Guy Lahat

MicroRNA expression signatures in intraductal papillary mucinous neoplasm of the pancreas

BACKGROUNDnIntraductal papillary mucinous neoplasms (IPMN) represent a spectrum of tumors that range from low-grade (LG) dysplastic tumors to invasive cancer. Identification of IPMN at high risk for malignant transformation is important for the prevention and early treatment of pancreatic cancer. The roles of microRNA expression in the development of IPMN have not been extensively evaluated.nnnMETHODSnExpression patterns of 846 human microRNAs (miRNAs) was analyzed using microRNA microarray in 55 tissues, including LG IPMN (n = 10), moderate-grade (MG) IPMN (n = 5), high-grade (HG) IPMN (n = 5), invasive cancer with IPMN (IPMC; n = 10), pancreatic ductal adenocarcinoma without IPMN (PDA; n = 5), LG IPMN extracted from specimens that contain IPMCxa0(LG_Ca; n = 10), and normal pancreatic tissues (n = 10).nnnRESULTSnFourteen miRNAs were differentially expressed in all IPMN tissues compared with normal pancreatic tissue. Expression level of 3 miRNAs was proportional to dysplasia level. Hierarchical clustering demonstrated grouping of 2 IPMN subgroups: LG and MG IPMN verses HG IPMN and IPMC. Expression of 15 miRNAs was significantly different between these groups. LG_Ca tissues clustered with the HG IPMC group, and 12 miRNAs were differentially expressed in LG_Ca, HG lesions, and IPMC compared with LG lesions. The expression patterns of selected miRNAs were validated using quantitative reverse-transcription real-time polymerase chain reaction. Hierarchical clustering demonstrated microRNA expression profile in IPMC was significantly different from PDA, suggesting that different pathways are involved in these cancer types.nnnCONCLUSIONnThis study demonstrates that miRNAs are involved in the development and progression of IPMN. We identified potential targets for diagnosis, prognostication, and treatment of IPMN.

Pancreatic cancer: Surgery is a feasible therapeutic option for elderly patients

BackgroundCompromised physiological reserve, comorbidities, and the natural history of pancreatic cancer may deny pancreatic resection from elderly patients. We evaluated outcomes of elderly patients amenable to pancreatic surgery.MethodsThe medical records of all patients who underwent pancreatic resection at our institution (1995-2007) were retrospectively reviewed. Patient, tumor, and outcomes characteristics in elderly patients aged ≥ 70 years were compared to a younger cohort (<70y).ResultsOf 460 patients who had surgery for pancreatic neoplasm, 166 (36%) aged ≥ 70y. Compared to patients < 70y (n = 294), elderly patients had more associated comorbidities; 72% vs. 43% (p = 0.01) and a higher rate of malignant pathologies; 73% vs. 59% (p = 0.002). Operative time and blood products consumption were comparable; however, elderly patients had more post-operative complications (41% vs. 29%; p = 0.01), longer hospital stay (26.2 vs. 19.7 days; p < 0.0001), and a higher incidence of peri-operative mortality (5.4% vs. 1.4%; p = 0.01). Multivariable analysis identified age ≥ 70y as an independent predictor of shorter disease-specific survival (DSS) among patients who had surgery for pancreatic adenocarcinoma (n = 224). Median DSS for patients aged ≥ 70y vs. < 70y were 15 months (SE: 1.6) vs. 20 months (SE: 3.4), respectively (p = 0.05). One, two, and 5-Y DSS rates for the cohort of elderly patients were 58%, 36% and 23%, respectively.ConclusionsProperly selected elderly patients can undergo pancreatic resection with acceptable post-operative morbidity and mortality rates. Long term survival is achievable even in the presence of adenocarcinoma and therefore surgery should be seriously considered in these patients.

Intraductal papillary mucinous neoplasm of the pancreas: associated cancers, family history, genetic predisposition?

