Jin Seok Heo

Treatment Guidelines for Branch Duct Type Intraductal Papillary Mucinous Neoplasms of the Pancreas: When Can We Operate or Observe?

BackgroundThe objectives of this study were to investigate the clinicopathological features of branch intraductal papillary mucinous neoplasm (IPMN) and to determine safe criteria for its observation. Most clinicians agree that surgical resection is required to treat main duct-type IPMN because of its high malignancy rate. However, no definite treatment guideline (with respect to surgery or observation) has been issued on the management of branch duct type IPMN.MethodsWe retrospectively reviewed the clinicopathological data of 138 patients who underwent operations for IPMN between 1993 and 2006 at five institutes in Korea.ResultsOf 138 patients (mean age, 60.6 years; 87 men, 51 women), 76 underwent pancreatoduodenectomy, 39 distal pancreatectomy, 4 total pancreatectomy, and 20 limited pancreatic resection. There were 112 benign cases: 47 adenoma, 63 borderline cases, and 26 malignant cases, with 9 of these being noninvasive and 17 invasive. By univariate analysis, tumor size and the presence of a mural nodule were identified as meaningful predictors of malignancy. By receiver operating characteristic curve analysis, a tumor size of >2 cm was found to be the most valuable predictor of malignancy. When cases were classified according to tumor size and the presence of a mural nodule, the malignancy rate for a tumor ≤2 cm without a mural nodule was 9.2%, for a tumor of ≤2 cm plus a mural nodule was 25%, and for other conditions such as tumor >2 cm, >25%.ConclusionsMany branch duct IPMNs are malignant. Surgical treatment is recommended, except in cases that are strongly suspected to be benign or cases that present a high operative risk. Observation is only recommended in patients with a tumor size of ≤2 cm without a mural nodule.

Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients

AbstractBackgroundStatins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer.nMethodsPatients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000xa0mg/m2 on days 1, 8, and 15 plus simvastatin 40xa0mg once daily) or GP (gemcitabine 1,000xa0mg/m2 on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP).ResultsBetween December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4xa0months (95xa0% CI 0.7–4.1xa0months) and 3.6xa0months (95xa0% CI 3.1–4.1xa0months) in the GS and GP arms, respectively (Pxa0=xa00.903). The overall disease control rate was 39.7xa0% (95xa0% CI 12.2–33.8xa0%) and 57.1xa0% (95xa0% CI 19.8–44.2xa0%) in the GS and GP arms, respectively (Pxa0=xa00.09). The 1-year expected survival rates were similar (27.7 and 31.7xa0% in the GS and GP arms, respectively; Pxa0=xa00.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis.ConclusionsAdding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.

Risk Factors Influencing Recurrence, Patterns of Recurrence, and the Efficacy of Adjuvant Therapy After Radical Resection for Gallbladder Carcinoma

BackgroundsGallbladder carcinoma (GBC) is an aggressive neoplasm, and resection is the only curative modality. Recurrence frequently occurs after the curative resection of advanced GBC. Adjuvant treatment, particularly radiotherapy, is recommended and is used without any evidence of a beneficial effect. The aim of this study was to characterize patterns of recurrence and to identify the factors that influence recurrence and the efficacy of adjuvant therapy after the curative resection of GBC.MethodsThe records of patients that underwent surgical resection with curative intent for gallbladder carcinoma from October 1994 and August 2007 were retrospectively reviewed. Recurrence patterns, times to recurrence, and survival rates were analyzed. Sites of recurrence were identified retrospectively and categorized as locoregional or distant.ResultsOne hundred sixty-six patients underwent surgical resection with curative intent for gallbladder adenocarcinoma. The 5-year recurrence rates of stages IA, IB, IIA, and IIB patients were 0%, 24.3%, 44.9%, and 58.3%, retrospectively. Positivity for lymph node metastases was found to have predictive significance for disease-free survival (pu2009=u20090.009). Regional lymph node recurrence (27.7%) was observed most frequently. There was no significant disease-free survival rates between the no adjuvant therapy and the adjuvant therapy groups.ConclusionsThe regional lymph nodes and the liver were found to be the most common sites of recurrence after curative resection. Lymph node metastases were identified as an independent predictor of tumor recurrence by multivariate analysis. Based on the disease-free survivals observed in this study, the authors find it would be difficult to advocate the routine use of adjuvant radiotherapy and/or chemotherapy

Prognostic Factors and Adjuvant Chemoradiation Therapy After Pancreaticoduodenectomy for Pancreatic Adenocarcinoma

