Fear,Helplessness, and Horror in Posttraumatic Stress Disorder: Investigating DSM-IV Criterion A2 in Victims of Violent Crime

A DSM-IV diagnosis of posttraumatic stress disorder (PTSD) required for the first time that individuals must report experiencing intense fear, helplessness, or horror at the time of the trauma. In a longitudinal study of 138 victims of violent crime, we investigated whether reports of intense trauma-related emotions characterized individuals who, after 6 months, met criteria for PTSD according to the DSM-III-R. We found that intense levels of all 3 emotions strongly predicted later PTSD. However, a small number of those who later met DSM-III-R or ICD criteria for PTSD did not report intense emotions at the time of the trauma. They did, however, report high levels of either anger with others or shame.     

Segmental IMRT for oropharyngeal cancer in a clinical setting.

BACKGROUND AND PURPOSE: To develop a segmental intensity-modulated radiotherapy (IMRT) technique for the treatment of oropharyngeal cancer. PATIENTS AND METHODS: Eight patients previously treated for oropharyngeal cancer were replanned with segmental IMRT. The dose distribution was optimized using beam geometries consisting of 3, 5, 7 and 9 equiangular beams. The optimization procedure resulted in a theoretical fluence for each beam. In order to vary the number of segments, the optimized fluence was divided into four different equidistant levels. The final dose distribution was calculated using clinically deliverable segments obtained from optimized fluence. RESULTS: For our segmental IMRT technique the dose homogeneity within the target volumes improved when the total number of segments increased and reached a saturation level at approximately 150 segments. Seven beams were sufficient to achieve the saturation level for dose homogeneity. The mean dose to the parotid glands depended on the beam geometry and tumor location and did not depend on the number of segments. On average the mean dose to the contralateral parotid gland was 35.7 Gy (27.1-39.9 Gy) for all seven beam plans. CONCLUSIONS: Seven beams are sufficient to achieve an acceptable dose homogeneity within the target volumes and significant parotid sparing. These results will be used to introduce IMRT in routine clinical practice.     

Phase I pharmacological and bioavailability study of oral diflomotecan (BN80915), a novel E-ring-modified camptothecin analogue in adults with solid tumors.

PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability.     

A phase I study of 5-fluorouracil, leucovorin and levamisole

 Purpose: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer. Methods: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. Results: A group of 38 patients with incurable etastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m² per day) and leucovorin (200 mg/m² per day) were administered intravenously (days 1–5). Levamisole was administered orally (days 1–3 and 15–17) at doses from 30 to 470 mg/m² per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m² per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes. Conclusion: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m². However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies. Received: 20 October 1995 / Accepted: 16 June 1996     

Systemic neutrophil intrinsic 5-lipoxygenase activity and CD 18 receptor expression linked to reperfusion injury

Objective: To determine if systemic neutrophil intrinsic 5-lipoxygenase (5-LO) inhibition correlates with decreased expression of surface adhesion molecules and attenuation of ischemia-reperfusion (i/r) injury in guinea pig island skin flaps. Methods: Eighty-one adult female Hartley guinea pigs were divided into one control group, three 2-hour ischemia groups, and four 10-hour ischemia groups. Island dorsal skin flaps were developed (except in the control group), and 2 hours before reperfusion, zileutin (a 5-LO inhibitor) or vehicle was administered orally. Postreperfusion systemic neutrophil receptor expression, neutrophil flap infiltration, and flap survival were measured. Neutrophils from whole blood were analyzed for CD 18 containing surface receptor expression using monoclonal antibodies and cell associated fluorescence. Neutrophil infiltration into a distal centimeter squared of flap tissue was assessed using myeloperoxidase antibodies, and flap survival was determined within 7 days postoperatively. Results: Flaps in the treated 2? and 10-hour ischemic groups survived totally intact, while the untreated 10-hour ischemic flaps underwent total necrosis. A significant main effect of the drug was detected using analysis of variance (ANOVA) (P =.0001). Surface receptor detection and neutrophil infiltration were significantly increased in the untreated animals. Conclusions: Zileuton, a 5-LO inhibitor, reduces adhesion receptor expression on systemic neutrophils and attenuates i/r injury. Systemic neutrophil intrinsic 5-LO activity and CD18 receptor expression are linked to reperfusion injury and may be fundamental events in its pathogenesis.     

Ki-67 and p53 in T2 laryngeal cancer

Objective: To study the relationship between the proliferative capacity, represented by the immunohistochemical labeling index (LI) of proliferation marker Ki-67, and the p53 status, as in theory an intact p53 cell cycle checkpoint system should result in a lower proliferative capacity. Study Design: From a group of 128 patients with a T2 laryngeal carcinoma, presented from 1989 to 1993 at the University Hospital Utrecht, 20 patients with recurrent disease and 16 patients without recurrent disease were randomly selected. All patients received primary irradiation. Methods: Denaturing gradient gel electrophoresis and immunohistochemistry determined the p53 status. MIB-1 staining was used to determine the Ki-67 LI. Results: In 36% of specimens we found a p53 mutation with overexpression (LI, 31%). In 8% a p53 mutation without p53 overexpression was found (LI, 18%). Forty-two percent showed no mutation but, nevertheless, overexpression (LI, 35%). Neither mutation nor overexpression was found in 14% (LI, 38%). No correlation exists between p53 status and proliferative capacity of tumors (analysis of variance [ANOVA]; P = .104). The proliferation rate as established with Ki-67 LI positively correlates with response to radiotherapy (P = .006). Conclusions: 1. Overexpression of wild-type p53 protein does not result in cell cycle arrest measurable by a lower Ki-67 LI in comparison with cases overexpressing mutant type p53 protein. 2. A high Ki-67 LI correlates with a favorable response to radiotherapy. Laryngoscope, 108:1548–1552, 1998     

Human Herpesvirus Type 8 and Kaposi's Sarcoma

Kaposi's sarcoma-associated herpesvirus or human herpesvirus type8 (HHV-8) is present in all forms of Kaposi's sarcoma (KS) aswell as in primary effusion lymphomas and some cases of Castleman'sdisease. In KS tissues, HHV-8 is present in endothelial andspindle cells. Current serologic tests suggest that HHV-8 ispredominantly found in those at risk of KS and is not as widespreadas most other human herpesviruses. HHV-8 encodes various proteinsthat may play a role in promotion of cellular growth, includingcyclin- and G-coupled protein receptor homologues, and anti-apoptoticproteins, including Bcl-2, IL-6 (i.e., interleukin 6), and FLIP(i.e., FLICE inhibitory protein) homologues. In addition, HHV-8encodes two macrophage inflammatory-like proteins with anti-humanimmunodeficiency virus and angiogenic potential.