Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers. Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts. A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms. We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.
Tumor size (> 45 mm), resection margin involvement, and perineural invasion were independent prognostic factors. Preoperative assessment of DPC4/Smad4 expression has potential as a prognostic indicator in patients with PC since resection did not benefit those patients whose cancers expressed DPC4/Smad4 and accurate assessment of DPC4/Smad4 expression, unlike tumor size, margin status, and perineural invasion, does not require resection.
Orbital and intracranial invasion from skin cancer is an uncommon but serious consequence of skin cancer located around the orbit, particularly the forehead. Perineural spread is an aggressive manifestation of skin cancer similar to lymph node metastases. Such spread can provide access to the orbit and squamous cell carcinoma is the most common histology reported. Treatment should be directed at preventing such orbital spread. Adjuvant radiotherapy is strongly recommended. Disease may present in an advanced state within the orbit or beyond the orbital apex and involve the cavernous sinus. Palliative radiotherapy should be considered in such advanced cases. Presented are the cases of four patients treated for advanced orbital and intracranial spread from periorbital skin cancer.
The development of pancreatic cancer (PC) several years after curative resection for noninvasive intraductal papillary mucinous neoplasm (IPMN) and the presence of PC distant from IPMN suggest that PC may develop independently of the IPMN. Here, we identified pancreatic intraepithelial neoplasia (PanIN) lesions, the putative precursors of PC, in the ducts of pancreata resected for IPMN and assessed the frequency of molecular aberrations common to PanIN and PC, within these lesions. The protein expression of p53, p21(WAF1/CIP1), cyclin D1, p16(INK4A) and DPC4/Smad4 were examined by immunohistochemistry in 267 PanIN lesions from a cohort of 23 patients with IPMN. Overexpression of p21(WAF1/CIP1) was present in PanIN-1A and -1B lesions and increased in frequency in PanIN-2 and PanIN-3. Overexpression of p53 and cyclin D1, and loss of p16(INK4A) expression were detected in PanIN-2 and PanIN-3 lesions. Loss of DPC4/Smad4 expression occurred only in the PanIN-3 lesions. PanIN lesions that were more dysplastic than the coincident IPMN were identified in 5 of 12 patients, and 2 of these contained a greater number of aberrations in protein expression than the IPMN. PanIN lesions seen in association with IPMN demonstrate molecular and histologic changes identical to PanIN lesions found in association with PC and, in some cases, are more advanced than the associated IPMN. These data suggest that PanIN lesions found in the ducts of a pancreas with IPMN may be relevant to the development of PC either coincident with IPMN or in the remnant pancreas after curative resection of IPMN.
OBJECTIVE -To investigate the reproducibility of the plasma glucose (PG) response to exercise in subjects with type 1 diabetes on a nonintensive insulin regimen.RESEARCH DESIGN AND METHODS -Subjects cycled for 45 min at 50% VO 2max on two occasions (studies 1 and 2) either 1 h after lunch and usual insulin (protocol A) or after overnight fasting without morning insulin (protocol B). Identical diet, activity, and insulin (twice daily neutral and intermediate) were maintained before and during each study day. A total of 13 type 1 diabetic subjects (6 men and 7 women, BMI 24.0 Ϯ 0.9 kg/m 2 [means Ϯ SE], age 42.6 Ϯ 2.7 years, diabetes duration 14.1 Ϯ 2.8 years) completed protocol A, and 7 (3 men and 4 women, BMI 25.8 Ϯ 1.3 kg/m 2 , age 39.7 Ϯ 1.3 years, diabetes duration 14 Ϯ 4.4 years) completed protocol B.RESULTS -In protocol A (fed), the fall in PG during exercise was 4.5 Ϯ 1.0 and 5.0 Ϯ 0.8 mmol/l in studies 1 and 2, respectively, whereas in protocol B (fasted), it was 0.6 Ϯ 0.8 and 3.4 Ϯ 1.6 mmol/l. Regression analysis of the change in PG in protocol A in study 1 versus study 2 showed poor reproducibility (r 2 ϭ 0.12, P ϭ 0.25) despite uniform conditions. In protocol B, the fall in PG was more reproducible (r 2 ϭ 0.81, P ϭ 0.006). In fed subjects, there was better (P ϭ 0.01) and clinically useful reproducibility of the PG at exercise completion (r 2 ϭ 0.77, P ϭ 0.0001) compared with preexercise.CONCLUSIONS -These results indicate poor reproducibility of the change in PG during exercise after feeding in type 1 diabetes on nonintensive insulin regimens but reasonable reproducibility when fasting. Exercise apparently decreases the glycemic variability after feeding, so that PG concentrations after exercise seek a reproducible "target." Thus, the absolute PG level after a typical bout of exercise in the fed state should be a good guide to carbohydrate or insulin adjustment on subsequent occasions.
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