Concurrent gemcitabine and radiotherapy with and without neoadjuvant gemcitabine for locally advanced unresectable or resected pancreatic cancer: a phase I-II study

PURPOSE: To determine the safety, efficacy, and tolerability of biweekly gemcitabine with concurrent radiotherapy (RT) for resected and locally advanced (LA) pancreatic cancer. METHODS AND MATERIALS: Eligible patients had either LA or resected pancreatic cancer. Between March 1999 and July 2001, 63 patients (31 with LA and 32 with resected disease) were treated. Of the 63 patients, 28 were enrolled in a Phase I study of increasing radiation doses (35 Gy [n = 7], 43.75 Gy [n = 11], and 52.5 Gy [n = 10] given within 4, 5, or 6 weeks, respectively, in 1.75-Gy fractions) concurrently with 40 mg/m(2) gemcitabine biweekly. Subsequently, 35 were enrolled in a Phase II study with the addition of induction gemcitabine 1000 mg/m(2) within 7 or 8 weeks to concurrent biweekly gemcitabine (40 mg/m(2)) and 52.5 Gy RT within 6 weeks. RESULTS: In the LA population, the best response observed was a complete response in 1, partial response in 3, stable disease in 10, and progressive disease in 17. In the phase II trial, gemcitabine plus RT was not delivered to 8 patients because of progression with induction gemcitabine alone (n = 5) or by patient request (n = 3). On intent-to-treat analysis, the median survival in the LA patients was 13.9 months and the 2-year survival rate was 16.1%. In the resected population, the median progression-free survival was 8.3 months, the median survival was 18.4 months, and the 2- and 5-year survival rate was 36% and 19.4%, respectively. The treatment was well tolerated; the median gemcitabine dose intensity was 96% of the planned dose in the neoadjuvant and concurrent portions of the Phase II study. No treatment-related deaths occurred. CONCLUSION: Biweekly gemcitabine (40 mg/m(2)) concurrently with RT (52.5 Gy in 30 fractions of 1.75 Gy) with or without induction gemcitabine is safe and tolerable and shows efficacy in patients with LA and resected pancreatic cancer.     

The interaction of age and hormone replacement therapy on colon adenoma risk

BACKGROUND: Several studies have identified a possible interaction between age and hormone replacement therapy on colon neoplasm risk. We re-evaluated this interaction and determined if this interaction may be explained by the longer duration of estrogen use in older, rather than younger, women. METHODS: Included in the case-control study were 755 women (169 cases and 586 controls.) who were recruited from patients with no prior history of colorectal neoplasm and undergoing an elective colonoscopy examination. RESULTS: There was a significant interaction between age and hormone replacement therapy use (P=0.03) with current estrogen users who were over 56 years of age having a reduced odds of colon adenoma (OR, 0.40; 95% CI, 0.16-0.98) when compared to never users. Both older women who had used hormone replacement therapy for 3 or less years (OR, 0.07; 95% CI, 0.006-0.81) and those reporting greater than 10 years of use (OR, 0.27; 95% CI, 0.09-0.80) had a reduced adjusted odds for adenomas when compared to non-users. No apparent association with estrogen replacement therapy was found among younger women (<56 years). CONCLUSIONS: Duration of use is not likely to explain the stronger association of hormone replacement therapy use with colon neoplasm in older women. Additional work is needed to better characterize the underlying mechanisms associated with this interaction.     

NSAIDs and breast cancer recurrence in a prospective cohort study

Objective We examined the association between NSAID use and breast cancer recurrence in a prospective cohort of 2,292 early-stage breast cancer survivors diagnosed from 1997 to 2000 participating in the Life After Cancer Epidemiology (LACE) Study. Methods From 2000 to 2002, mailed questionnaires were used to obtain information on aspirin, ibuprofen, and other NSAID use and subsequent breast cancer events. A total of 270 recurrences (local, regional, and distant disease and new primary breast cancers) were reported and verified by medical record review. Cox proportional hazard models were used to estimate rate ratios (RR) and 95% confidence intervals (CI), adjusting for age at diagnosis, race, cancer stage, tamoxifen treatment, chemotherapy use, body mass index, and cyclooxygenase-2 (COX2) inhibitor use. Results Current, regular use (at least three days per week at time of questionnaire administration) of ibuprofen (RR, 0.56; 95% CI, 0.32–0.98), but not aspirin (RR, 1.09; 95% CI, 0.74–1.61), was associated with a statistically significant decreased risk of breast cancer recurrence. The combination of ibuprofen and other non-aspirin NSAIDs such as naproxen and sulindac reflected a similar reduction in risk (RR, 0.56; 95% CI, 0.33–0.95). No association was found for the non-NSAID analgesic acetaminophen. Conclusion Our findings provide support for an inverse association between current, regular ibuprofen use and breast cancer recurrence.     

