic events in cancer genomes. Seurat is available at https://sites.google.com/site/seuratsomatic.

Purpose New anticancer agents that target a single cell surface receptor, up-regulated or amplified gene product, or mutated gene, have met with some success in treating advanced cancers. However, patients' tumors still eventually progress on these therapies. If it were possible to identify a larger number of targetable vulnerabilities in an individual's tumor, multiple targets could be exploited with the use of specific therapeutic agents, thus possibly giving the patient viable therapeutic alternatives. Experimental Design In this exploratory study, we used next-generation sequencing technologies (NGS) including whole genome sequencing (WGS), and where feasible, whole transcriptome sequencing (WTS) to identify genomic events and associated expression changes in advanced cancer patients. Results WGS on paired tumor and normal samples from nine advanced cancer patients and WTS on six of these patients' tumors was completed. One patient's treatment was based on targets and pathways identified by NGS and the patient had a short-lived PET/CT response with a significant reduction in his tumor-related pain. To design treatment plans based on information garnered from NGS, several challenges were encountered: NGS reporting delays, communication of results to out-of-state participants and their treating oncologists, and chain of custody handling for fresh biopsy samples for Clinical Laboratory Improvement Amendments (CLIA) target validation. Conclusion While the initial effort was a slower process than anticipated due to a variety of issues, we demonstrate the feasibility of using NGS in advanced cancer patients so that treatments for patients with progressing tumors may be improved.

Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets.We profiled 44 ACC and 4 normal adrenals on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by Western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation.Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Overexpression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average β-actin-3.04) was 1.8 years compared with 9.0 years if tumors expressed lower levels of PTTG1 (P.0001). Analysis of a previously published dataset confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of 2 ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (median inhibition concentrations of 1.69 μmol/L and 0.891 μmol/L, for SW-13 and H295R, respectively).Overexpression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.

Background. An essential difference between benign and malignant follicular thyroid tumors is the ability to invade and metastasize. Thyrotropin (TSH) stimulates invasion of cultured human follicular thyroid cancer cells (FTG-133) via a protein kinase C (PKC) dependent mechanism. Tumor invasion depends on degradation of extracellular matrix by proteases. Methods. We analyzed protease activity in FTC-133 and its more invasive clone, FTC-238. Cells were treated with TSH or 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a PKC agonist, for 24 hours. Conditioned medium and cellular extract were subjected to substrate gel zymography with either casein-plasminogen or gelatin (collagen). Western blot and immunohistochemistry confirmed protease identity. Results. We found increased 50 kd urokinase-like plasminogen activator (uPA) and 62 kd gelatinase activity by FTC-238 cells compared with the less invasive FTC-133 cells. There was no effect of TSH on uPA or collagenase activity at concentrations of 0.01 to 10 mU/ml. In both FTC-133 and FTC-238, TPA incubations of 0.1 to 100 ng/ml caused a dose-dependent increase in uPA and a 94 kd type IV collagenase. Conclusions. These findings show that TSH-stimulated invasion may be due to PKC-induced activation of uPA and 94 kd type IV collagenase. uPA and basement membrane type IV collagenase warrant investigation as markers for follicular thyroid cancer.

Some manifestations of secondary hyperparathyroidism affect most if not all patients with chronic renal failure and can affect many different organ systems. Proper medical treatment is essential and should be attempted before considering surgical intervention. The symptoms that most often resolve after parathyroidectomy include bone pain and intractable pruritus. Other useful indications for operation include a marked elevation of the parathyroid hormone level and the elevation of the calcium x phosphate product over 70. Both subtotal parathyroidectomy and total parathyroidectomy with autotransplantation have been advocated as the best operative approach. Each of these procedures has its own advantages and disadvantages which should be considered for each individual case. Localizing procedures should be reserved for patients with persistent or recurrent hyperparathyroidism, as diffuse parathyroid hyperplasia is the most common operative finding in secondary hyperparathyroidism.