BACKGROUNDnHigh rates of extrapancreatic malignancies (EPM) have been observed in patients with intraductal papillary mucinous neoplasm (IPMN). IPMN in patients with familial pancreatic cancer have also been reported. Our purpose was to evaluate the association of IPMN with EPM, malignancies in family members, and germline BRCA1 and BRCA2 mutations.nnnMETHODSnUsing retrospective analysis on prospectively collected data from 82 patients with IPMN and direct contact for familial cancer history, data were compared with those of 150 patients with pancreatic ductal adenocarcinoma (PDAC). The common germline mutations in the BRCA1 and BRCA2 genes were evaluated on available IPMN patients.nnnRESULTSnEPM rates were greater in IPMN than PDAC patients (P = .002). Malignancies in first-degree relatives, specifically pancreatic cancer, were more common among IPMN than PDAC patients (P = .028). IPMN patients with EPM had high rates of relatives with colorectal cancer (31%). Two of the 51 genetically tested patients (4%) were BRCA2 mutation carriers, and both had first-degree relatives with pancreatic cancer. One patient fulfilled the Amsterdam criteria for hereditary nonpolyposis colon cancer; however, the neoplasm was microsatellite stable.nnnCONCLUSIONnOur results demonstrated high rates of EPM among IPMN patients. There was an increased rate of cancer in families of IPMN patients, specifically pancreatic cancer. A high rate of colorectal cancer in families of IPMN patients who have EPM was also observed. These findings suggest a genetic component in the pathogenesis of IPMN. Possible genetic changes include BRCA2 mutations, which are found in 25% of IPMN patients with a family history of pancreatic cancer.

Efficacy of high vs low dose TNF-isolated limb perfusion for locally advanced soft tissue sarcoma

AIMSnThe administration of a high dose of rTNF-alpha (3-4 mg) and Melphalan via isolated limb perfusion (ILP) for patients with locally advanced limb STS was shown to be effective. Reports that a low dose of TNF (1mg) is as effective, led to the adoption of the low dose regimen as the treatment of choice. The purpose of this study was to compare two groups of patients with locally advanced limb STS, that was treated with high and low dose TNF-ILP, in terms of limb preservation.nnnMETHODSnRetrospective study of 41 patients who underwent ILP, with high dose (HD) and low dose (LD) TNF. ILP/TNF was performed on candidates to either amputation or significantly mutilating surgery without this treatment. In both groups, all patients, with the exception of three in each group, underwent resection of the residual tumor or tumor bed or limb 8-12 weeks after the procedure.nnnRESULTSnIn the HD group, marked tumor softening occurred within 48 h, and in tumors protruding through the skin, hemorrhagic necrosis was evident within 24h. The overall response rate was 65.2%. Five patients achieved a CR and 10 had a PR; in five of these patients >90% necrosis of the tumor occurred. In eight patients, only minimal regression was observed (stabilization of disease). The rate of limb sparing was 69.5%. In the LD group, the overall response rate was 30.7%. CR was achieved in one patient. PR was observed in two. Two patients were lost to follow up. Of the remaining 15 patients, limb preservation was achieved in 53.3%.nnnCONCLUSIONnDespite the retrospective comparison and possible selection bias, it is possible to raise the concern that at least some patients may benefit from a higher TNF dose perfusion in ILP for advanced limb STS.

Clinical presentation can predict disease course in patients with intraductal papillary mucinous neoplasm of the pancreas.