Transketolase protein TKTL1 overexpression: A potential biomarker and therapeutic target in breast cancer

Malignant tumors degrade glucose to lactate even in the presence of oxygen via the pentose phosphate pathway (ppp). The non-oxidative part of the ppp is controlled by thiamine-dependant transketolase enzyme reactions. Overexpression of the transketolase-like-1-gene (TKTL1) in urothelial and colorectal cancer is associated with poor patient outcome. We analyzed the expression of the TKTL1 protein in a retrospective institution-based patient cohort with invasive breast cancer by immunohistochemical analysis of 124 paraffin-embedded breast cancer tissues. Our study revealed TKTL1 expression in 86% of breast cancer specimens with 45% showing high expression levels. In contrast, only 29% of corresponding non-neoplastic breast tissues were TKTL1 immunopositive, including 9% with high expression levels. High expression levels of TKTL1 correlated significantly to Her2/neu overexpression (p=0.015). However, TKTL1 expression failed to reach statistical significance for other common prognostic parameters. In contrast to recent data for e.g. colorectal cancer TKTL1 overexpression did not correlate to patient outcome and survival. However, in the context of novel insights into TKTL1-related tumor metabolism and the high proportion of TKTL1 overexpressing breast cancers, this enzyme represents a potential candidate for targeted inhibition of tumor growth in this tumor entity.     

A rapid method for skin grafting in mice that greatly enhances graft and recipient survival

A streamlined method of skin grafting in mice is described. This procedure eliminates bandages, sutures, and dressings. The elimination of bandages renders the overall procedure fast and easy to learn. More importantly, the elimination of bandaging results in an increased survival of engrafted mice and a drastic reduction in graft displacement. Finally the lack of bandages also makes it possible to monitor the graft even in the earliest stages after engraftment.     

Clinical predictors of posttraumatic stress disorder after closed head injury in children

OBJECTIVE: To describe injury, demographic, and neuropsychiatric characteristics of children who develop posttraumatic stress disorder (PTSD) and posttraumatic stress symptoms (PTSS) after closed head injury (CHI). METHOD: Ninety-five children with severe CHI and amnesia for the event were prospectively followed for 1 year. Structured interviews were administered twice to the parents: shortly after injury to cover the child's premorbid status, and 1 year after injury. The child was also interviewed twice: shortly after injury to cover current status, and 1 year after injury. Outcome measures were diagnostic status (PTSD by parent or child) and symptom severity (PTSS by parent or child). RESULTS: Twelve children developed PTSD by 1 year after injury, 5 according to parent report, 5 according to child report, and 2 according to both parent and child report. Predictors of PTSD at 1 year post-CHI included female gender and early post-CHI anxiety symptoms. Predictors of PTSS at 1 year post-CHI were (1) premorbid psychosocial adversity, premorbid anxiety symptoms, and injury severity; and (2) early post-CHI depression symptoms and nonanxiety psychiatric diagnoses. CONCLUSIONS: PTSD developed in 13% of children with severe CHI accompanied by traumatic amnesia. Predictors of PTSD and PTSS after CHI, according to parent and child report, are consistent with predictors of PTSD and PTSS that develop after non-head injury trauma.     

Semantic bias, homograph comprehension, and event-related potentials in schizophrenia.

OBJECTIVES: It is controversial whether a semantic processing bias for strong associates is present in schizophrenia, and unknown whether the language abnormalities observed in schizophrenia can be attributed to dysfunctions early or late in cognitive processing. Combined behavioral and event-related potential (ERP) data can indicate the nature and timing of such abnormalities. METHODS: Sensibility judgements of dominant and subordinate homograph sentences were measured in 12 schizophrenia patients and 13 normal controls. ERPs were recorded to the disambiguating sentence-ending word. RESULTS: All subjects showed greatest misinterpretation of subordinate homograph sentences, but schizophrenia patients particularly misinterpreted these sentence types. For control subjects, subordinate homograph sentences that were classified as nonsensical showed greater N400 than those classified as sensible. By contrast, the N400 of patients was large, regardless of the sensibility judgement--patients' brains initially responded to all subordinate sentences as if nonsensical. These data are consonant with a semantic bias. However, the patients' N400 to dominant homograph sentence endings was also larger than that of controls, a finding not consonant with a semantic bias. CONCLUSIONS: The behavioral results indicate a selective comprehension abnormality in schizophrenia dependent on the content of verbal memory. The ERP results suggest a pervasive contextual memory failure. A semantic activation decay model is proposed to explain these results.