Xing M, Alzahrani AS, Carson KA, et al.
Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer.
JAMA. 2013; 309(14):1493-501 [PubMed]

IMPORTANCE: BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established.
OBJECTIVE: To investigate the relationship between BRAF V600E mutation and PTC-related mortality.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. MAIN OUTCOMES AND MEASURES: Patient deaths specifically caused by PTC.
RESULTS: Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]).
CONCLUSIONS AND RELEVANCE: In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

Chandra SR, Shenoy RK, Karthikeyan, et al.
Rare treatable limb girdle muscle disease.
J Assoc Physicians India. 2012; 60:62-5 [PubMed]

We report two cases of Limb Girdle pattern of muscle weakness caused by hyperparathyroidism due to parathyroid adenoma. It can be easily missed as early symptoms are non specific but once diagnosed it is easily treatable and complete recovery occurs over a period of time.

Salehi P, Koh CJ, Pitukcheewanont P, et al.
Persistent Müllerian duct syndrome: 8 new cases in Southern California and a review of the literature.
Pediatr Endocrinol Rev. 2012 Dec-2013 Jan; 10(2):227-33 [PubMed]

Persistent Müllerian Duct Syndrome (PMDS) is a 46,XY disorder of sex development (DSD) in which Müllerian structures are found in genotypic males with normally virilized external genitalia and unilateral or bilateral cryptorchidism. It is usually diagnosed incidentally during surgical repair of cryptorchidism or inguinal hernia. The majority of cases are due to a mutation of the anti-Müllerian hormone (AMH) gene or the AMH receptor, type II (AMH-RII) gene. Management of patients with PMDS requires a multidisciplinary approach. Long-term prognosis is good although fertility appears to be decreased and there may be a risk of malignancy due to cryptorchidism and retained Müllerian remnants. We describe 8 new cases of PMDS diagnosed in Southern California in the past 10 years and review the literature.

Son J, Lyssiotis CA, Ying H, et al.
Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.
Nature. 2013; 496(7443):101-5 [PubMed] Article available free on PMC after 04/10/2013

Cancer cells have metabolic dependencies that distinguish them from their normal counterparts. Among these dependencies is an increased use of the amino acid glutamine to fuel anabolic processes. Indeed, the spectrum of glutamine-dependent tumours and the mechanisms whereby glutamine supports cancer metabolism remain areas of active investigation. Here we report the identification of a non-canonical pathway of glutamine use in human pancreatic ductal adenocarcinoma (PDAC) cells that is required for tumour growth. Whereas most cells use glutamate dehydrogenase (GLUD1) to convert glutamine-derived glutamate into α-ketoglutarate in the mitochondria to fuel the tricarboxylic acid cycle, PDAC relies on a distinct pathway in which glutamine-derived aspartate is transported into the cytoplasm where it can be converted into oxaloacetate by aspartate transaminase (GOT1). Subsequently, this oxaloacetate is converted into malate and then pyruvate, ostensibly increasing the NADPH/NADP(+) ratio which can potentially maintain the cellular redox state. Importantly, PDAC cells are strongly dependent on this series of reactions, as glutamine deprivation or genetic inhibition of any enzyme in this pathway leads to an increase in reactive oxygen species and a reduction in reduced glutathione. Moreover, knockdown of any component enzyme in this series of reactions also results in a pronounced suppression of PDAC growth in vitro and in vivo. Furthermore, we establish that the reprogramming of glutamine metabolism is mediated by oncogenic KRAS, the signature genetic alteration in PDAC, through the transcriptional upregulation and repression of key metabolic enzymes in this pathway. The essentiality of this pathway in PDAC and the fact that it is dispensable in normal cells may provide novel therapeutic approaches to treat these refractory tumours.

Pushkarev VM, Kovzun OI, Pushkarev VV, Tronko MD
Biochemical effects of combined action of gamma-irradiation and paclitaxel on anaplastic thyroid cancer cells.
Ukr Biokhim Zh. 2013 Jan-Feb; 85(1):51-61 [PubMed]

The aim of the paper was to describe the biochemical effects of Paclitaxel (Ptx), gamma-irradiation (IR) and their combination in undifferentiated thyroid cancer cells (ATC). IR activated common DNA damage-induced signaling and manifested certain mitogenic effect by inactivation of retinoblastoma protein (pRb). There was clear antagonism between Ptx and IR relative to cell cycle regulators--tumor suppressor p53, pRb, CHK2 and c-Abl as well as proapoptotic Bax expression, but combined action of both agents enhanced caspase-3 and, especially, caspase-8 activation. The Ptx at low (1-25 nM) concentrations caused noticeable radioprotective effect. Thus, in ATC cells the ionizing radiation and Ptx exhibited competitive effects upon phosphorylation of cell cycle controllers: p53, pRb, CHK2, cAbl and expression of Bax. At the same time, the combined effect of radiation and Ptx enhanced antiapoptotic Bcl-2 phosphorylation, caspases activation and survivin expression. The net effect of these events during the first 48-72 h of cells incubation can be considered as antiapoptotic--Ptx attenuated cytotoxic effect of IR.

