Lymph node metastases in young patients with gastrointestinal stromal tumor: A nationwide analysis.

BACKGROUND: Children, adolescents, and young adults (CAYA) (age ≤39 years) with GIST have high rates of LNM, but their clinical relevance is undefined. This study analyzed the impact of LNM on overall survival (OS) for CAYA with GIST. METHODS: The National Cancer Database was queried for patients with resected GIST and pathologic nodal staging data from 2004-2019. Factors associated with LNM were identified. Survival was assessed stratified by presence of LNM. RESULTS: Of 4420 patients with GIST, 238 were CAYA (5.4%). When compared to older adults, CAYA more often had small intestine primaries (51.8% vs. 36.6%, p < 0.0001), T4 tumors (30.7% vs. 24.5%, p = 0.0275) and pN1 disease (11.3% vs. 4.7%, p < 0.0001). Within a multivariable Cox proportional hazards regression model adjusting for age, comorbid disease, mitotic rate, tumor size, and primary site, LNM were associated with increased hazard of death for older adults (hazard ratio [HR]: 1.83; confidence interval [CI]: 1.35-2.42; p < 0.0001), but not CAYA (HR: 3.38; CI: 0.50-14.08; p = 0.13). For CAYA, only high mitotic rate predicted mortality (HR: 4.68; CI: 1.41-18.37: p = 0.02). CONCLUSIONS: LNM are more commonly identified among CAYA with resected GIST who undergo lymph node evaluations, but do not appear to impact OS as observed in older adults. High mitotic rate remains a predictor of poor outcomes for CAYA with GIST.

Racial Disparity in Pathologic Response following Neoadjuvant Chemotherapy in Resected Pancreatic Cancer: A Multi-Institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Major pathologic response (MPR) following neoadjuvant therapy (NAT) in pancreatic ductal adenocarcinoma (PDAC) patients undergoing resection is associated with improved survival. We sought to determine whether racial disparities exist in MPR rates following NAT in patients with PDAC undergoing resection. METHODS: Patients with potentially operable PDAC receiving at least 2 cycles of neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ± radiation followed by pancreatectomy (2010-2019) at 7 high-volume centers were reviewed. Self-reported race was dichotomized as Black and non-Black, and multivariable models evaluated the association between race and MPR (i.e., pathologic complete response [pCR] or near-pCR). Cox regression evaluated the association between race and disease-free (DFS) and overall survival (OS). RESULTS: Results of 486 patients who underwent resection following NAT (mFOLFIRINOX 56%, gemcitabine/nab-paclitaxel 25%, radiation 29%), 67 (13.8%) patients were Black. Black patients had lower CA19-9 at diagnosis (median 67 vs. 204 U/mL; P = 0.003) and were more likely to undergo mild/moderate chemotherapy dose modification (40 vs. 20%; P = 0.005) versus non-Black patients. Black patients had significantly lower rates of MPR compared with non-Black patients (13.4 vs. 25.8%; P = 0.039). Black race was independently associated with worse MPR (OR 0.26, 95% confidence interval [CI] 0.10-0.69) while controlling for NAT duration, CA19-9 dynamics, and chemotherapy modifications. There was no significant difference in DFS or OS between Black and non-Black cohorts. CONCLUSIONS: Black patients undergoing pancreatectomy appear less likely to experience MPR following NAT. The contribution of biologic and nonbiologic factors to reduced chemosensitivity in Black patients warrants further investigation.

Intraoperative Pancreatic Neck Margin Assessment During Pancreaticoduodenectomy for Pancreatic Adenocarcinoma in the Era of Neoadjuvant Therapy: A Multi-institutional Analysis from the Central Pancreatic Consortium.

