A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia.

BACKGROUND: Uncontrolled studies comparing pentostatin (P), cyclophosphamide (C), and rituximab (R) (PCR) to fludarabine plus C+R (FCR) suggest similar efficacy with fewer infectious complications with PCR. We compared FCR and PCR in previously-untreated or minimally-treated B-cell chronic lymphocytic leukemia (CLL). TREATMENT: FCR (F 20 mg/m(2) Days 1-5, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (28-day cycles) or PCR (P 4 mg/m(2) Day 1, C 600 mg/m(2) Day 1, R 375 mg/m(2) Day 1) (21-day cycles). Dose 1 of R: 100 mg/m(2) was given on Day 8 Cycle 1 and the remainder on Day 9; in subsequent cycles the entire dose was given on Day 1. RESULTS: Ninety-two patients were randomly assigned to each group (N = 184). Groups were balanced; ~20% had received prior chemotherapy. The infection rate (FCR/PCR) was 31%/36%, the infective event rate was 38%/45%; 30 (35%)/37 (44%) patients were hospitalized; total hospitalization days was 271/404. 12 (14%)/6 (7%) patients achieved complete remissions (CR); the overall response rate (ORR) including CR+nodular PR (nPR)+PR was 59%/49%. Grade 3-4 treatment related AEs: neutropenia (69%/57%), leukopenia (34%/17%), thrombocytopenia (13%/6%). Grade 3-4 infections: febrile neutropenia (8%/6%), fever (2%/6%), infection (1%/3%), urinary tract infection (1%/0%), pneumonia (3%/1%), and sepsis (1%/2%); 5 deaths (1 FCR/4 PCR) were treatment-related. CONCLUSIONS: PCR and FCR have significant activity in CLL and can be given safely in the community setting despite significant toxicity. ORRs were lower than expected; the CR rate was higher (NS) with FCR. This trial did not demonstrate a lower infection rate with PCR.

Phase I study of pemetrexed and pegylated liposomal doxorubicin in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer.

PURPOSE: Pemetrexed and pegylated liposomal doxorubicin (PLD) are clinically active as single agents and preclinically synergistic. This phase I, open-label trial evaluated the maximum tolerated dose (MTD) and safety of pemetrexed followed by PLD in patients with breast or gynecologic cancers. PATIENTS: Using 3 + 3 dose escalation, cohorts of 3-9 patients received escalating doses of pemetrexed 400-500 mg/m(2) on days 1 and 15 and PLD 30-45 mg/m(2) on day 1 of a 28-day cycle. All patients received folic acid and vitamin B(12) until 21 days after last pemetrexed dose. Patients continued until dose-limiting toxicity (DLT) or progression (PD). RESULTS: From 11/05 to 2/08, 29 patients entered treatment; median age: 60.6 years (range, 47.5-80.1); ECOG PS 0/1: 27.6%/72.4%; primary disease site: ovarian (55.2%), breast (34.5%), peritoneum (10.3%); prior therapies: chemotherapy (100.0%), surgery (72.4%), hormones/biologics (35%), and radiation (20.7%). Pemetrexed/PLD dose levels: L1 = 400/30 (n = 4), L2 = 400/35 (n = 6), L3 = 500/35 (n = 9), L4 = 500/40 (n = 7), and L5 = 500/45 (n = 3). Treatment-related grade 3-4 toxicities: hematologic-neutropenia (86.2%), leukopenia (58.6%), thrombocytopenia (48.3%), anemia (41.4%); nonhematologic-mucosal inflammation (24.1%), febrile neutropenia (24.1%), hand-foot syndrome (13.8%), hypokalaemia (10.3%). Reasons for discontinuation: PD (48.3%), toxicity (27.6%), patient request (13.8%), and investigator request (10.3%). EFFICACY: 5 ovarian patients (20.8%) achieved partial response; median time to progression (TTP) was 6.1 months (range, 1.2-12.5). CONCLUSION: Pemetrexed plus PLD was reasonably tolerated in this heavily-pretreated population. MTD: pemetrexed 500 mg/m(2) and PLD 40 mg/m(2) may be carried forward to phase II studies in specific patient populations. TTP in platinum-refractory ovarian patients was greater than expected.

Device recalls and the recalling company's website.

An ongoing issue with respect to medical device recalls is getting the information to the right people in a timely manner so that appropriate action can be taken. For Class I recalls, this is often addressed by one or more means of professional and public communications, including after-the-fact posting of such recalls by the U.S. Food and Drug Administration (FDA). One resource that could be included in a recall strategy is the recalling company's own website where the information could be readily available in close association with other information on the product, and where it would be readily found by someone making a product specific inquiry. However an investigation of 13 Class I recalls from the 4th quarter of 2010 shows that only four of these included a web presence, and even among these, the recall information was not necessarily easily found, nor closely linked, to other product information.