Background: The promise of precision medicine is vast and efforts are needed to increase utilization of precision oncology tests. Studies have suggested that mutations in cancer predisposition are more common than previously thought. Herein, we investigated germline alterations in cancer patients undergoing tumor profiling to identify the potential genetic predisposing factors as well as therapeutically relevant germline variants. Methods: Comprehensive genomic profiling was performed on tumor samples from 67 patients from 24 cancer types with ages ranging 23-77 years. We performed targeted exome sequencing of 562 genes in tumor and paired normal DNA which included 116 genes that have been associated with cancer predisposition syndromes. In addition to identifying the somatic changes, we characterized germline mutations in select 116 genes using public databases (ClinVar, Ensembl). Results: Pathogenic germline mutations were found in 17.91% (12/67) of cases, which included 10 unique variants in 8 genes, the majority of which included DNA repair genes (ATM, BRCA2, ERCC4, NBN, PSM2, MUTYH, XPC and AR). Likely pathogenic mutations were found in 23% (16/67) of the cases and 12% (8/67) were predicted pathogenic by SIFT/PolyPhen. In select cases we found existence of a 2nd hit which may have an impact on certain targeted therapeutics such as PARP inhibitors. All of the cases profiled carried either benign or variants of unknown significance (VUS) mutations. Germline findings in cancer susceptibility genes that were concordant with the individual's cancer type included ATM (R2227C) in HER2+ breast cancer patient; BRCA2 missense mutation (K944X) in peritoneal cancer and HER2+ breast cancer; BRCA2 (W1692MfsX3, I2588YfsX60) in patients with pancreatic and breast cancer respectively and PMS2(L729QfsX6) in colorectal cancer (CRC). Germline pathogenic findings in cancer susceptibility genes that were dis-concordant with the individual's cancer type included ERCC4 (R799W) in endometrial cancer; XPC (P334H) in CRC; MUTYH (G393D) in esophageal and CRC; NBN (K219NfsX16) in HER2+ breast cancer and AR (A646D) mutation in CRC. Interestingly, FLT4 (R1324L) mutation which is associated with decreased response and toxicity to sunitinib in renal cell cancer was found across several tumor types including lung adenocarcinoma (n = 3), pancreatic cancer (n = 3), HER2+ breast cancer (n = 2), CRC (n = 2) and n = 1 in gallbladder carcinoma, cholangiocarcinoma and endometrial adenocarcinoma. The comparison of somatic to germline mutation will be presented. Conclusion: Germline data analysis of a small cohort of advanced cancer patients revealed that unselected cancer patients may benefit from germline evaluation which may influence the evaluation and care of the patient or the patient's family members. Even though majority of germline mutations were VUS, several mutations were identified which may be amenable to targeted therapeutic strategies. Citation Format: Subha Krishnan, Gargi D. Basu, Laura Gonzalez-Malerva, Thomas Royce, Tracey White, Janine R. Lobello, Amy King, Kevin Lau, Ahmet Kurdoglu, Matthew Halbert, Jeff Kiefer, Irene Cherni, Jessica Aldrich, Tyler Izatt, Megan Russell, Sara Nasser, John D. Carpten, David W. Craig, Jeffrey Trent, Michael J. Demeure. Germline findings in targeted tumor sequencing using matched normal DNA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4493.

11599Background: Immune checkpoint inhibitors have therapeutic benefit in the treatment of various cancers; however, an elucidation of the molecular determinants of response to such therapy is need...

e17044Background: Gynecologic cancers (GC) affect women's reproductive organs and are associated with the highest mortality rates due to late stage detection and lack of effective treatments. The t...

2547Background: Polo-like kinase 1 (PLK1) regulates critical aspects of tumor progression. High expression levels correlate with poor survival in ACC. TKM-080301 is a lipid nanoparticle formulation of a siRNA against PLK1. Methods: TKM-080301 was evaluated in an open-label study with dose escalation and expansion phases in patients with refractory ACC. TKM-080301 was infused IV over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Primary study objectives included assessment of safety and anti-tumor activity by RECIST 1.1 after every 2 cycles. Results: Sixteen patients were treated at 0.6 or 0.75 mg/kg/week for up to 18 cycles. Eight received at least 2 cycles of study treatment and were evaluable for tumor response. Four had a best response of stable disease including one with a 13% reduction of target tumor diameter. One 51 yo man with metastatic intraperitoneal non-functional ACC had a partial response (target tumor reduction of 19% after cycle 2 and 49% after cycle 14). Residual tumor was resected a...