BACKGROUND: Data regarding the survival impact of converting frozen-section (FS):R1 pancreatic neck margins to permanent section (PS):R0 by additional resection (i.e., converted-R0) during upfront pancreaticoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) are conflicting. The impact of neoadjuvant therapy on this practice and its relationship with overall survival (OS) is incompletely understood. METHODS: We reviewed PDAC patients (80% borderline resectable/locally advanced [BR/LA]) undergoing pancreaticoduodenectomy after neoadjuvant therapy at seven, academic, high-volume centers (2010-2018). Multivariable models examined the association of PS:R0, PS:R1, and converted-R0 margins with OS. RESULTS: Of 272 patients receiving at least 2 (median 4) cycles of neoadjuvant chemotherapy (71% mFOLFIRINOX or gemcitabine/nab-paclitaxel) and undergoing pancreaticoduodenectomy with intraoperative frozen-section assessment of the transected pancreatic neck margin, PS:R0 (n = 220, 80.9%) was observed in a majority of patients; 18 patients (6.6%) had converted-R0 margins following additional resection, whereas 34 patients (12.5%) had persistently positive PS:R1 margins. At a median follow-up of 42 months, PS:R0 resection was associated with improved OS compared with either converted-R0 or PS:R1 resection (median 25 vs. 14 vs. 16 months, respectively; p = 0.023), with no survival difference between the converted-R0 and PS:R1 groups (p = 0.9). On Cox regression, SMA margin positivity (hazard ratio 2.2, p = 0.012), but not neck margin positivity (hazard ratio 1.2, p = 0.65), was associated with worse OS. CONCLUSIONS: In this multi-institutional cohort of predominantly BR/LA PDAC patients undergoing pancreaticoduodenectomy following modern neoadjuvant therapy, pursuing a negative neck margin intraoperatively if the initial margin is positive does not appear to be associated with improved survival.

Objective postoperative pain assessment using incentive spirometry values: a prospective observational study.

Aim: Determine if incentive spirometry (IS) values correlate with postoperative pain control. Design: Prospective observational study. Setting & participants: A total of 100 patients undergoing major abdominal procedures at the University of North Carolina Medical Center. Interventions: Patients studied as a single cohort. All patients received thoracic epidural analgesia preoperatively. Outcome: Preoperative and daily postoperative numeric pain scores, subjective pain description and IS values were collected for all patients. Results: There was a strong correlation with IS values relative to baseline for both the numeric pain scores (p < 0.0001), postoperative day (p < 0.0001) and the subjective pain score (p < 0.0007). Conclusion: IS values are an objective surrogate data point for pain control after surgery, particularly when followed over time and compared with a preoperative baseline value.

Survival Outcomes Associated With Clinical and Pathological Response Following Neoadjuvant FOLFIRINOX or Gemcitabine/Nab-Paclitaxel Chemotherapy in Resected Pancreatic Cancer.

OBJECTIVE: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy. BACKGROUND: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown. METHODS: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19-9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC. RESULTS: Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19-9 decrease ≥50% vs <50%; OS: 42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response [pCR vs pPR vs pLR: OS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017]. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP. CONCLUSION: This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.

Cyst location and presence of high grade dysplasia or invasive cancer in intraductal papillary mucinous neoplasms of the pancreas: a seven institution study from the central pancreas consortium.

BACKGROUND: Traditionally, intraductal papillary mucinous neoplasms (IPMNs) of the pancreas with "high risk stigmata" (HRS) or "worrisome features" (WF) are referred for resection. We aim to assess if IPMN location is predictive of harboring either high grade dysplasia (HGD) or invasive cancer (IC). METHODS: Patients undergoing resection for IPMN from seven institutions between 2000 and 2015 (n = 275) were analyzed. HRS and WF were defined by the 2012 Fukuoka international consensus guidelines. RESULTS: 168 (61%) patients had head/uncinate cysts, while 107 (39%) had neck/body/tail cysts. No differences were noted between groups with regard to age, duct type, cyst size, or presence of at least one WF. Patients with cysts in the head/uncinate were more often male (55% vs. 40%), had at least one HRS (24% vs. 11%), and more often harbored HGD or IC(49% vs. 27%)[all p < 0.05]. On multivariate analysis, only cyst location in the head/uncinate remained associated with presence of HGD or IC(odds ratio 4.76, p = 0.02). DISCUSSION: Cyst location is predictive of HGD or IC in patients with IPMNs. Head/uncinated cysts are more likely to harbor malignancy compared to those of the neck/body/tail. Additional studies are needed to confirm these findings, however, cyst location should be considered part of the decision making process for surveillance vs. resection for IPMNs.

Does Surgical Margin Impact Recurrence in Noninvasive Intraductal Papillary Mucinous Neoplasms?: A Multi-institutional Study.