Gültekin SS, Sahmaran T
The efficacy of patient-dependent practices on exposure rate in patients undergoing iodine-131 ablation.
Health Phys. 2013; 104(5):454-8 [PubMed]

The authors investigated the efficacy of the patient-dependent practices (micturition, defecation, and taking a shower) after I ablation therapy in patients with thyroid cancer. Exposure rates were measured from a 1-m distance at 2, 4, and 24 h after the I administration. The comparisons for 2-4 h and 2-24 h time intervals were carried out among the patients with good and poor compliance, according to the relative amount of the patient-dependent practices, over mean values calculated for an effective half-life (h) or exposure rate decline ratio (%). In the 2-4 h interval, the mean values for good versus poor compliance were found to be: 4.16 h versus 8.14 h and 31% versus 17% in micturition; 5.70 h versus 6.84 h and 26% versus 21% in defecation; and 6.68 h versus 5.69 h and 24% versus 24% in taking a shower. Among patients with good versus poor compliance during a 2-24 h interval, the mean values were: 11.63 h versus 16.62 h and 74% versus 61% in micturition; 12.75 h versus 15.88 h and 71% versus 63% in defecation; and 13.77 h versus 14.21 h and 68% versus 67% in taking a shower.

Aich RK, Dasgupta S, Chakraborty B, et al.
Primary fallopian tube carcinoma with metastasis in the contralateral ovary.
J Indian Med Assoc. 2012; 110(7):494-5, 498 [PubMed]

Primary malignant neoplasm of the fallopian tube is one of the rarest gynaecological malignancies and a pre-operative diagnosis is often missed due to its diagnostic confusion with the tubo-ovarian mass, hydrosalpinx, ectopic pregnancy and ovarian malignancy. Transcoelomic, lymphatic, transluminal and haematogenous spread may occur to the other abdominal and pelvic organs as well as to the distant sites. Though the body of the uterus, ovaries and the contralateral fallopian tube are frequently involved, in the present case the contralateral ovary was the only site of involvement which is very unusual.

Vindenes T, Crump N, Casenas R, Wood K
Pheochromocytoma causing cardiomyopathy, ischemic stroke and acute arterial thrombosis: a case report and review of the literature.
Conn Med. 2013; 77(2):95-8 [PubMed]

Pheochromocytoma is a rare catecholamine secreting neuroendocrine tumor with an estimated annual incidence of one to four per million and prevalence among hypertensive patients of 0.1 to 0.6%. The symptoms and signs of pheochromocytoma include the classic triad of episodic headache, increased sweating, and palpitations. These are as a result of an uncontrolled release of catecholamines. There exist only a small number of reports of pheochromocytoma simulating hypertrophic obstructive cardiomyopathy, few reports of pheochromocytoma-induced ischemic stroke and only two reported cases with pheochromocytoma-induced arterial thrombosis. We present a case of multiple, rare clinical complications of pheochromocytoma occurring in the same patient and the review of literature of these complications.

Bertsch T, Aschenneller C, Bewarder N, et al.
European proficiency study with control serum for the tumor marker CA 19-9 measured on different test systems.
Clin Lab. 2013; 59(1-2):185-92 [PubMed]

BACKGROUND: Reliable and precise CA 19-9 testing is required for the long-term follow-up of patients with pancreatic carcinoma during therapy. The aim of this longitudinal proficiency study was to evaluate the comparability, linearity, and precision of CA 19-9 determinations performed in different laboratories using currently available test systems under routine conditions.
METHODS: During the one year study period, 15 laboratories applied 7 different tests and included a liquid BIOREF control serum with pancreatic carcinoma derived CA 19-9 in their routine testing and quality control procedures. The results were collected centrally and evaluated statistically.
RESULTS: The comparability of CA 19-9 results is limited especially when different tests are used, albeit, some tests show a good correlation: The CA 19-9 values obtained by different laboratories using different test systems vary up to a factor of 2. The precision of CA 19-9 determinations was acceptable in most laboratories with coefficients of variation ranging between very low 3.2% and high 17.8%. The imprecision was slightly increased when automatic dilution procedures of the analysers were used.
CONCLUSIONS: The comparability of CA 19-9 test results must be improved. The precision is acceptable in most cases. In order to monitor key performance parameters, every laboratory should participate in external quality assessment schemes and should perform a routine internal quality control with a control serum independent from the test kit manufacturer.

Yin Q, Wang C, Wu Z, et al.
Adenosquamous carcinoma of the pancreas: multidetector-row computed tomographic manifestations and tumor characteristics.
J Comput Assist Tomogr. 2013 Mar-Apr; 37(2):125-33 [PubMed]

OBJECTIVE: The purpose of this article was to present the adenosquamous carcinoma (ASqC) of the pancreas: multidetector-row computed tomographic (CT) features and tumor characteristics.
MATERIALS AND METHODS: The clinical data and CT studies of 12 patients with pathologically proven ASqC of the pancreas between the dates February 2001 and February 2010 were retrospectively analyzed.
RESULTS: The presenting symptoms of ASqC of the pancreas were nonspecific. Elevated serum levels of carbohydrate antigen 19-9, carbohydrate antigen 12-5, and carcinoembryonic antigen were noted. The tumor was most commonly involved in the pancreatic head in 6 patients, with the dilation of the common bile duct and the upstream main pancreatic duct. All ASqCs exhibited invasive growth. No calcification and intratumoral hemorrhage were noted in ASqCs. Ten tumors showed enhancement in the early arterial phase and persistent enhancement in the portal vein phase.
CONCLUSION: The typical CT appearance of ASqC was solitary oval or round without any capsule and a defined margin. The dilation of the main pancreatic duct and/or the common bile duct was always discovered. The huge infiltrative lesion outside the pancreas was detected in the tail and/or the body of the pancreas. Not only the elevation of carbohydrate antigen 19-9 is common, but also Ca12-5 and CEA, whereas human alpha fetoprotein elevation is not observed. The enhancement pattern of tumor showed persistence in the portal vein phase.

