Citations

AbstractBackgroundLaparoscopic insulinoma resection (LIR) for sporadic disease is increasingly supported as a feasible and safe operation in small series of patients. To determine whether LIR is an acceptable alternative to the open operation, it is necessary to compare LIR to historical controls. The purpose of this study was to identify the skills and technology needed for LIR and establish outcome standards.MethodsA database of patients with benign sporadic insulinoma who underwent an open procedure at the Mayo Clinic was reviewed for demographics, imaging, operative/pathology reports, and outcomes. Outcomes were compared to a world‐wide meta‐analysis of patients who had undergone LIR reported in the English literature between 1996 and 2009.ResultsTwo hundred fifteen patients underwent a primary open operation for benign sporadic insulinoma. Solitary tumors were found in 97%. Meta‐analysis identified 232 patients who underwent LIR. The open and LIR groups underwent comparable operations that included enucleations (64 vs. 68%) and distal pancreatectomies (28 vs. 35%) (p = 0.06). The mean estimated blood loss, operating time, and length of stay were comparable between the open and LIR groups (p = NS). Pancreatic fistula occurred more often in the LIR group (24 vs. 11%, p < 0.05). A curative operation was performed in 98% of control patients and in 99% of the LIR group (p = NS).ConclusionsMultiple insulinomas are rare and a focused resection guided by imaging may be performed. LIR is associated with an increased incidence of pancreatic fistula. Success of LIR will depend on accurate multimodality preoperative imaging, skilled use of lap‐US to replace palpation for localization, and safe methods to dissect the tumor adjacent to the pancreatic duct.

Purpose Patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC) were randomly assigned to 21-day doxorubicin and cyclophosphamide administered for five cycles (standard arm) versus weekly doxorubicin and daily oral cyclophosphamide administered with granulocyte colony-stimulating factor support for 15 weeks (continuous arm). All patients had subsequent weekly paclitaxel for 12 weeks before surgery. Patients and Methods Patients (n = 372) were randomly assigned to the standard arm (n = 186) or the continuous arm (n = 186) stratified by disease type (LABC, n = 256; IBC, n = 116). The primary outcome was microscopic pathologic complete response (pCR) at surgery. Secondary outcomes included disease-free survival, overall survival, and toxicity. Results More patients in the standard arm had grade 3 to 4 leukopenia and neutropenia, but there were more instances of stomatitis/pharyngitis and hand-foot skin reaction in the continuous arm. Assessed among 356 eligible patients, pCR was not different between the treatment groups stratified by disease type (P = .42). In subset analysis, higher pCR rates were observed in the continuous arm versus the standard arm only for stage IIIB disease (P = .0057) and in IBC (P = .06). Comparison of overall survival and disease-free survival showed no difference between treatment groups (P = .37 and P = .87, respectively). Conclusion No significant clinical benefit was seen for the investigational arm in this trial overall.

Background: Historical outcomes in anaplastic thyroid carcinoma (ATC) are poor, with a median survival of only 5 months and <20% of patients surviving 1 year from diagnosis. We hypothesized that survival in newly diagnosed patients with stages IVA and IVB locoregionally confined ATC might be improved by utilizing an aggressive therapeutic approach, prioritizing both the eradication of disease in the neck and preemptive treatment of occult metastatic disease. Methods: Between January 1, 2003, and December 31, 2007, 25 new ATC patients were evaluated at our institution. Of these 25 patients, 10 (40%) had metastatic disease at diagnosis and therefore underwent palliative treatment, whereas 5 (20%) had regionally confined disease and desired treatment at their local medical facilities. The remaining 10 consecutive patients (40%) had regionally confined ATC and elected aggressive therapy combining individualized surgery (where feasible), intensity-modulated radiation therapy (IMRT), and radiosensitizing + adjuvant chemotherapy intending four cycles of docetaxel + doxorubicin. Outcomes were assessed on an intention to treat basis. Results: There were no deaths from therapy, but hospitalization was required in two patients (20%) because of treatment-related adverse events. Five patients (50%) are alive and cancer-free, all having been followed >32 months (range: 32–89 months; median: 44 months) with a median overall Kaplan–Meier survival of 60 months. Overall survival at 1 and 2 years was 70% and 60%, respectively, compared to <20% historical survival at 1 year in analogous patients previously treated with surgery and conventional postoperative radiation at our and other institutions. Conclusions: Although based upon a small series of consecutively treated patients, an aggressive approach combining IMRT and radiosensitizing plus adjuvant chemotherapy appears to improve outcomes, including survival in stages IVA and IVB regionally confined ATC, but remains of uncertain benefit in patients with stage IVC (metastatic) disease. Also uncertain is the optimal chemotherapy regimen to use in conjunction with IMRT. Further multicenter randomized trials are required to define optimal therapy in this rare but deadly cancer.

Hepatocelluar carcinoma (HCC) is the most common primary malignancy of the liver in adults and the third most common cause of cancer death worldwide. The incidence of HCC in the United States is rising steadily because of the prevalence of hepatitis C viral infection and other causes of hepatic cirrhosis. The majority of patients have underlying hepatic dysfunction, which complicates patient management and the search for safe and effective therapies. The Clinical Trials Planning Meeting (CTPM) in HCC was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to identify the key knowledge gaps in HCC and define clinical research priorities. The CTPM structured its review according to current evidence-based treatment modalities in HCC and prioritized the recommendations on the basis of the patient populations representing the greatest unmet medical need.