OBJECTIVE: The relevance of margin positivity on recurrence after resection of intraductal papillary mucinous neoplasms (IPMNs) is poorly defined and represents one reason controversy remains regarding optimal surveillance recommendations. METHODS: Patients undergoing surgery for noninvasive IPMN at 8 academic medical centers from the Central Pancreas Consortium were analyzed. A positive margin was defined as presence of IPMN or pancreatic intraepithelial neoplasia. RESULTS: Five hundred two patients underwent surgery for IPMN; 330 (66%) did not have invasive cancer on final pathology and form the study cohort. Of these, 20% harbored high grade dysplasia. A positive margin was found in 20% of cases and was associated with multifocal disease (P = 0.02). The majority of positive margins were associated with low grade dysplasia. At a median follow-up of 36 months, 34 (10.3%) patients recurred, with 6.7% developing recurrent cystic disease and 3.6% developing invasive cancer. On multivariate analysis, margin positivity was not associated with recurrence of either IPMN or invasive cancer (P > 0.05). No association between margin status and development of recurrence at the margin was found. Only 6% of recurrences developed at the resection margin and median time to recurrence was 22 months. Of note, 18% of recurrences occurred > 5 years following surgery. CONCLUSION: Margin positivity after resection for noninvasive IPMNs is primarily due to low grade dysplasia and is not associated with developing recurrence in the remnant pancreas or at the resection margin. Long-term surveillance is required for all patients, as a significant number of recurrences developed over 5 years after the index operation.

The Hand-Assisted Laparoscopic Approach to Resection of Pancreatic Mucinous Cystic Neoplasms: An Underused Technique?

Pancreatic mucinous cystic neoplasms (MCNs) are rare tumors typically of the distal pancreas that harbor malignant potential. Although resection is recommended, data are limited on optimal operative approaches to distal pancreatectomy for MCN. MCN resections (2000-2014; eight institutions) were included. Outcomes of minimally invasive and open MCN resections were compared. A total of 289 patients underwent distal pancreatectomy for MCN: 136(47%) minimally invasive and 153(53%) open. Minimally invasive procedures were associated with smaller MCN size (3.9 vs 6.8 cm; P = 0.001), lower operative blood loss (192 vs 392 mL; P = 0.001), and shorter hospital stay(5 vs 7 days; P = 0.001) compared with open. Despite higher American Society of Anesthesiologists class, hand-assisted (n = 46) had similar advantages as laparoscopic/robotic (n = 76). When comparing hand-assisted to open, although MCN size was slightly smaller (4.1 vs 6.8 cm; P = 0.001), specimen length, operative time, and nodal yield were identical. Similar to laparoscopic/robotic, hand-assisted had lower operative blood loss (161 vs 392 mL; P = 0.001) and shorter hospital stay (5 vs 7 days; P = 0.03) compared with open, without increased complications. Hand-assisted laparoscopic technique is a useful approach for MCN resection because specimen length, lymph node yield, operative time, and complication profiles are similar to open procedures, but it still offers the advantages of a minimally invasive approach. Hand-assisted laparoscopy should be considered as an alternative to open technique or as a successive step before converting from total laparoscopic to open distal pancreatectomy for MCN.

Grading Using Ki-67 Index and Mitotic Rate Increases the Prognostic Accuracy of Pancreatic Neuroendocrine Tumors.

OBJECTIVES: To measure the usefulness of Ki-67 proliferative index (Ki-67 index) as a prognostic variable for grading pancreatic neuroendocrine tumors. METHODS: A multi-institutional prospective database comprising 350 patients. Grading based on mitotic activity (<2 mitoses/10 high-power fields, 2-20 and >20) and Ki-67 index (<3% per 10 high-power fields, 3%-20% and >20%). Final grade selected based on higher grade of either variable. RESULTS: Most patients were in the less than 3% (n = 158) and 3% to 20% Ki-67 category (n = 107), with a minority being high-grade (Ki-67 > 20%, n = 27). Discordance between Ki-67 and mitotic rate was noted in 58 patients. On multivariate analysis, final-grade (grade 2: P = 0.010, hazard ratio [HR], 1.2; grade 3: P = 0.002; HR, 2.8), Ki-67, mitotic rate, and lymph node status were significant prognostic markers for overall survival (OS). For disease-free survival (DFS), only final-grade (grade 2: P = 0.05; HR, 1.4; grade 3: P = 0.009; HR, 2.3), Ki-67, mitotic rate, and margin status significantly predicted DFS. Ki-67 was a better model for OS and mitotic rate for DFS. Overall combined final grade was the best model based on HR. CONCLUSION: Ki-67 is a strong prognostic factor for OS and DFS and should be included in all pancreatic neuroendocrine tumor pathology.