Gómez-Ramírez J, Tagarro D, Bravo JM, et al.
Preoperative parathyroid harpoon localisation: a new technique helpful in reoperative patients with persistent hyperparathyroidism.
Ann R Coll Surg Engl. 2013; 95(2):e25-6 [PubMed]

Surgery for persistent primary hyperparathyroidism remains a major challenge for surgeons and these reoperative procedures require an experienced parathyroid surgeon. The goal of reoperative surgery is to excise the abnormal parathyroid gland(s) and limit exploration to help minimise the potential complications. At least two positive and concordant localising studies should be available before reoperation because the technical difficulties in these cases make an exact localisation necessary before surgery. We describe the placement of a metallic harpoon under ultrasonography guidance as a safe, simple and inexpensive technique for localisation of the enlarged gland prior to conservative surgery.

Yang HJ, Lee SW, Lee HJ, et al.
Extralobar pulmonary sequestration mimicking an adrenal tumor.
JSLS. 2012 Oct-Dec; 16(4):671-4 [PubMed] Article available free on PMC after 04/10/2013

Pulmonary sequestration is a rare cystic malformation composed of bronchopulmonary tissue that is discontinuous from the tracheobronchial tree and has an anomalous systemic blood supply. We present a case of a 40-year old male who presented with an extralobar pulmonary sequestration and underwent a laparoscopic retroperitoneal mass excision. Preoperative imaging revealed a large 11.3-cm retroperitoneal tumor consisting of a multiloculated cystic lesion. The patient was discharged home, and at 3-mo follow-up no complaints were reported.

Konstantinos TG, Dimitrios T, Panagiotis KB, et al.
Laparoscopic resection of an adrenal schwannoma.
JSLS. 2012 Oct-Dec; 16(4):663-7 [PubMed] Article available free on PMC after 04/10/2013

BACKGROUND AND OBJECTIVES: Schwannomas are tumors originating from Schwann cells of the peripheral nerve sheath (neurilemma) of the neuroectoderm. Rarely, schwannomas can arise from the retroperitoneum and adrenal medulla. We describe a case of a 71-y-old woman who presented with an incidentally discovered adrenal tumor.
METHODS: Ultrasound and computed tomography scans revealed a lesion with solid and cystic areas originating from the left adrenal gland. The patient underwent complete laparoscopic resection of the tumor and the left adrenal gland.
RESULTS: Histopathological examination and immunohistochemical staining of the excised specimen revealed a benign schwannoma measuring 5.5×5 3.7 cm. To our knowledge, few other cases of laparoscopic resection of adrenal schwannomas have been reported.
CONCLUSION: Because preoperative diagnosis of adrenal tumors is inconclusive, complete laparoscopic excision allows for definitive diagnosis with histological evaluation and represents the treatment of choice.

Jarry J, Bodin R, Peycru T, et al.
Role of laparoscopic distal pancreatectomy for solid pseudopapillary tumor.
JSLS. 2012 Oct-Dec; 16(4):552-8 [PubMed] Article available free on PMC after 04/10/2013

BACKGROUND: Since the first case report regarding laparoscopic distal pancreatectomy (DP) for solid pseudopapillary tumor (SPT), few additional articles have been published. The objective of this study was to evaluate the feasibility, safety, and long-term outcome of the laparoscopic DP based on a series of adult SPT patients.
METHODS: In a single-center study, we screened all adult patients undergoing a laparoscopic DP for SPT. Preoperative, operative, and postoperative data were retrospectively analysed and compared to the results of open DP for SPT published in the medical literature.
RESULTS: From April 2000 to June 2010, 5 adult female patients (median age 34 y) underwent a laparoscopic DP for an SPT. No conversion to open surgery was required. The median size of the tumor was 45 mm. The postoperative mortality rate was 0%, and serious complications (Dindo IV) occurred in 2 patients. The postoperative quality of life was not significantly altered by the laparoscopic procedure. At a median follow-up of 60 mo, all patients were alive and without evidence of local recurrence, distant metastasis, diabetes, or exocrine insufficiency.
CONCLUSION: Laparoscopy may offer an alternative to open surgery in the treatment of SPT of the distal pancreas in adult female patients. The laparoscopic procedure impacts neither the oncologic outcome nor the quality of life. However, due to the risk of postoperative complications, this procedure should be reserved for specialized centers.