BackgroundPreoperative diagnosis of malignancy within intraductal papillary mucinous neoplasm of the pancreas (IPMN) solely by clinical or radiological findings is not always possible. We sought a correlation between preoperative clinico-radiological findings and outcome.MethodsA prospective database of pancreatic resections for IPMN (2002–2008) and a retrospective pathological revision of all pancreatic cancer specimens (1995–2001) were analyzed. The patients were grouped into asymptomatic with preoperative diagnosis of IPMN (group 1), symptomatic with a preoperative diagnosis of IPMN (group 2), and those with a preoperative diagnosis of pancreatic cancer whose specimen revealed a background of IPMN (group 3). The groups were compared for demographics, clinical presentation, pathological findings, and outcome.ResultsOf the 62 patients with IPMN, 19 were in group 1, 23 in group 2, and 20 in group 3. Their median age (range) was 65.6 (46–80), 67 (50–84), and 73.4 (57–86) years, respectively. The clinical presentation for groups 2 and 3 included abdominal pain (56% vs. 32 %), weight loss (8% vs. 52%), obstructive jaundice (4% vs. 57%), pancreatitis (22% and 5%), and new onset of diabetes (14% and 44%). Invasive cancer was found in one patient in group 1 (5.2%), two patients in group 2 (8.7%), and all patients in group 3. IPMN was present in 23 of 217 (10.6%) of all resected pancreatic cancer specimens. Five year survival for patients with invasive disease was 47% and 92% for patients with noninvasive disease (mean follow-up 37.6 months).ConclusionsBenign IPMN can usually be differentiated from adenocarcinoma preoperatively. The clinical presentation is highly indicative of disease course.

Optimal management of sarcomas of the breast: an update.

Breast sarcomas are rare mesenchymal-derived breast tumors. The small number of patients, the different histological subtypes, and the variation in clinical practice impairs the ability to draw firm practice recommendations. Patient management is often extrapolated from other soft tissue sarcomas, mostly of the extremities in which more clinical data is available. Surgical resection with negative margins is the goal of treatment, irrespective of the surgical procedure; the implication of radiation and chemotherapy is variable. Further advances in treatment should follow the assembly of breast sarcoma patients in specific cancer networks in specialized sarcoma referral centers. The characterization of molecular pathways active in tumorogenesis of these tumors may pave the way for the application of novel therapeutic agents.

Safety and Outcome of Laparoscopic Sleeve Gastrectomy Following Removal of Adjustable Gastric Banding: Lessons from 109 Patients in a Single Center and Review of the Literature

BackgroundAlthough considered a common bariatric procedure, laparoscopic adjustable gastric banding (LAGB) is associated with high rates of weight loss failure and long-term complications.PurposeThe purpose of this study was to re-assess the safety and outcome of conversion of failed LAGB to laparoscopic sleeve gastrectomy (LSG).Materials and MethodsOne hundred and nine patients underwent conversion from LAGB to LSG (78 females, mean age 43xa0±xa011.3xa0years, mean BMI 42.4xa0±xa07.4xa0kg/m2). Patient demographics, obesity-related co-morbidities, BMI before and after the procedure, post-operative complications, and length of hospital stay were documented.ResultsAll cases were completed laproscopically, with 88% (nxa0=xa096) performed in a single stage. Fourteen patients developed early post-operative complications (12.8%), including two leaks and three post-operative bleeding. There were no mortalities in this series. Average BMI at least 1-year following surgery was 33xa0±xa05.3xa0kg/m2 (excess weight loss (EWL)xa0=xa053.7%).ConclusionsOur data suggests that conversion of failed LAGB to LSG is both safe and effective. Randomized controlled studies comparing conversion of a failed LAGB to sleeve gastrectomy versus other bariatric operations are necessary to clarify the optimal conversion procedure.

Analysis of histological and immunological parameters of metastatic lymph nodes from colon cancer patients reveals that T-helper 1 type immune response is associated with improved overall survival

AbstractLymph node (LN) involvement in colonic carcinoma (CC) is a grave prognostic sign and mandates the addition of adjuvant treatment. However, in light of the histological variability and outcomes observed, we hypothesized that patients with LN metastases (LNM) comprise different subgroups.We retrospectively analyzed the histological sections of 82 patients with CC and LNM. We studied various histological parameters (such as tumor grade, desmoplasia, and preservation of LN architecture) as well as the prevalence of specific peritumoral immune cells (CD8+, CD20+, T-bet+, and GATA-3+). We correlated the histological and immunological data to patient outcome.Tumor grade was a significant prognostic factor even in patients with LNM. So was the number of LN involved (N1/N2 stage). From the morphological parameters tested (LN extracapsular invasion, desmoplasia in LN, LN architecture preservation, and mode of metastases distribution), none was found to be significantly associated with overall survival (OS). The mean OS of CD8+ low patients was 66.6u200a±u200a6.25 versus 71.4u200a±u200a5.1 months for CD8+ high patients (Pu200a=u200a0.79). However, T-helper (Th) 1 immune response skewing (measured by Th1/Th2 ratio >1) was significantly associated with improved OS. For patients with low ratio, the median OS was 35.5u200a±u200a5 versus 83.5 months for patients with high Th1/Th2 ratio (Pu200a=u200a0.001).The histological presentation of LNM does not entail specific prognostic information. However, the finding of Th1 immune response in LN signifies a protective immune response. Future studies should be carried to verify this marker and develop a strategy that augments this immune response during subsequent adjuvant treatment.