Folic acid is necessary for proliferation and differentiation of C2C12 myoblasts.

Folic acid, a water soluble B vitamin, plays an important role in cellular metabolic activities, such as functioning as a cofactor in one-carbon metabolism for DNA and RNA synthesis as well as nucleotide and amino acid biosynthesis in the body. A lack of dietary folic acid can lead to folic acid deficiency and result in several health problems, including macrocytic anemia, elevated plasma homocysteine, cardiovascular disease, birth defects, carcinogenesis, muscle weakness, and walking difficulty. However, the effect of folic acid deficiency on skeletal muscle development and its molecular mechanisms are unknown. We, therefore, investigated the effect of folic acid deficiency on myogenesis in skeletal muscle cells and found that folic acid deficiency induced proliferation inhibition and cell cycle breaking as well as cellular senescence in C2C12 myoblasts, implying that folic acid deficiency influences skeletal muscle development. Folic acid deficiency also inhibited differentiation of C2C12 myoblasts and induced deregulation of the cell cycle exit and many cell cycle regulatory genes. It inhibited expression of muscle-specific marker MyHC as well as myogenic regulatory factor (myogenin). Moreover, immunocytochemistry and Western blot analyses revealed that DNA damage was more increased in folic acid-deficient medium-treated differentiating C2C12 cells. Furthermore, we found that folic acid resupplementation reverses the effect on the cell cycle and senescence in folic acid-deficient C2C12 myoblasts but does not reverse the differentiation of C2C12 cells. Altogether, the study results suggest that folic acid is necessary for normal development of skeletal muscle cells.

The diagnosis of pancreatic mucinous cystic neoplasm and associated adenocarcinoma in males: An eight-institution study of 349 patients over 15 years.

BACKGROUND: Per WHO, 2000 classification, pancreatic mucinous cystic neoplasms (MCN) are defined by presence of ovarian stroma, and are primarily located in the pancreatic body/tail of females. The incidence of MCN and associated malignancy in males, since, standardization of MCN diagnostic-criteria is unknown. METHODS: MCN resections from 2000 to 2014 at eight institutions of the Central-Pancreas-Consortium were included, and divided into early (2000-2007) and late (2008-2014) time-periods. Primary aim was to characterize MCN and associated adenocarcinoma/high-grade-dysplasia (AC/HGD) in males versus females over time. RESULTS: Of 1667 resections for pancreatic cystic lesions, 349 pts (21%) had MCNs: 310 (89%) female, 39 (11%) male. Patients were equally divided between early (n = 173) and late (n = 176) time-periods. MCN in male-patients decreased over time (early: 15%, late: 7%; P = 0.036), as did pancreatic head/neck location (early: 22%, late: 11%; P = 0.01). MCN-associated AC/HGD was more frequent in males versus females (39 vs. 12%; P < 0.001). The overall rate of MCN-associated AC/HGD remained stable (early: 17%, late: 13%; P = 0.4), and was identical in males (39%) over both time-periods. Males with AC/HGD had more LN-positive disease versus females (57 vs. 22%; P = 0.039). CONCLUSIONS: As the diagnostic-criteria of MCN have standardized over time, MCN diagnosis has decreased in males and head/neck location. Despite this, MCN-associated adenocarcinoma/high-grade dysplasia has been stable and remains high in males. Any male with suspected MCN, regardless of location, should undergo resection.

Association of Preoperative Risk Factors With Malignancy in Pancreatic Mucinous Cystic Neoplasms: A Multicenter Study.