Sherwinter DA, Lewis J, Hidalgo JE, Arad J
Laparoscopic distal pancreatectomy.
JSLS. 2012 Oct-Dec; 16(4):549-51 [PubMed] Article available free on PMC after 04/10/2013

BACKGROUND: Laparoscopic management of distal pancreatic malignancies has been slow to gain a foothold in all but high-volume tertiary referral centers. The aim of this study was to assess the safety and outcomes of laparoscopic distal pancreatectomy (LDP) performed in a low-volume community hospital by a diverse group of surgeons, none of whom have a specialized laparoscopic background.
METHODS: We conducted a retrospective review of all patients who underwent open distal pancreatectomies (ODPs) and LDPs between August 2001 and June 2008. Data included type of surgery, open versus laparoscopy, demographics, operative time, blood loss, length of hospital stay, histopathologic diagnosis, postoperative complications, American Society of Anesthesiologists score, and mortality.
RESULTS: Twenty-seven patients with pancreatic masses underwent distal pancreatic resection during the study period. Fifty-nine percent (n = 16) underwent LDP, and 41% (n = 11) underwent ODP. Mean patient age was 66 y (range, 40 to 86) for the LDP group and 62 (range, 40 to 84) for the ODP group. Mean operative time was 231 min (range, 195 to 305) for LDP and 240 (range, 150 to 210) for the ODP technique. Mean length of stay for LDP and ODP was 8 (range, 3 to 22) and 12 d (range, 5 to 2), respectively. Morbidity was 25% (n = 4) in the LDP group and 36% (n = 4) in the ODP group. None of the differences between the LDP and ODP groups were statistically significant. No mortalities occurred in either group.
CONCLUSION: This study supports the idea that LDP can be safely and effectively performed by any surgeon comfortable with basic laparoscopy and may not require specialized training or a specialized center. Further data are required to make more definitive conclusions.

Nezhat FR, Denoble SM, Cho JE, et al.
Safety and efficacy of video laparoscopic surgical debulking of recurrent ovarian, fallopian tube, and primary peritoneal cancers.
JSLS. 2012 Oct-Dec; 16(4):511-8 [PubMed] Article available free on PMC after 04/10/2013

BACKGROUND AND OBJECTIVE: Studies on the role of laparoscopy in secondary or tertiary cytoreduction for recurrent ovarian cancer are limited. Our objective is to describe our preliminary experience with laparoscopic secondary/tertiary cytoreduction in patients with recurrent ovarian, fallopian, and primary peritoneal cancers.
METHODS: This is a retrospective analysis of a prospective case series. Women with recurrent ovarian, fallopian tube, or primary peritoneal cancers deemed appropriate candidates for laparoscopic debulking by the primary surgeon(s) were recruited. The patients underwent exploratory video laparoscopy, biopsy, and laparoscopic secondary/tertiary cytoreduction between June 1999 and October 2009. Variables analyzed include stage, site of disease, extent of cytoreduction, operative time, blood loss, length of hospital stay, complications, and survival time.
RESULTS: Twenty-three patients were recruited. Only one surgery involved conversion to laparotomy. Seventeen (77.3%) of the patients had stage IIIC disease at the time of their initial diagnosis, and 20 (90.9%) had laparotomy for primary debulking. Median blood loss was 75 mL, median operative time 200 min, and median hospital stay 2 d. No intraoperative complications occurred. One patient (4.5%) had postoperative ileus. Eighteen (81.8%) of the patients with recurrent disease were optimally cytoreduced to 1cm. Overall, 12 patients have no evidence of disease (NED), 6 are alive with disease (AWD), and 4 have died of disease (DOD), over a median follow-up of 14 mo. Median disease-free survival was 71.9 mo.
CONCLUSIONS: In a well-selected population, laparoscopy is technically feasible and can be utilized to optimally cytoreduce patients with recurrent ovarian, fallopian, or primary peritoneal cancers.

Tsubamoto H, Kawaguchi R, Ito K, et al.
Phase II study of carboplatin and weekly irinotecan combination chemotherapy in recurrent ovarian cancer: a Kansai clinical oncology group study (KCOG0330).
Anticancer Res. 2013; 33(3):1073-9 [PubMed]

BACKGROUND: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of irinotecan plus carboplatin chemotherapy in patients with epithelial ovarian cancer (EOC).
PATIENTS AND METHODS: Patients with either radiologically- or serologically-recurrent EOC were administered intravenous irinotecan (60 mg/m(2); days 1 and 8) and carboplatin area under the curve of 5 mg/ml/min (day 1), repeated every 21 days. The primary end-point was response rate (RR), while the secondary end-points were adverse events and progression-free survival (PFS).
RESULTS: Between 2005 and 2009, 40 patients (median age=59 years) with EOC were enrolled. Intention-to-treat analysis showed an RR of 43% [95% confidence interval (CI)=27-58%]. For patients with a platinum-free interval (PFI) of <6 months, overall RR based on RECIST was 21% (95% CI=0-43%) and median PFS was 3.7 months (95% CI=2.5-7.7 months), while those in patients with PFI ≥6 months were 52% (95% CI=31-74%) and 9.1 months (95% CI=7.9-11.2 months), respectively. Grade 3/4 toxicity encountered during the first cycle included G3/G4 neutropenia in 65% of patients (12/14), G3/G4 thrombocytopenia in 48% (18/1), G3 febrile neutropenia in 5% (2), G3 nausea in 5% (2), G3 diarrhea in 5% (2), and G3 fatigue in 5% of patients (2).
CONCLUSION: This carboplatin plus irinotecan combination demonstrated a modest activity in recurrent EOC. However, considering its hematological toxicities, the regimen should be further investigated to establish the feasibility of the modified dose for platinum-sensitive disease.