Intraoperative Localization of Rectal Tumors Using Liposomal Indocyanine Green

Background: Tumor localization may pose a significant challenge during minimally invasive rectal resection. Near-infrared (NIR) imaging can penetrate biological tissue and afford tumor localization from the external surface of the rectum. Our aim was to develop an NIR-based tool for rectal tumor imaging that can be administered intravenously. Methods: We prepared indocyanine-green (ICG)–loaded liposomes by sonication. Liposomes were evaluated for their size and morphology. We then used an endoscopically induced rectal cancer in mice as a model for rectal cancer. After intravenous administration, tumors were evaluated for their fluorescence intensity. Tumor intensity was expressed in relation to the background signal, that is, tumor to background ratio (TBR). Results: Liposomes in various sizes could be prepared by adjusting sonication time. We selected 100-nm-sized liposomes for further experiments. Transmission electron microscopy showed spherical particles and confirmed the size measurements. The liposomes could be lyophilized and then rehydrated again before use without compromising their structure or signal. Fluorescence intensity was kept for 24 hours after solubilization. Testing the optimal time course for rectal tumor imaging revealed that early time course (up to 3 hours) yielded nonspecific imaging, whereas after long time course (24 hours), a very weak signal remained in the tissue. The optimal time window for imaging was after 12 hours from injection, with TBR = 8.1 ± 3.6 (P = .002). Free ICG could not achieve similar results. Conclusions: The liposomal ICG can be reproducibly prepared and kept in lyophilized form. Liposomal ICG could serve as a tool for intraoperative tumor localization.

Gastric Bypass as a Third Bariatric Procedure—Our Experience with 42 Cases

BackgroundIt is not uncommon to encounter patients seeking a third, fourth, or even fifth bariatric procedure. With higher expected complication rates and questionable patient benefit, the indication for multiple revisions is still in doubt. To evaluate the perioperative and post-operative outcomes of patients undergoing gastric bypass after two previous bariatric surgeries or more.MethodsWe identified all patients that underwent gastric bypass following at least 2 previous bariatric surgeries. We looked at patient demographics, previous bariatric surgeries, pre-operative body mass index (BMI) and obesity-related co-morbidities, perioperative complications, length of stay (LOS), re-admissions and re-operations, percentage of excess weight loss, and resolution or improvement in comorbidities.ResultsForty-two patients met the inclusion criteria, the majority being females (31, 73.8%). Average age was 45.6xa0years (range 27–62), average weight and BMI was 116xa0kg (range 75–175xa0kg) and 41.1xa0kg/m2 (range 25.6–58.7xa0kg/m2), respectively. Thirty-two patients had two previous bariatric surgeries (73.8%), and 10 patients had 3 former bariatric surgeries (23.8%), and for one patient, this was the fifth bariatric procedure (2.4%). Mean LOS was 10xa0days (range 2–56xa0days). Eight patients (19%) needed re-admission and 5 (11.9%) needed re-operation. At a median follow up of 48xa0months (range 7–99xa0months), the average BMI was 34.5xa0kg/m2 (range 23.7–55.1xa0kg/m2) reflecting an excess BMI loss of 43.3%.ConclusionsGastric bypass as a third or more bariatric procedure is effective yet associated with high complication rates, re-admissions, and re-operations.