BackgroundThe aim of this study was to determine prognostic factors for survival after resection of pancreatic adenocarcinoma (PC) and to compare outcomes after surgery alone versus surgery plus adjuvant therapy.MethodsWe performed a retrospective review of 219 patients who underwent pancreaticoduodenectomy for PC with curative intent between 1995 and 2007. Data were collected prospectively. Postoperative adjuvant chemoradiation therapy (CRT) consisted of fluorouracil or gemcitabine-based chemotherapy; the median radiation dose was 45xa0Gy.ResultsThe 3- and 5-year overall survival (OS) rates were 24.3% and 14.2%, respectively. Median OS was 14.0xa0months [95% confidence interval (CI), 12–16xa0months]. Patients with metastatic lymph nodes experienced improved median survival (16 vs 10xa0months; Pu2009<u20090.001) and 3-year OS (3-year OS 28% vs 8%) after adjuvant CRT compared with those who had no CRT. Patients who underwent non-curative resection had the same effect (median OS, 13 vs 8xa0months; Pu2009=u20090.037). Lymph node metastasis and non-curative resection showed no significance on multivariate analysis. Poor differentiation [risk ratio (RR)u2009=u20092.10; Pu2009<u20090.001] and tumor size >3xa0cm (RRu2009=u20091.57; Pu2009=u20090.018) were found to be adverse prognostic factors; adjuvant CRT had borderline significance (RRu2009=u20090.70; Pu2009=u20090.087).ConclusionsAdjuvant CRT benefited a subset of patients with resected PC, particularly those with lymph node metastasis and those undergoing non-curative resection. Multivariate analysis demonstrated that patients with tumors larger than 3xa0cm and poor differentiation had poor prognosis.

RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression.

Lymph node (LN) metastasis is one of the most important adverse prognostic factors for pancreatic cancer. The aim of this study was to identify novel lymphatic metastasis-associated markers for pancreatic cancer. DNA microarray analysis was used to determine and compare the expression profiles of 17 pancreatic cancer tissues with LN metastasis and 17 pancreatic cancer tissues without LN metastasis. The microarray results were validated by real-time reverse transcription-polymerase chain reaction and immunohistochemistry. Only 58 genes were differentially expressed between the two groups with a difference in signal intensity ratio greater than a 1.5-fold change. Of these genes, 30 were significantly down-regulated in the LN metastasis group. Among five selected down-regulated genes for validation using real-time PCR, the expression of DST, FosB, RGS16, and CXCL12 was significantly lower in the LN metastasis group. Immunohistochemical analysis confirmed RGS16 and FosB underexpression in pancreatic cancer tissues with LN metastasis. RGS16 and FosB underexpression was associated with poor patient survival. Our findings show that RGS16 and FosB are underexpressed in pancreatic cancer with lymph node metastasis and associated with reduced survival, suggesting that RGS16 and FosB might be prognostic markers for pancreatic cancer.

Prognostic relevance of pathologic subtypes and minimal invasion in intraductal papillary mucinous neoplasms of the pancreas

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are classified into the following four histopathologic subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. However, the clinicopatholgic characteristics of IPMN subtypes have not been fully clarified. Recently, a subgroup classification of minimally invasive intraductal papillary mucinous carcinomas (MI-IPMCs) was suggested in contrast to overt invasive carcinoma from IPMCs (IC-IPMCs). The purpose of this study was to determine whether or not the pathologic subtype classification can predict prognosis and to validate the usefulness of the newly proposed diagnostic criteria of MI-IPMCs. We reviewed the clinicopathologic characteristics of 142 surgically resected cases of IPMNs. There were 54, 56, 30, and two cases of the gastric, intestinal, pancreatobiliary, and oncocytic types of IPMNs, respectively. The intestinal and pancreatobiliary types were more likely to have a main duct type. All gastric type tumors were adenomas or moderate dysplasia, whereas greater than one half of the intestinal and pancreatobiliary types were carcinomas in situ or invasive carcinomas. A significant difference in recurrence and death rate was noted for invasive carcinoma between the intestinal and pancreatobiliary types. The majority of MI-IPMCs were the intestinal type, whereas the majority of IC-IPMCs were the pancreatobiliary type. The IC-IPMC group showed a decreased recurrence-free and overall survival with statistically significance (pu2009<u20090.001 and pu2009=u20090.001, respectively). Our results suggest that the pathologic subtype classification and the newly proposed diagnostic criteria for minimal invasion may also be useful to predict prognosis of IPMNs of the pancreas.

Clinical Validation of the ISGPF Classification and the Risk Factors of Pancreatic Fistula Formation Following Duct-to-Mucosa Pancreaticojejunostomy by One Surgeon at a Single Center