Importance: Pancreatic mucinous cystic neoplasms (MCNs) harbor malignant potential, and current guidelines recommend resection. However, data are limited on preoperative risk factors for malignancy (adenocarcinoma or high-grade dysplasia) occurring in the setting of an MCN. Objectives: To examine the preoperative risk factors for malignancy in resected MCNs and to assess outcomes of MCN-associated adenocarcinoma. Design, Setting, and Participants: Patients who underwent pancreatic resection of MCNs at the 8 academic centers of the Central Pancreas Consortium from January 1, 2000, through December 31, 2014, were retrospectively identified. Preoperative factors of patients with and without malignant tumors were compared. Survival analyses were conducted for patients with adenocarcinoma. Main Outcomes and Measures: Binary logistic regression models were used to determine the association of preoperative factors with the presence of MCN-associated malignancy. Results: A total of 1667 patients underwent resection of pancreatic cystic lesions, and 349 (20.9%) had an MCN (310 women [88.8%]; mean (SD) age, 53.3 [14.7] years). Male sex (odds ratio [OR], 3.72; 95% CI, 1.21-11.44; P = .02), pancreatic head and neck location (OR, 3.93; 95% CI, 1.43-10.81; P = .01), increased radiographic size of the MCN (OR, 1.17; 95% CI, 1.08-1.27; P < .001), presence of a solid component or mural nodule (OR, 4.54; 95% CI, 1.95-10.57; P < .001), and duct dilation (OR, 4.17; 95% CI, 1.63-10.64; P = .003) were independently associated with malignancy. Malignancy was not associated with presence of radiographic septations or preoperative cyst fluid analysis (carcinoembryonic antigen, amylase, or mucin presence). The median serum CA19-9 level for patients with malignant neoplasms was 210 vs 15 U/mL for those without (P = .001). In the 44 patients with adenocarcinoma, 41 (93.2%) had lymph nodes harvested, with nodal metastases in only 14 (34.1%). Median follow-up for patients with adenocarcinoma was 27 months. Adenocarcinoma recurred in 11 patients (25%), with a 64% recurrence-free survival and 59% overall survival at 3 years. Conclusions and Relevance: Adenocarcinoma or high-grade dysplasia is present in 14.9% of resected pancreatic MCNs for which risks include male sex, pancreatic head and neck location, larger MCN, solid component or mural nodule, and duct dilation. Mucinous cystic neoplasm-associated adenocarcinoma appears to have decreased nodal involvement at the time of resection and increased survival compared with typical pancreatic ductal adenocarcinoma. Indications for resection of MCNs should be revisited.

A Multi-institutional Comparison of Perioperative Outcomes of Robotic and Open Pancreaticoduodenectomy.

OBJECTIVES: Limited data exist comparing robotic and open approaches to pancreaticoduodenectomy (PD). We performed a multicenter comparison of perioperative outcomes of robotic PD (RPD) and open PD (OPD). METHODS: Perioperative data for patients who underwent postlearning curve PD at 8 centers (8/2011-1/2015) were assessed. Univariate analyses of clinicopathologic and treatment factors were performed, and multivariable models were constructed to determine associations of operative approach (RPD or OPD) with perioperative outcomes. RESULTS: Of the 1028 patients, 211 (20.5%) underwent RPD (4.7% conversions) and 817 (79.5%) underwent OPD. As compared with OPD, RPD patients had higher body mass index, rates of prior abdominal surgery, and softer pancreatic remnants, whereas OPD patients had a higher percentage of pancreatic ductal adenocarcinoma cases, and greater proportion of nondilated (<3 mm) pancreatic ducts. On multivariable analysis, as compared with OPD, RPD was associated with longer operative times [mean difference = 75.4 minutes, 95% confidence interval (CI) 17.5-133.3, P = 0.01], reduced blood loss (mean difference = -181 mL, 95% CI -355-(-7.7), P = 0.04) and reductions in major complications (odds ratio = 0.64, 95% CI 0.47-0.85, P = 0.003). No associations were demonstrated between operative approach and 90-day mortality, clinically relevant postoperative pancreatic fistula and wound infection, length of stay, or 90-day readmission. In the subset of 522 (51%) pancreatic ductal adenocarcinomas, operative approach was not a significant independent predictor of margin status or suboptimal lymphadenectomy (<12 lymph nodes harvested). CONCLUSIONS: Postlearning curve RPD can be performed with similar perioperative outcomes achieved with OPD. Further studies of cost, quality of life, and long-term oncologic outcomes are needed.

No mutations in hnRNPA1 and hnRNPA2B1 in Dutch patients with amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy.

Inclusion body myopathy (IBM) associated with Paget disease of the bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), sometimes called IBMPFD/ALS or multi system proteinopathy, is a rare, autosomal dominant disorder characterized by progressive degeneration of muscle, brain, motor neurons, and bone with prominent TDP-43 pathology. Recently, 2 novel genes for multi system proteinopathy were discovered; heterogenous nuclear ribonucleoprotein (hnRNP) A1 and A2B1. Subsequently, a mutation in hnRNPA1 was also identified in a pedigree with autosomal dominant familial ALS. The genetic evidence for ALS and other neurodegenerative diseases is still insufficient. We therefore sequenced the prion-like domain of these genes in 135 familial ALS, 1084 sporadic ALS, 68 familial FTD, 74 sporadic FTD, and 31 sporadic IBM patients in a Dutch population. We did not identify any mutations in these genes in our cohorts. Mutations in hnRNPA1 and hnRNPA2B1 prove to be a rare cause of ALS, FTD, and IBM in the Netherlands.