671 Background: The gene encoding the AT-rich interacting domain (ARID1A) is a tumor suppressor and a subunit of the Switch/Sucrose Non fermentable (SWI/SNF) chromatin remodeling complex that regulates gene expression. Additionally, ARID1A functions to maintain genomic integrity by interacting with ATR. Mutations in ARID1A have been observed in a number of cancers. Inactivation of ARID1A has been reported to lead to increased sensitivity to inhibitors of PARP and PI3K/AKT pathway. We evaluated ARID1A alterations in gastrointestinal (GI) cancers to identify new therapeutic options. Methods: Comprehensive genomic profiling was performed on 55 GI cancer samples with 28 metastatic and 27 primary samples. Targeted sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA samples. Results: ARID1A alterations were noted in 20% (11/55) of GI cancers. Alterations included frameshift and nonsense mutations, INDELs and structural breakpoints which are predicted to cause loss of ARID1A function. Tumor tissues harboring ARID1A alterations included 2/8 gastro-esophageal cancers, 2/2 duodenal cancers, 3/29 colorectal (CRC) cancers, 2/2 small bowel cancers, and 2/7 bile duct cancers. Mutations in the C-terminal half of ARID1A, known to interact with ATR and mediate its recruitment to double strand breakpoints was present in 2/11 samples. No pathogenic changes in the DNA repair genes (BRCA1/2, CHEK1/2, ATM, ATR or PALB2) or MMR genes were present in the tumors harboring ARID1A alterations. Interestingly, ARID1A mutations frequently coexisted with alterations leading to activation of the PI3K pathway. We found 45% (5/11) samples with mutated ARID1A had pathogenic alterations in PIK3CA, AKT, NF1, STK11, TSC1 and TSC2 genes which may increase sensitivity to PI3K pathway inhibitors. Conclusions: Targeted sequencing demonstrated that ARID1A is a frequent event in GI cancer. Our results suggest there may be a correlation between samples with ARID1A alteration and PI3K/AKT pathway activation which may lead to therapeutic opportunities with PI3K pathway inhibitors. The presence of ARID1A mutations especially those in the C-terminal half may predict clinical utility of PARP inhibitors in GI cancer.

Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P

Altered adhesion plaques have been observed in transformed cell lines and are associated with enhanced metastatic potential. The prototypical adhesion plaque is formed by alpha 5 beta 1 fibronectin receptors (FnRs) interacting with the cellular actin network. We have found differences in the actin networks of noninvasive (FTC-133) and invasive (FTC-236, FTC-238) clones of a human follicular thyroid cancer cell line. Furthermore, thyroid-stimulating hormone (TSH) induces stress fibers in FTC-133. In order to investigate differences in adhesion plaques, expression of fibronectin (FN) and its receptor by these cells was analyzed. For these studies FTC-133, FTC-236, and FTC-238 were cultured in serum-depleted DME-H21 medium for 24 hours before the addition of TSH 30 mU/ml. No quantitative differences were noted in FN expression on Western blot in either the conditioned medium or cellular extracts. Western blots and immunohistochemical studies indicated that TSH induced secretion of FN only in FTC-133. Flow cytometry with an alpha 5 antibody demonstrated a 52% and 45% reduction (p0.01) in expression of FnR by FTC-236 and FTC-238, respectively, compared to FTC-133; this finding was supported by immunohistochemistry results. TSH treatment did not alter FnR expression. From these studies, we conclude that invasive clones of FTC decrease their expression of FnRs without changing their expression of FN. Furthermore, TSH treatment may promote FN secretion by FTC-133, although it does not seem to affect FnR or absolute FN expression. The diminished expression of FnR adhesion plaques may enhance metastatic potential in some follicular thyroid cancers.

BACKGROUND Traditional drug discovery methods have a limited role in rare cancers. We hypothesized that molecular technology including gene expression profiling could expose novel targets for therapy in adrenocortical carcinoma (ACC), a rare and lethal cancer. SPARC (secreted protein acidic rich in cysteine) is an albumin-binding matrix-associated protein that is proposed to act as a mechanism for the increased efficacy of a nanoparticle albumin-bound preparation of the antimicrotubular drug Paclitaxel (nab-paclitaxel). METHODS The transcriptomes of 19 ACC tumors and 4 normal adrenal glands were profiled on Affymetrix U133 Plus2 expression microarrays to identify genes representing potential therapeutic targets. Immunohistochemical analysis for target proteins was performed on 10 ACC, 6 benign adenomas, and 1 normal adrenal gland. Agents known to inhibit selected targets were tested in comparison with mitotane in the 2 ACC cell lines (H295R and SW-13) in vitro and in mouse xenografts. RESULTS SPARC expression is increased in ACC samples by 1.56 ± 0.44 (μ ± SD) fold. Paclitaxel and nab-paclitaxel show in vitro inhibition of H295R and SW-13 cells at IC50 concentrations of 0.33 μM and 0.0078 μM for paclitaxel and 0.35 μM and 0.0087 μM for nab-paclitaxel compared with mitotane concentrations of 15.9 μM and 46.4 μM. In vivo nab-paclitaxel treatment shows a greater decrease in tumor weight in both xenograft models than mitotane. CONCLUSIONS Biological insights garnered through expression profiling of ACC tumors suggest further investigation into the use of nab-paclitaxel for the treatment of ACC.