Inactive cortisone is converted to active cortisol within the liver by 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11β-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11β-HSD1 inhibitor (compound 531) or placebo for 5 h. 11β-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11β-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11β-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.

AbstractPurpose: Over the past two decades, there has been significant interest in targeting HER-2/neu in immune-based approaches for the treatment of HER-2/neu+ cancers. For example, peptide vaccination using a CD8 T cell–activating HER-2/neu epitope (amino acids 369-377) is an approach that is being considered in advanced phase clinical trials. Studies have suggested that the persistence of HER-2/neu–specific CD8 T cells could be improved by incorporating human leukocyte antigen (HLA) class II epitopes in the vaccine. Our goal in this study was to identify broad coverage HLA-DR epitopes of HER-2/neu, an antigen that is highly expressed in a variety of carcinomas.Experimental Design: A combination of algorithms and HLA-DR–binding assays was used to identify HLA-DR epitopes of HER-2/neu antigen. Evidence of preexistent immunity in cancer patients against the identified epitopes was determined using IFN-γ enzyme-linked immunosorbent spot (ELIspot) assay.Results: Eighty-four HLA-DR epitopes of HER-2/neu were predicted, 15 of which had high binding affinity for ≥11 common HLA-DR molecules. A degenerate pool of four HLA-DR–restricted 15-amino acid epitopes (p59, p88, p422, and p885) was identified, against which &gt;58% of breast and ovarian cancer patients had preexistent T-cell immunity. All four epitopes are naturally processed by antigen-presenting cells. Hardy-Weinberg analysis showed that the pool is useful in ∼84% of population. Lastly, in this degenerate pool, we identified a novel in vivo immunodominant HLA-DR epitope, HER-2/neu88-102 (p88).Conclusion: The broad coverage and natural immunity to this epitope pool suggests potential usefulness in HER-2/neu–targeting, immune-based therapies such as vaccines. Clin Cancer Res; 16(3); 825–34

Abstract Background Controversy exists regarding the aggressiveness of initial therapy in childhood papillary thyroid cancer (PTC). Few studies with long‐term outcome exist and second primary malignancies have rarely been analyzed. Methods We studied 215 PTC patients younger than 21 years old managed during 1940 through 2008. The patients were aged 3–20 year old (median age = 16 years); the median follow‐up was 29 years. Recurrence and mortality details were taken from a computerized database. Results Median primary tumor size was 2.2 cm. Six percent had distant metastases at presentation, 5% had incomplete tumor resection, 86% had nodes removed at initial surgery, and 78% had nodal metastases. After complete surgical resection, PTC recurred in 32% by 40 years. At 20 years, the recurrence rates at local, regional, and distant sites were 7, 21, and 5%, respectively. During 1940–1969, local and regional recurrence rates after unilateral lobectomy (UL) were significantly ( P < 0.001) higher than after bilateral lobar resection (BLR). During 1950–2008 radioiodine remnant ablation (RRA) was administered within 18 months to 32%; it did not diminish the 25‐year regional recurrence rate of 16% seen after BLR alone ( P = 0.86). Only two fatal events from PTC occurred at 28 and 30 years, for a cause‐specific mortality at 40 years of only 2%. All‐causes mortality rates did not exceed expectation through 20 years, but from 30 through 50 years, the number of deaths was significantly ( P < 0.001) higher than predicted. Fifteen of 22 deaths (68%) resulted from nonthyroid malignancy. Conclusion Survival from childhood PTC should be expected, but later death from nonthyroid malignancy is disconcerting. Seventy‐three percent of those who died from nonthyroid malignancy had received postoperative therapeutic irradiation.

AbstractBackgroundIntense disease surveillance and frequent lymph node metastases (LNMs) in papillary thyroid cancer (PTC) have resulted in increased locoregional recurrences. We examined the safety and efficacy of an optimized surgical approach including preoperative ultrasonograpy (US), bilateral thyroidectomy, routine compartment VI dissection, and lateral neck dissection for LNM.MethodsDuring 1999–2006, a total of 420 patients underwent optimized primary surgery; 291(69%) females, median age 46 years; follow‐up 98%, median 4.4 years. Patients were reviewed for tumor characteristics, pattern of LNM, staging, and outcomes.ResultsTotal or near‐total thyroidectomy was performed in 212 (51%) and 208 (49%) patients, respectively. Tumors were multicentric, 40% (average 1.7 cm); were bilateral, 30%; and showed extrathyroidal extension, 17%. Overall, 223 (53%) patients had LNMs: 213 (51%) were central and 85 (20%) were lateral jugular. pTNM staging: I, 258 (61%); II, 35 (8%); III, 88 (21%); IV, 39 (9%). AGES (age, grade, extension, and size—thyroid tumor; and MACIS (metastasis, age, completeness of resection, invasion, and size) prognostic scores were low risk in 362 (86%) and 352 (84%), respectively. Relapse developed in 57 (14%) patients: LNM in 44, soft tissue local recurrence (LR) in 5, distant metastases (DM) in 8. Hypoparathyroidism occurred in 5 (1.2%) patients and 1 had unintentional laryngeal nerve damage. Relapse with LNM occurred in previously operated fields in 19 (5%) patients, 11(3%) from disease virulence (LR or DM), preoperative false‐negative (FN) US in 12 (3%), and combination of FN‐US and recurrence in the operated field in 5 (1%) patients.ConclusionsRecurrence was limited to 5% of patients when the extent of disease was accurately defined and potentially curable. This optimized surgical strategy is relatively safe.