The influence of YMDD mutation patterns on clinical outcomes in patients with adefovir add-on lamivudine combination treatment.

BACKGROUND/AIM: The aim of this study was to assess the patterns of lamivudine (LAM)-resistant mutations and the influence on biochemical and virological responses to adefovir (ADV) add-on LAM combination therapy in patients with LAM-resistant chronic hepatitis B (CHB). METHODS: Seventy-eight CHB patients with confirmed genotypic resistance to LAM, who initiated ADV add-on LAM combination treatment, were enrolled at our institution between April 2007 and April 2009. RESULTS: The baseline tyrosine-methionine-aspartate-aspartate (YMDD) mutation patterns were as follows: rtM204I 45 (57.7%); and rtM204V + rtM204I/V 33 (42.3%). The decrease in the mean ± standard deviation (SD) serum log(10) HBV-DNA level did not differ between the patients carrying the rtM204I vs. rtM204IV +rtM204I/V mutations at 3, 6 and 12 months after the initiation of ADV add-on LAM combination treatment. The proportion of patients who achieved ALT normalization (<40 IU/L) 12 months after the initiation of ADV add-on LAM combination treatment were significantly higher in patients with a rtM204I mutation than rtM204V+ rtM204I/V mutations (39 [86.7%] vs. 22 [66.7%], P = 0.05). The proportion of patients in whom the log(10) HBV-DNA decreased <2 log(10) copies/ml, 6 months after the initiation of ADV add-on LAM combination treatment (non-responders), was significantly higher in patients with a rtM204V + rtM204I/V mutations than rtM204I mutation (7 [21.2%] vs. 2 [4.4%], P = 0.032). CONCLUSION: Biochemical response at 12 months from baseline was better in patients with a rtM204I mutation than rtM204V+ rtM204I/V mutations. In addition, early treatment failure was more common in patients with rtM204V+ rtM204I/V mutations than a rtM204I mutation.

Laparoscopic versus open left pancreatectomy: can preoperative factors indicate the safer technique?

BACKGROUND: Laparoscopic left pancreatectomy (LLP) is associated with favorable outcomes compared with open left pancreatectomy (OLP). However, it is unclear if the risk factors associated with operative morbidity differ between these two techniques. Guidelines for determining which patients should undergo OLP versus LLP do not exist. METHODS: A multi-institutional analysis of OLP and LLP performed in 9 academic medical centers was undertaken. LLP cases were defined in an intent-to-treat manner. Perioperative variables were analyzed to identify factors associated with complications and pancreatic fistulae after OLP and LLP. In addition, complication and fistula rates for patients undergoing OLP and LLP were compared in matched cohorts to determine if one approach resulted in superior outcomes over the other. RESULTS: Six hundred and ninety-three left pancreatectomy cases (439 OLP, 254 LLP) were analyzed. OLP and LLP cases were similar with respect to patient age and American Society of Anesthesiologists score. Body mass index (BMI) was higher in patients undergoing LLP. OLP was more often performed for adenocarcinoma and larger tumors, resulted in longer resected specimen lengths, and more commonly involved concomitant splenectomy. Estimated blood loss was higher and operative times were longer during OLP. On multivariate analysis, variables associated with major complications and clinically significant fistulae differed between OLP and LLP. Patients with body mass index ≤27, without adenocarcinoma, and with pancreatic specimen length ≤8.5 cm had significantly higher rates of significant fistulae after OLP than after LLP; in contrast, no preoperatively evaluable variables were associated with a higher likelihood of significant fistula after LLP versus OLP. CONCLUSIONS: Risk factors for complications and pancreatic fistulae after left pancreatectomy differ when open versus laparoscopic techniques are employed. Preoperative characteristics may identify cohorts of patients who will benefit more from LLP, and no patient cohorts had higher postoperative complication rates after LLP than OLP. These observations suggest that LLP may be the operative procedure of choice for most patients with left-sided pancreatic lesions; a more definitive prospective and randomized comparison may be warranted.

