Purpose To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival. Patients and Methods From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. Results Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34). Conclusion Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.

Introduction Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC. Methods We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed. Results During the median follow up duration of 31 months (range 1–208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extra-hepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34–3.21; P <.001), nodal metastasis (HR, 1.55; 95% CI, 1.01–2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10–2.25; P = .04), and tumor size ≥5 cm (HR, 1.84; 95% CI, 1.28–2.65; P <.001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively. Conclusion Recurrence after operative intervention for ICC was common. Disease recurred both at intra-and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence.

The transforming growth factor-B (TGF-B) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation-induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-B. Although the loss of expression of either the type I (TBRI) or type II (TBRII) TGF-B receptor has been documented in f30% of prostate cancers, most prostate cancers become TGF-B resistant without mutation or deletion of TBRI, TBRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-B receptor (TBRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TBRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TBRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TBRIII promoter. Functionally, restoring TBRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TBRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity. [Cancer Res 2007;67(3):1090-8]

The transforming growth factor-b (TGF-b) superfamily has essential roles in lung development, regulating cell proliferation, branching morphogenesis, differentiation and apoptosis. Although most lung cancers become resistant to the tumor suppressor effects of TGF-b, and loss or mutation of one of the components of the TGF-b signaling pathway, including TbRII, Smad2 and Smad4 have been reported, mutations are not common in non-small cell lung cancer (NSCLC). Here we demonstrate that the TGF-b superfamily co-receptor, the type III TGF-b receptor (TbRIII or betaglycan) is lost in the majority of NSCLC specimens at the mRNA and protein levels, with loss correlating with increased tumor grade and disease progression. Loss of heterozygosity at the TGFBR3 genomic locus occurs in 38.5% of NSCLC specimens and correlates with decreased TbRIII expression, suggesting loss of heterozygosity as one mechanism for TbRIII loss. In the H460 cell model of NSCLC, restoring TbRIII expression decreased colony formation in soft agar. In the A549 cell model of NSCLC, restoring TbRIII expression significantly decreased cellular migration and invasion through Matrigel, in the presence and absence of TGF-b1, and decreased tumorigenicity in vivo. In a reciprocal manner, shRNA-mediated silencing of endogenous TbRIII expression enhanced invasion through Matrigel. Mechanistically, TbRIII functions, at least in part, through undergoing ectodomain shedding, generating soluble TbRIII, which is able to inhibit cellular invasiveness. Taken together, these results support TbRIII as a novel tumor suppressor gene that is commonly lost in NSCLC resulting in a functional increase in cellular migration, invasion and anchorageindependent growth of lung cancer cells.

Recurrence of duodenal GIST is dependent on tumor biology rather than surgical approach. PD was associated with longer hospital stays and higher risk of perioperative complications. When feasible, LR is appropriate for duodenal GIST and PD should be reserved for lesions not amenable to LR.

A major hepatectomy should be defined as resection of four or more liver segments.

Background Desmoid tumors are rare soft-tissue neoplasms with limited data on their management. We sought to determine the rates of recurrence following surgery for desmoid tumors and identify factors predictive of disease-free survival. Methods Between January 1983 and December 2011, 211 patients with desmoid tumors were identified from three major surgical centers. Clinicopathologic and treatment characteristics were analyzed to identify predictors of recurrence. Results Median age was 36 years; patients were predominantly female (68 %). Desmoid tumors most commonly arose in extremities (32 %), abdominal cavity (23 %) or wall (21 %), and thorax (15 %); median size was 7.5 cm. Most patients had an R0 surgical margin (60 %). The 1- and 5-year recurrence-free survival was 81.3 and 52.8 %, respectively. Factors associated with worse recurrence-free survival were: younger age (for each 5-year increase in age, hazard ratio [HR] = 0.90, 95 % confidence interval [95 % CI] 0.82–0.98) and extra-abdominal tumor location (abdominal wall referent: extra-abdominal site, HR = 3.28, 95 % CI, 1.46–7.36) (both P <0.05). Conclusions Recurrence remains a problem following resection of desmoid tumors with as many as 50 % of patients experiencing a recurrence within 5 years. Factors associated with recurrence included age, tumor location, and margin status. While surgical resection remains central to the management of patients with desmoid tumors, the high rate of recurrence highlights the need for more effective adjuvant therapies.

Background Hyperthermic isolated limb perfusion (HILP) and isolated limb infusion (ILI) are utilized to manage advanced extremity melanoma but no consensus exists as to which treatment is preferable and how to monitor patients post-treatment. Study Design Using a prospectively-maintained database, we reviewed our experience with melphalan based HILP (that included 62 first time and 10 second time) and ILI (that included 126 first time and 18 second time) procedures performed in 188 patients. PET/CT was obtained 3 months post regional treatment for one year and then every 6 months thereafter. Results The overall response rate (complete response (CR) + partial response (PR)) of HILP was 81% (80% CI: 73-87%) while the overall response rate from ILI was 43% (80% CI: 37-49%) for first time procedures only. HILP had a CR rate of 55% with a median duration of 32 months, while ILI had a CR rate of 30% with median duration of 24 months. Patients who experienced a regional recurrence after initial regional treatment were more likely to achieve a CR following repeat HILP (50%, n = 10) compared to repeat ILI (28%, n = 18). Although the spectrum of toxicity was similar for ILI and HILP, the likelihood of rare catastrophic complication of limb loss was greater with HILP (2/62) than ILI (0/122). PET/CT was effective for surveillance after regional therapy to identify regional nodal and pulmonary disease that was not clinically evident, but often amenable to surgical resection (25/49, 51% of cases). In contrast, PET/CT was not effective at predicting complete response to treatment with an accuracy of only 50%. Conclusions In the largest single institution regional therapy series reported to date, we found that while ILI is effective, and well-tolerated, HILP is a more definitive way to control advanced disease.