Jung PS, Kim DY, Kim MB, et al.
Progression-free survival is accurately predicted in patients treated with chemotherapy for epithelial ovarian cancer by the histoculture drug response assay in a prospective correlative clinical trial at a single institution.
Anticancer Res. 2013; 33(3):1029-34 [PubMed]

This study aimed to prospectively correlate clinical outcomes of advanced epithelial ovarian cancer (AEOC), with the results of in vitro chemosensitivity testing of taxol and carboplatin using the in vitro histoculture drug response assay (HDRA). A total of 104 patients with AEOC were treated with combination chemotherapy of taxol and carboplatin after primary cytoreductive surgery between 2007 and 2012 at the Asan Medical Center, Seoul, Korea. To compare chemosensitivity in the HDRA with clinical response, all patients were first categorized into two groups as either sensitive to both taxol and carboplatin (SS), or not sensitive to one or both drugs (R) based on HDRA results. The recurrence rate was much lower in the SS group compared to the R group; 29.2% vs 69.8%, respectively (p=0.02). The SS group had a significantly longer progression-free survival compared to the R group, 34.0 months vs 16.0 months, respectively (p=0.025). These results demonstrate that the HDRA prospectively correlates to clinical outcome from chemotherapy and that treatment regimens can be individualized based on the HDRA.

Paulsson G, Andersson S, Sorbe B
A population-based series of ovarian carcinosarcomas with long-term follow-up.
Anticancer Res. 2013; 33(3):1003-8 [PubMed]

AIM: The aim of the present study was to evaluate a consecutive series of ovarian carcinosarcomas with regard to prognosis, treatment and prognostic factors.
PATIENTS AND METHODS: A consecutive series of 81 ovarian carcinosarcomas from two well-defined geographic regions were studied with regard to survival, type of primary and adjuvant therapy and prognostic factors. All patients but one underwent primary surgery and some patients also received adjuvant chemotherapy (platinum-based) alone or in combination with radiotherapy. Univariate and multivariate Cox proportional regression analysis was used. Survival was analyzed by the Kaplan-Meier technique and differences were assessed by the log-rank test.
RESULTS: The mean age of the patients was 73 years. Fifty-one patients received adjuvant chemotherapy and nine patients pelvic irradiation. The 5-year overall survival rate was 10%. Adjuvant therapy (any type) and six completed cycles of chemotherapy were highly significant factors with regard to improved overall survival rate. The only significant tumor-associated prognostic factor was the International Federation of Gynecology and Obstetrics (FIGO) grade of the tumor. FIGO stage, site of metastatic spread, tumor size, histology, DNA ploidy, and tumor necrosis were non-significant factors. Therapy was rather well-tolerated and 29 patients (57%) completed at least six cycles of adjuvant chemotherapy.
CONCLUSION: Adjuvant and completed chemotherapy according to the treatment plan were the most important prognostic factors. FIGO grade (grade 3 vs. 1-2) of the epithelial component of the tumor was also a significant prognostic factor in multivariate Cox analysis.

Zou B, Li QQ, Zhao J, et al.
β-Elemene and taxanes synergistically induce cytotoxicity and inhibit proliferation in ovarian cancer and other tumor cells.
Anticancer Res. 2013; 33(3):929-40 [PubMed]

β-Elemene, originally derived from plants, has been recently investigated as a new anticancer agent. The purpose of this study was to explore the efficacy and mechanisms of action of the combined use of β-elemene plus a taxane as an antitumor therapeutic strategy for ovarian cancer and other carcinomas. The interaction of β-elemene with paclitaxel or docetaxel produced additive to moderately synergistic effects against the platinum-resistant ovarian cancer cell line A2780/CP70 and its parental cell line A2780, and showed moderately synergistic activity against PC-3 prostate cancer cells. In addition, the co-administration of β-elemene and a taxane at low-micromolar concentrations dramatically increased the rate of micronucleus formation and the percentage of mitotic arrest in both ovarian cancer cell lines, as compared with treatment with either agent alone. The highest synergy towards the ovarian cancer cells was observed with β-elemene plus docetaxel. Consistent with these data, treatment of A2780/CP70 cells with β-elemene plus a taxane strikingly reduced cell viability and increased cell apoptosis, as assessed by annexin V binding. Moreover, β-elemene plus docetaxel induced elevated levels of caspase-9 and p53 proteins in A2780/CP70 cells, and the combination of β-elemene plus a taxane caused marked cell-cycle arrest at the G2/M phase in these cells. One possible mechanism to account for the enhanced cytotoxic efficacy of this combination treatment is a β-elemene-induced increase in taxane influx into cancer cells. These observations indicate that combination therapy with β-elemene and taxanes has synergistic antitumor activity against ovarian and prostate carcinomas in vitro. This promising new therapeutic combination warrants further pre-clinical exploration for the treatment of chemoresistant ovarian cancer and other types of tumors.