BackgroundPostoperative pancreatic fistula remains a troublesome complication after pancreatoduodenectomy (PD), and many authors have suggested factors that affect pancreatic leakage after PD. The International Study Group on Pancreatic Fistula (ISGPF) published a classification, but the new criteria adopted have not been substantially validated. The aims of this study were to validate the ISGPF classification and to analyze the risk factors of pancreatic leakage after duct-to-mucosa pancreatojejunostomy by a single surgeon.MethodsAll patient data were entered prospectively into a database. The risk factors for pancreatic fistula were analyzed retrospectively for 247 consecutive patients who underwent conventional pancreatoduodenectomy or pylorus-preserving pancreatoduodenectomy between June 2005 and March 2009 at the Samsung Medical Center by a single surgeon. Duct-to-mucosa pancreatojejunostomy was performed on all patients. The ISGPF criteria were used to define postoperative pancreatic fistula.ResultsConventional pancreatoduodenectomy was performed in 84 patients and pylorus-preserving pancreatoduodenectomy in 163. Postoperative complications occurred in 144 (58.3%) patients, but there was no postoperative in-hospital mortality. Pancreatic fistula occurred in 105 (42.5%) [grade A, 82 (33.2%); grade B, 9 (3.6%); grade C, 14 (5.7%)]. However, no difference was evident between the no fistula group and the grade A fistula group in terms of clinical findings, including postoperative hospital stays (11 versus 12xa0days, respectively, pu2009=u20090.332). Mean durations of hospital stay in the grade B and C fistula groups were significantly longer than in the no fistula group (21 and 28.5xa0days, respectively; pu2009<u20090.001). Multivariate analysis revealed that a soft pancreas and a long operation time (>300xa0min) were individually associated with pancreatic fistula formation of grades B and C.ConclusionsAlthough the new ISGPF classification appears to be sound in terms of postoperative pancreatic leakage, grade A fistulas lack clinical implications; thus, we are of the opinion that only grade B and C fistulas should be considered in practice. A soft pancreatic texture and an operation time exceeding 300xa0min were found to be risk factors of grade B and C pancreatic fistulas.

Role of Radical Antegrade Modular Pancreatosplenectomy for Adenocarcinoma of the Body and Tail of the Pancreas

AbstractBackgroundnStudies have claimed that in the surgical treatment of pancreas body and tail cancer, radical antegrade modular pancreatosplenectomy (RAMPS) is associated with effective tangential margin and extensive lymph node dissection. In the present study, the authors have compared the surgical outcomes between RAMPS and conventional distal pancreatosplenectomy (DPS) in patients with adenocarcinoma of the pancreas body and tail, and also identified prognostic factors associated with survival after surgery.MethodsRetrospective review of 92 consecutive patients who underwent surgical resection for pancreas body and tail adenocarcinoma with curative intent between 1995 and 2010. Median follow-up duration was 16.1xa0months.ResultsOf the 92 patients, 38 patients received RAMPS and 54 patients received DPS. Patients who underwent RAMPS had a greater number of retrieved lymph nodes than patients undergoing DPS [median 14 (5–52) vs. 9 (1–36), pxa0<xa00.05]. Conventional DPS, no adjuvant chemoradiation therapy (CRT), and non-curative resection were associated with poor overall survival (OS) on univariate analysis. After multivariate analysis for these variables, only the lack of adjuvant CRT and resection margin status were found to adversely affect OS.ConclusionsWhile the RAMPS procedure is effective in performing an extensive LN dissection, it is not associated with better retroperitoneal resection margin or retrieval of more positive LNs, and it does not lead to better curability or OS survival compared to DPS. Lack of adjuvant CRT and resection margin status are poor prognostic factors in patients with pancreas body and tail cancer.

Intraductal papillary neoplasms and mucinous cystic neoplasms of the hepatobiliary system: demographic differences between Asian and Western populations, and comparison with pancreatic counterparts

To improve the characterization of intraductal papillary neoplasm of the bile duct (IPNB) and mucinous cystic neoplasm of the liver (MCN‐L).

A phase II trial of gemcitabine plus capecitabine for patients with advanced pancreatic adenocarcinoma

PurposeWhile gemcitabine (GEM) is widely accepted for the treatment of advanced pancreatic cancer, capecitabine (CAP) has shown single agent activity and promising efficacy in combination with GEM. This phase II study was conducted to evaluate the efficacy and toxicity of GEM combined with dose escalated 14-day CAP as first-line chemotherapy for advanced pancreatic cancer. In addition, we also analyzed the correlation between CA19-9 response and clinical outcomes.MethodsPatients had advanced pancreatic adenocarcinoma, no prior systemic chemotherapy other than that given concurrently with radiation therapy, at lease one measurable disease, and adequate organ functions. The patients were treated with GEM 1,000xa0mg/m2 IV on daysxa01, 8 and CAP 1,000xa0mg/m2 twice a day PO on daysxa01–14, in 21-day cycles.ResultsThe objective RR among 45 patients was 40.0% (95% CI; 25.1–54.9), including 1CR (2.2%). The median TTP and OS were 5.4xa0months (95% CI; 1.8–9.0) and 10.4xa0months (95% CI; 6.2–14.5), respectively. Patients with ≥25% decline of serum CA19-9 had significantly better outcomes in terms of TTP and OS than those who did not (Pxa0<xa00.03). The most frequent, grade 3–4, non-hematologic toxicity was hand–foot syndrome (6.7%).ConclusionsThe combination of GEM with dose escalated 14-day CAP is well tolerated and offers encouraging activity in the treatment of advanced pancreatic cancer. In addition, CA19-9 response correlates well with clinical outcomes in this population.