Skin cancer: knowledge, behaviors, and attitudes of college students.

OBJECTIVES: Knowledge, attitudes, and behaviors of college students regarding melanoma and skin protection were examined. METHODS: We surveyed 492 students at a mid-sized southern university. The Melanoma Risk Behavior Survey was administered in lecture classes. RESULTS: Mean knowledge score was 10.6 ± 3.8 (24 questions). A majority of participants knew that sun exposure increases the risk for skin cancer; however, only 29% correctly identified behaviors that reduce this risk. Mean attitude score was 5.26 ± 2.73 (11 questions). Sixty-nine percent agreed that all people should take precautions against skin cancer; however, only 51% believed they themselves should practice sun safe behaviors. Mean behavior score was 1.29 ± 1.22 (9 possible). Only 3.1% reported avoiding the sun during peak hours, and only 5.1% regularly use sunscreen when exposed to the sun. CONCLUSION: Campus programs for increasing awareness of skin cancer risk are warranted. Changing attitudes and behaviors regarding exposure and protective measures is increasingly important.

Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: a role for prenatal vitamin d deficiency and infections?

Previous surveys found a large (>10-fold) variation in schizophrenia prevalence at different geographic sites and a tendency for prevalence to increase with latitude. We conducted meta-analyses of prevalence studies to investigate whether these findings pointed to underlying etiologic factors in schizophrenia or were the result of methodological artifacts or the confounding of sites' latitude with level of healthcare at those sites. We found that these patterns were still present after controlling for an index of healthcare--infant mortality--and focusing on 49 studies that used similar diagnostic and ascertainment methods. The tendencies for schizophrenia prevalence to increase with both latitude and colder climate were still large and significant and present on several continents. The increase in prevalence with latitude was greater for groups with low fish consumption, darker skin, and higher infant mortality--consistent with a role of prenatal vitamin D deficiency in schizophrenia. Previous research indicates that poor prenatal healthcare and nutrition increase risk for schizophrenia within the same region. These adverse conditions are more prevalent in developing countries concentrated near the equator, but schizophrenia prevalence is lowest at sites near the equator. This suggests that schizophrenia-producing environmental factors associated with higher latitude may be so powerful they overwhelm protective effects of better healthcare in industrialized countries. The observed patterns of correlations of risk factors with prevalence are consistent with an etiologic role for prenatal vitamin D deficiency and exposure to certain infectious diseases. Research to elucidate environmental factors that underlie variations in schizophrenia prevalence deserves high priority.

Results of a phase II trial of cetuximab plus capecitabine/irinotecan as first-line therapy for patients with advanced and/or metastatic colorectal cancer.

BACKGROUND: XELIRI (capecitabine/irinotecan) is effective and well tolerated in metastatic colorectal cancer (mCRC). Cetuximab is active in mCRC alone or with chemotherapy. This study evaluated cetuximab plus XELIRI in first-line treatment of mCRC. PATIENTS AND METHODS: Subjects had histologically confirmed unresectable colorectal adenocarcinoma (with T4 lesions) after preoperative chemoradiation and/or metastases. Treatment was capecitabine 1700 mg/m2 (850 mg/m2 orally twice a day on days 1-14 for 3 weeks), irinotecan 200 mg/m2 intravenously (I.V.) on day 1 every 3 weeks, and weekly cetuximab (initially 400 mg/m2 I.V. [120 minutes], subsequently 250 mg/m2 [30 minutes]). RESULTS: Baseline characteristics (N = 70): 43 men (61%); median age, 61.5 years; Eastern Cooperative Oncology Group performance status 0/1 = 66%/34%; 94% adenocarcinoma. Previous therapy: surgery (91%), chemotherapy (14%), or radiation therapy (7%). Responses (patients completing > or = 2 cycles): complete response (5.7%), partial response (37.7%), stable disease (43.4%), and progressive disease (PD; 13.2%); 16 patients discontinued early (n = 4 allergic reaction, n = 2 withdrew consent, n = 2 death, and n = 8 other adverse events [AEs]). The overall per-protocol response rate was 43.4% (34% intent to treat [ITT]; disease control rate, 86.8%; 69% ITT). The median time to progression was 8.1 months (range, < 1-27.0 months), and the median time to response was 1.6 months (range, 1.1-8.4 months). The median survival was 20.5 months, and 45.7% of patients remain alive. Of the 38 deaths, 84% were because of PD. No death was treatment related. The most frequent grade 3/4 treatment-related AEs included diarrhea, neutropenia, and nausea/vomiting; 32% of patients required dose reductions. All patients are off the study primarily because of PD (34.3%) or AEs (40.0%). CONCLUSION: In summary, XELIRI plus cetuximab is a promising regimen that merits further study for first-line mCRC.