Shah MM, Zerlin M, Li BY, et al.
The role of Notch and gamma-secretase inhibition in an ovarian cancer model.
Anticancer Res. 2013; 33(3):801-8 [PubMed]

BACKGROUND: The Notch pathway is dysregulated in ovarian cancer. We sought to examine the role of Notch and gamma-secretase (GS) inhibition in ovarian cancer.
MATERIALS AND METHODS: Established ovarian cancer cell lines were used. Quantitative polymerase chain reaction (qPCR) was used to determine the relative expression of Notch receptor and ligands. Effects of GS inhibition on proliferation, colony formation, and downstream effectors were examined via methylthiazole tetrazolium (MTT) and Matrigel assays, and qPCR, respectively. In vivo experiments with a GS inhibitor and cisplatin were conducted on nude mice. Tumors were examined for differences in microvessel density, proliferation, and apoptosis.
RESULTS: Notch3 was the most up-regulated receptor. The ligands JAGGED1 and DELTA-LIKE4 were both up-regulated. GS inhibition did not affect cellular proliferation or anchorage-independent cell growth over placebo. The GS inhibitor Compound-E reduced microvessel density in vivo.
CONCLUSION: GS inhibition does not directly affect cellular proliferation in ovarian carcinoma, but Notch pathway blockade may result in angiogenic alterations that may be therapeutically important.

Skelton WP, Skelton M, Vesely DL
Inhibition of AKT in human pancreatic, renal and colorectal cancer cells by four cardiac hormones.
Anticancer Res. 2013; 33(3):785-90 [PubMed]

BACKGROUND: Protein kinase-B (AKT) is a serine/threonine protein kinase that has a key role in cell proliferation and cancer cell invasiveness. Four cardiac peptide hormones, namely vessel dilator, atrial natriuretic peptide (ANP), kaliuretic peptide, and long-acting natriuretic peptide (LANP) have anticancer effects both in vitro and in vivo.
MATERIALS AND METHODS: Four cardiac hormones were examined for their ability to inhibit AKT, measured with a solid-phase enzyme-linked immunosorbent assay (ELISA) in human colorectal, pancreatic, and renal cancer cells.
RESULTS: Vessel dilator, kaliuretic peptide, ANP, and LANP maximally reduced the concentration of AKT by 47%, 45%, 52%, and 46% in human colorectal cancer cells (p<0.0001), by 60%, 61%, 64%, and 59% in human pancreatic carcinoma cells (p<0.0001), and by 31%, 32%, 31%, and 31% in renal adenocarcinoma cells (p<0.001).
CONCLUSION: These four cardiac hormones are significant inhibitors of AKT in human cancer cells, as part of their anticancer mechanism(s) of action.

Batisse M, Raverot G, Maqdasy S, et al.
Aggressive silent GH pituitary tumor resistant to multiple treatments, including temozolomide.
Cancer Invest. 2013; 31(3):190-6 [PubMed]

Temozolomide (TMZ) has been proposed as a therapeutic option in aggressive pituitary tumors. Among the published cases, GH expressing tumors were rare. We describe a patient with initially benign silent GH adenoma that transformed into an aggressive GH secreting tumor resistant to usual therapy. MGMT expression was high and the MGMT promoter was unmethylated. Before this aggressive course, patient received three cycles of TMZ; no response was observed. Four cases of GH aggressive tumor treated by TMZ have been reported. Response to TMZ was observed in one of these four patients. Predictive factors of failure of TMZ remain unclear.

Lim SD, Kim WS, Kwon GY
ROR2 and Wnt5a expression in stage 1 pure testicular seminomas.
Anal Quant Cytol Histol. 2013; 35(1):41-51 [PubMed]

OBJECTIVE: To elucidate the prognostic utility of several biomarkers including ROR2/Wnt5a in stage 1 pure seminoma, which is a highly curable tumor in need of prognostic markers to avoid unnecessary treatment.
STUDY DESIGN: A total of 47 patients of stage 1 seminoma who underwent radical orchiectomy were included in the study. Tissue microarray-based immunohistochemical analysis of placental alkaline phosphatase, D2-40, c-Kit, Oct-3/4, ROR2, Wnt5a, beta-catenin, CD30, vimentin, pancytokeratin, beta-hCG and p53 was conducted, and relevant clinicopathologic features were assessed.
RESULTS: ROR2 protein revealed strong diffuse membranous immunoreactivity (IR) in 12.8% and partial weak IR in 40.4%, respectively. Cytoplasimc Wnt5a IR was observed in 27.7%. ROR2 IR was correlated with Wnt5a IR (p = 0.029) and Oct3/4 IR (p = 0.035). c-Kit IR was correlated with Wnt5a IR (p = 0.034). No significant differences were found between ROR2/Wnt5a protein expression and the prognostically relevant features such as lymphatic invasion or pathologic T stage. Pathologic T stage was not correlated with rete invasion (p= 0.23). The expression or loss of other aforementioned antibodies was not associated with the prognostic clinicopathologic characteristics.
CONCLUSION: Our results do not support the relevance of ROR2/Wnt5a as biomarkers in stage 1 pure seminomas. The utility of the explored biomarkers as prognostic or differentiation indicators remains to be clarified.