Quiescin sulfhydryl oxidase 1 (QSOX1) oxidizes sulfhydryl groups to form disulfide bonds in proteins. We previously mapped a peptide in plasma from pancreatic ductal adenocarcinoma (PDA) patients back to an overexpressed QSOX1 parent protein. In addition to overexpression in pancreatic cancer cell lines, 29 of 37 patients diagnosed with PDA expressed QSOX1 protein in tumor cells, but QSOX1 was not detected in normal adjacent tissues or in a transformed, but nontumorigenic cell line. To begin to evaluate the advantage QSOX1 might provide to tumors, we suppressed QSOX1 protein expression using short hairpin (sh) RNA in two pancreatic cancer cell lines. Growth, cell cycle, apoptosis, invasion, and matrix metalloproteinase (MMP) activity were evaluated. QSOX1 shRNA suppressed both short and long isoforms of the protein, showing a significant effect on cell growth, cell cycle, and apoptosis. However, QSOX1 shRNA dramatically inhibited the abilities of BxPC-3 and Panc-1 pancreatic tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, gelatin zymography indicated that QSOX1 plays an important role in activation of MMP-2 and MMP-9. Taken together, our results suggest that the mechanism of QSOX1-mediated tumor cell invasion is by activation of MMP-2 and MMP-9. Mol Cancer Res; 9(12); 1621–31. ©2011 AACR.

Background Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In rare tumors, where large-scale clinical trials are daunting, this targeted genomic approach offers a new perspective and hope for improved treatments. Cancers of the ampulla of Vater are rare tumors that comprise only about 0.2% of gastrointestinal cancers. Consequently, they are often treated as either distal common bile duct or pancreatic cancers. Methods We analyzed DNA from a resected cancer of the ampulla of Vater and whole blood DNA from a 63 year-old man who underwent a pancreaticoduodenectomy by whole genome sequencing, achieving 37× and 40× coverage, respectively. We determined somatic mutations and structural alterations. Results We identified relevant aberrations, including deleterious mutations of KRAS and SMAD4 as well as a homozygous focal deletion of the PTEN tumor suppressor gene. These findings suggest that these tumors have a distinct oncogenesis from either common bile duct cancer or pancreatic cancer. Furthermore, this combination of genomic aberrations suggests a therapeutic context for dual mTOR/PI3K inhibition. Conclusions Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.

Cancers frequently arise as a result of an acquired genomic instability and the subsequent clonal evolution of neoplastic cells with variable patterns of genetic aberrations. Thus, the presence and behaviors of distinct clonal populations in each patient's tumor may underlie multiple clinical phenotypes in cancers. We applied DNA content-based flow sorting to identify and isolate the nuclei of clonal populations from tumor biopsies, which was coupled with array CGH and targeted resequencing. The results produced high-definition genomic profiles of clonal populations from 40 pancreatic adenocarcinomas and a set of prostate adenocarcinomas, including serial biopsies from a patient who progressed to androgen-independent metastatic disease. The genomes of clonal populations were found to have patient-specific aberrations of clinical relevance. Furthermore, we identified genomic aberrations specific to therapeutically responsive and resistant clones arising during the evolution of androgen-independent metastatic prostate adenocarcinoma. We also distinguished divergent clonal populations within single biopsies and mapped aberrations in multiple aneuploid populations arising in primary and metastatic pancreatic adenocarcinoma. We propose that our high-definition analyses of the genomes of distinct clonal populations of cancer cells in patients in vivo can help guide diagnoses and tailor approaches to personalized treatment.

The development of DNA microarray and quantitative real-time polymerase chain reaction technologies has allowed for precise quantitation of RNA expression of hundreds to thousands of genes. These technologies have significantly impacted the study and understanding of cancer in terms of its molecular and genetic characteristics. In this review article, breast cancer, colon cancer, and adrenal carcinoma have been chosen to illustrate the principle and techniques of genomic profiling and to illustrate how such methods may be used to develop genomic signatures for personalized risk assessment and to individualize patient treatment.

The characteristic biochemical pathway of the APUDoma cell, namely amine precursor uptake and decarboxylation, are illustrated by the examples of serotonin and catecholamine metabolism. Increasing understanding of the origins of APUDomas as well as the biochemistry and physiology of the hormones they produce, has led to improved methods of detection, imaging and treatment of afflicted patients.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy causing up to 0.2% of all cancer deaths This article reviews the incidence, presentation, and pathology of ACC. Particular attention is paid to the molecular oncogenesis of this disease, and the surgical and therapeutic options available for its cure.