Utility of the omentum in pelvic floor reconstruction following resection of anorectal malignancy: patient selection, technical caveats, and clinical outcomes.

This study assesses the usefulness of the omentum in the reconstruction of complex perineal defects, following abdominoperineal resection or pelvic exenteration, for anorectal malignancy. Between 2000 and 2008, 70 patients (mean age: 59 years) with anorectal malignancy underwent abdominoperineal resection (n = 57) or pelvic exenteration (n = 13) and were reconstructed by primary repair alone (n = 13), primary repair with omentum (n = 16), myocutaneous flap alone (n = 28), or myocutaneous flap with omentum (n = 13). Patients with and without omental flaps were compared by Student t test and chi2 analysis. Omental flaps were based on a single pedicle, tunneled in the retrocolic plane lateral to the ligament of Treitz, and transposed across the sacrum to the pelvic floor. In total, 29 patients had pelvic floor and perineal reconstruction with the omentum, and 41 patients had reconstruction without the omentum. Incidence of major pelvic complications (abscess, urinoma, deep vein thrombosis, flap dehiscence, hernia, bowel obstruction, fistula) was greater in the "no omentum" group (25/41 patients, 61%), compared with the "omentum" group (6/29 patients, 21%) (P < 0.01). No differences were observed regarding age, stage, incidence of radiotherapy, blood loss, length of stay, or mortality. Use of the omentum as a primary flap, or in combination with a myocutaneous flap, in the reconstruction of complex perineal defects, is associated with a decreased incidence of postoperative complications, strongly supporting the use of the omentum in pelvic floor reconstruction.

Active roles for inhibitory kappaB kinases alpha and beta in nuclear factor-kappaB-mediated chemoresistance to doxorubicin.

Chemotherapy agents have been shown to induce the transcription factor nuclear factor-kappaB (NF-kappaB) and subsequent chemoresistance in fibrosarcomas and other cancers. The mechanism of NF-kappaB-mediated chemoresistance remains unclear, with a previous report suggesting that doxorubicin induces this response independent of the inhibitory kappaB kinases (IKK). Other studies have indicated that IKKbeta, but not IKKalpha, is required. Mouse embryo fibroblasts devoid of IKKalpha, IKKbeta, or both subunits (double knockout) were treated with doxorubicin. The absence of either IKKalpha or IKKbeta or both kinases resulted in impaired induction of NF-kappaB DNA-binding activity in response to doxorubicin. To provide a valid clinical correlate, HT1080 human fibrosarcoma cells were transfected with small interference RNA specific for IKKalpha or IKKbeta and then subsequently treated with doxorubicin. Knockdown of IKKalpha severely impaired the ability of doxorubicin to initiate NF-kappaB DNA-binding activity. However, a decrease in either IKKalpha or IKKbeta resulted in decreased phosphorylation of p65 in response to doxorubicin. The inhibition of doxorubicin-induced NF-kappaB activation by the knockdown of either catalytic subunit resulted in increased cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase and increased apoptosis when compared with doxorubicin alone. The results of this study validate current approaches aimed at NF-kappaB inhibition to improve clinical therapies. Moreover, we show that IKKalpha plays a critical role in NF-kappaB-mediated chemoresistance in response to doxorubicin and may serve as a potential target in combinational strategies to improve chemotherapeutic response.

Results of a pilot study of the effects of celecoxib on cancer cachexia in patients with cancer of the head, neck, and gastrointestinal tract.

BACKGROUND: Animal models suggest that cyclooxygenase-2 (COX-2) inhibitors may be beneficial in suppressing cancer cachexia. We investigated the effect of short-course celecoxib on body composition, inflammation, and quality of life (QOL) in patients with cancer cachexia in a phase II clinical pilot trial. METHODS: Eleven cachectic patients with head and neck or gastrointestinal cancer were randomly assigned to receive placebo or celecoxib for 21 days while awaiting the initiation of cancer therapy. Body composition, resting energy expenditure, QOL, physical function, and inflammatory markers were measured on days 1 and 21. RESULTS: Patients receiving celecoxib experienced statistically significant increases in weight and body mass index (BMI), while patients receiving placebo experienced weight loss and a decline in BMI. Patients receiving celecoxib also had increases in QOL scores. CONCLUSIONS: Cachectic patients receiving celecoxib gained weight, experienced increased BMI, and demonstrated improved QOL scores. Compliance was good and no adverse events were seen.