Results of a phase II multicenter trial of pentostatin and rituximab in patients with low grade B-cell non-Hodgkin's lymphoma: an effective and minimally toxic regimen.

This study explored the efficacy and toxicity of the combination of pentostatin and rituximab, effective single agents in low-grade non-Hodgkin's lymphoma (NHL). Sixty patients with previously treated low-grade NHL were enrolled. Except for day 1, both drugs were administered weekly for 4 weeks, with week 5 off. During week 1 (day 1) only rituximab was given; subsequent weekly treatments included both drugs. Patients received a minimum of 2 five-week cycles in order to be evaluable for efficacy. Responses were evaluated on week 5 of cycle 2. If partial response (PR) or stable disease (SD) responses were noted, 2 additional cycles were administered. Final evaluations were done on week 5 of cycle 4. Of 60 patients, 58.3% had an Eastern Cooperative Oncology Group performance status (PS) of 0, and 41.7% had PS of 1; 31.7% and 51.7% had stage III or stage IV disease, respectively. Histology included follicular center, follicular, grade I (45%), II (21.7%), III (1.7%), and small lymphocytic (31.7%). Seventeen patients had prior chemotherapy, but no patients had received prior pentostatin or rituximab. Median age was 60.3 years (range, 32.5-84.7 years). Among 57 evaluable patients, 77% responded (22.3% complete response [CR], 3.5% unconfirmed CR, 35.1% PR, and 10.5% unconfirmed PR); 19.3% had SD, and 8.8% progressive disease (PD). Response rate among previously untreated patients was 83% versus 63% in previously treated patients. Median duration of response was 11 months (range, 2.3-22.2 months); median time to progression was 15 months (range, < 1-25 months). Neutropenia was the only adverse event experienced by >/= 10% of patients. Six deaths were caused by PD, and one death each was caused by acute respiratory distress, possibly related respiratory failure, and cardiac toxicity. These results suggest the combination of pentostatin/rituximab is well tolerated and active in low-grade lymphoma.

Modeling of failure mode in knee ligaments depending on the strain rate.

BACKGROUND: The failure mechanism of the knee ligament (bone-ligament-bone complex) at different strain rates is an important subject in the biomechanics of the knee. This study reviews and summarizes the literature describing ligament injury as a function of stain rate, which has been published during the last 30 years. METHODS: Three modes of injury are presented as a function of strain rate, and they are used to analyze the published cases. The number of avulsions is larger than that of ligament tearing in mode I. There is no significant difference between the number of avulsions and ligament tearing in mode II. Ligament tearing happens more frequently than avulsion in mode III. RESULTS: When the strain rate increases, the order of mode is mode I, II, III, I, and II. Analytical models of ligament behavior as a function of strain rate are also presented and used to provide an integrated framework for describing all of the failure regimes. In addition, this study showed the failure mechanisms with different specimens, ages, and strain rates. CONCLUSION: There have been several a numbers of studies of ligament failure under various conditions including widely varying strain rates. One issue in these studies is whether ligament failure occurs mid-ligament or at the bone attachment point, with assertions that this is a function of the strain rate. However, over the range of strain rates and other conditions reported, there has appeared to be discrepancies in the conclusions on the effect of strain rate. The analysis and model presented here provides a unifying assessment of the previous disparities, emphasizing the differential effect of strain rate on the relative strengths of the ligament and the attachment.

Mechanical bone strength of the tibial resection surface at increasing distance from the joint line in total knee arthroplasty.

Few articles have addressed the bone strength of the proximal tibia. This study attempts to quantify the compressive strength of bone in the proximal tibia of human cadaveric knees at increasing distance from the joint surface. Sixteen fresh-frozen human cadaveric knees were tested. The proximal tibia was sequentially sectioned into 1-cm slices, starting 2 mm below the chondral surface of the medial tibial plateau. Four slices were obtained from each knee. Each slice was then loaded to failure under an axial load. The proximal slice of bone had a significantly higher average maximum load to failure than the more distal slices. The second, third, and fourth slices of bone withstood 77%, 61%, and 73% of the average load of the proximal slice, respectively. This study was designed to simulate how the proximal tibia is loaded under an uncemented tibial base plate after total knee arthroplasty. The results are in agreement with previous studies that have shown the proximal 1 cm of tibial bone to have the highest resistance to compressive loads. Previous studies on the bone strength of the proximal tibia have focused on more proximal portions of bone than the current study. This study demonstrates that the load to failure of tibial resection surface decreases significantly with increasing distance from the joint line until the 4th cm of bone beneath the joint line is encountered. This information may play a role in surgical decision making and implant design.