Unlü S, Ozdemir S, Sümer S, et al.
Investigation of DNA damage by the alkaline comet assay in 131I-treated thyroid cancer patients.
Anal Quant Cytol Histol. 2013; 35(1):36-40 [PubMed]

OBJECTIVE: To assess the possible applicability of comet assay in the evaluation of DNA damage caused by ionizing radiation. The alkaline comet assay or single-cell gel electrophoresis has been used as a standard method for measuring and analyzing DNA damage.
STUDY DESIGN: Peripheral blood samples were collected from papillary thyroid cancer patients who received 131I by oral administration. Blood samples were taken just before the treatment, on the first day of treatment, and 1 week posttreatment. To determine the radiation-induced DNA damage, alkaline comet assay was performed.
RESULTS: It was found that significantly high levels of DNA damage occurred in first day samples when compared to control samples according to tail moment measurements. Also, a decrease in the level of damage was observed in the 1-week samples.
CONCLUSION: Our observations and data confirmed that treatment with 131I for papilloma thyroid cancer can cause DNA damage in circulating lymphocytes, and the comet assay seemed suitable to assess the effect of radioactive iodine for the patients.

Mweempwa A, Prasad J, Islam S
A rare neoplasm of the thyroid gland.
N Z Med J. 2013; 126(1369):75-8 [PubMed]

Burkitt's lymphoma of the thyroid gland is a rare malignancy. We present a case of a 58-year-old female who developed a rapid enlargement of her thyroid gland. Core biopsy confirmed the diagnosis of Burkitt's lymphoma. The tumour resolved after three cycles of chemotherapy. This case report emphasises the importance of considering lymphoma when dealing with thyroid nodules and goitres, as its management is different from that of other thyroid pathologies and delaying treatment has an impact on prognosis.

Liu X, Ma S, Dai C, et al.
Antiproliferative, antiinvasive, and proapoptotic activity of folate receptor α-targeted liposomal doxorubicin in nonfunctional pituitary adenoma cells.
Endocrinology. 2013; 154(4):1414-23 [PubMed]

There is an urgent need for novel therapeutic strategies for the treatment of nonfunctional pituitary adenomas (NFPAs), especially those that are invasive. The folate receptor (FR)α is overexpressed in several cancers, including NFPA. The aim of this study was to determine the efficacy of FRα-targeted liposomes loaded with doxorubicin (F-L-DOX) in the treatment of NFPA. We evaluated targeting, cytotoxicity, antiinvasive, and proapoptotic activity of F-L-DOX in 25 primary cell lines derived from patients with NFPAs. We found that these liposomes effectively targeted NFPA cells through FRα and that endocytosis of the liposomes was blocked by 1mM free folic acid. F-L-DOX inhibited proliferation of NFPA cells and promoted apoptosis through activation of caspase-8, caspase-9, and caspase-3/7 more effectively than L-DOX. Furthermore, F-L-DOX also exerted greater antiinvasive ability in NFPA cells than L-DOX through suppression of the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Addition of 1mM free folic acid significantly reduced the pleotropic effects of F-L-DOX in NFPA cells, suggesting that FRα plays a critical role in mediating the antitumor effect of F-L-DOX. Our findings warrant further investigation of F-L-DOX as an alternative therapeutic strategy for the treatment of NFPAs that express FRα.

Pointer DT, Slakey LM, Slakey DP
Safety and effectiveness of vessel sealing for dissection during pancreaticoduodenectomy.
Am Surg. 2013; 79(3):290-5 [PubMed]

Traditional pancreaticoduodenectomy dissection techniques are tedious and time-consuming. The LigaSure(®) Vessel Sealing System is an alternative to standard dissection methods. LigaSure(®) can be used in replace of ligatures, clips, and sutures in most of the pancreaticoduodenectomy procedure. The objective of this study was to examine our experience with LigaSure(®) in pancreaticoduodenectomies and to show the safety and time-effectiveness. Forty-three pancreaticoduodenectomies were performed by a single surgeon using the LigaSure(®) device in place of traditional dissection techniques. A retrospective chart review was conducted to evaluate patient management and outcome. Demographics, preoperative, intraoperative, and postoperative data were analyzed. The average patient age was 61 years. Primary pathologic diagnoses were: periampullary carcinoma (56%), chronic pancreatitis (5%), cystic lesion (26%), neuroendocrine tumor (7%), and other (5%). Our patient population demonstrated American Society of Anesthesiologists Class I (2%), Class II (14%), III (75%), and IV (9%). Average operative time was 4:11 hours. The study group required an average of 0.49 ± 1.35 units of blood. Eight patients (19%) received blood transfusion, receiving an average of 2.63 ± 2.13 units. Patients had a median hospital stay of 10 days (range, 5 to 41 days). An oral diet was ordered for most patients by Day 4. Fourteen patients (32.5%) had a complication, including two patients requiring additional surgery for drainage of abscess. There were no postoperative deaths. The use of LigaSure(®) is a practical and safe alternative to standard dissection techniques. Operative time, blood loss, and complication rate are favorable compared with published series.

Kolačkov K, Tupikowski K, Bednarek-Tupikowska G
Genetic aspects of pheochromocytoma.
Adv Clin Exp Med. 2012 Nov-Dec; 21(6):821-9 [PubMed]

Pheochromocytomas are derived from chromaffin cells of the adrenal medulla which synthesize and secrete catecholamines, thus affecting the cardiovascular system and metabolic processes. Pheochromocytoma is a tumor of the following multicarcinoma hereditary syndromes: type 2 multiple endocrine neoplasia, von Hippel-Lindau disease, type 1 neurofibromatosis and the pheochromocytomas/paragangliomas syndrome. Pheochromocytomas are relatively rare, and because of non-specific manifestation of these tumors and the possible lack of signs and symptoms for extended periods of time, the diagnosis may be delayed, which may, in turn, lead to death. Pheochromocytomas may occur sporadically. However, due to the frequent incidence of hereditary forms of these cancers, the presymptomatic genetic testing of family members with a positive family history is indicated, thus allowing for selecting people with higher risk of cancer. Early detection of the syndrome and the coexisting tumors (which may be malignant) may lead to a correct diagnosis, regular surveillance, preventive examinations and implementation of appropriate early treatment. Recent examinations have shown significant involvement of RET, VHL, NF1, SDHB and SDHD as well as the newly discovered KIF1Bβ, TMEM127 and MAX genes in pathogenesis of these tumors. The microarray-gene expression studies, based on the analysis of cellular pathways, have revealed two distinct clusters indicating two different routes of tumorgenesis. The genotype-phenotype correlations are still being studied and future research can give us clearer information about the function of these genes, which may prove crucial from the clinical point of view.

Al Rawahi T, Lopes AD, Bristow RE, et al.
Surgical cytoreduction for recurrent epithelial ovarian cancer.
Cochrane Database Syst Rev. 2013; 2:CD008765 [PubMed]

BACKGROUND: The standard management of primary ovarian cancer is optimal cytoreductive surgery followed by platinum-based chemotherapy. Most women with primary ovarian cancer achieve remission on this combination therapy. For women achieving clinical remission after completion of initial treatment, most (60%) with advanced epithelial ovarian cancer will ultimately develop recurrent disease. However, the standard treatment of women with recurrent ovarian cancer remains poorly defined. Surgery for recurrent ovarian cancer has been suggested to be associated with increased overall survival.
OBJECTIVES: To evaluate the effectiveness and safety of optimal secondary cytoreductive surgery for women with recurrent epithelial ovarian cancer. To assess the impact of various residual tumour sizes, over a range between 0 cm and 2 cm, on overall survival.
SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to December 2012. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. For databases other than MEDLINE, the search strategy has been adapted accordingly.
SELECTION CRITERIA: Retrospective data on residual disease, or data from randomised controlled trials (RCTs) or prospective/retrospective observational studies that included a multivariate analysis of 50 or more adult women with recurrent epithelial ovarian cancer, who underwent secondary cytoreductive surgery with adjuvant chemotherapy. We only included studies that defined optimal cytoreduction as surgery leading to residual tumours with a maximum diameter of any threshold up to 2 cm.
DATA COLLECTION AND ANALYSIS: Two review authors (KG, TA) independently abstracted data and assessed risk of bias. Where possible the data were synthesised in a meta-analysis.
MAIN RESULTS: There were no RCTs; however, we found nine non-randomised studies that reported on 1194 women with comparison of residual disease after secondary cytoreduction using a multivariate analysis that met our inclusion criteria. These retrospective and prospective studies assessed survival after secondary cytoreductive surgery in women with recurrent epithelial ovarian cancer.Meta- and single-study analyses show the prognostic importance of complete cytoreduction to microscopic disease, since overall survival was significantly prolonged in these groups of women (most studies showed a large statistically significant greater risk of death in all residual disease groups compared to microscopic disease).Recurrence-free survival was not reported in any of the studies. All of the studies included at least 50 women and used statistical adjustment for important prognostic factors. One study compared sub-optimal (> 1 cm) versus optimal (< 1 cm) cytoreduction and demonstrated benefit to achieving cytoreduction to less than 1 cm, if microscopic disease could not be achieved (hazard ratio (HR) 3.51, 95% CI 1.84 to 6.70). Similarly, one study found that women whose tumour had been cytoreduced to less than 0.5 cm had less risk of death compared to those with residual disease greater than 0.5 cm after surgery (HR not reported; P value < 0.001).There is high risk of bias due to the non-randomised nature of these studies, where, despite statistical adjustment for important prognostic factors, selection is based on retrospective achievability of cytoreduction, not an intention to treat, and so a degree of bias is inevitable.Adverse events, quality of life and cost-effectiveness were not reported in any of the studies.
AUTHORS' CONCLUSIONS: In women with platinum-sensitive recurrent ovarian cancer, ability to achieve surgery with complete cytoreduction (no visible residual disease) is associated with significant improvement in overall survival. However, in the absence of RCT evidence, it is not clear whether this is solely due to surgical effect or due to tumour biology. Indirect evidence would support surgery to achieve complete cytoreduction in selected women. The risks of major surgery need to be carefully balanced against potential benefits on a case-by-case basis.