Association between KRAS mutation and lung metastasis in advanced colorectal cancer.

BACKGROUND: KRAS mutations have been associated with lung metastases at diagnosis of metastatic colorectal cancer (mCRC), but the impact of this mutation on subsequent development of lung metastasis is unknown. We investigated KRAS mutation as a predictor of lung metastasis development. METHODS: We retrospectively evaluated data from patients with mCRC whose tumour was tested for KRAS mutation from 2008 to 2010. The relationships of KRAS mutational status with time-to-lung metastasis (TTLM) and overall survival (OS) were analysed. RESULTS: Of the 494 patients identified, 202 (41%) had tumours with KRAS mutation. KRAS mutations were associated with a shorter TTLM (median 15.2 vs 22.4 months; hazard ratio=1.40; P=0.002) and a two-fold greater odds of developing lung metastases during the disease course in patients with liver-limited mCRC at diagnosis (72 vs 56%, P=0.007). Overall survival did not differ by KRAS status. CONCLUSIONS: Lung metastasis was more likely to develop during the disease course in patients whose tumour had a KRAS mutation than in those whose tumour did not have a KRAS mutation. This finding may have an impact on decision making for surgical resection of metastatic disease.

Prospective randomised evaluation of traditional Chinese medicine combined with chemotherapy: a randomised phase II study of wild toad extract plus gemcitabine in patients with advanced pancreatic adenocarcinomas.

BACKGROUND: An intravenous formulated extract of the venom of the wild toad Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, huachansu, is currently used in China for the treatment of lung, liver, pancreatic, and colorectal cancers. We performed a randomised, single-blinded, phase II clinical study of huachansu plus gemcitabine versus placebo plus gemcitabine in patients with locally advanced and/or metastatic pancreatic adenocarcinomas. METHODS: Patients with tissue-proven locally advanced and/or metastatic pancreatic adenocarinoma were randomly assigned to receive either gemcitabine 1000 mg m(-2) on days 1, 8, and 15 with huachansu 20 ml m(-2) daily for 21 days (arm A) or placebo (arm B); treatment cycles were 28 days in length. Primary end point was 4-month progression-free overall survival (PFS); secondary end points were objective radiographical response rate (ORR), time to progression (TTP), and toxicity. RESULTS: A total of 80 subjects were enrolled; 76 patients were evaluable (received at least 1 week therapy). Median overall survival was 160 days for arm A and 156 days for arm B (P=0.339); ORR was 9 and 3% in arms A and B, respectively (P=0.332), median TTP was 98 and 115 days, respectively (P=0.825); the median 4-month PFS was 99 and 98 days, respectively (P=0.679). CONCLUSION: Huachansu when combined with gemcitabine did not improve the outcome of patients with locally advanced and/or metastatic pancreatic cancer.

Survival advantage observed with the use of metformin in patients with type II diabetes and colorectal cancer.

BACKGROUND: Patients with type II diabetes mellitus (DM) have an increased risk of adenomatous colorectal (CRC) polyps and CRC cancer. The use of the anti-hyperglycemic agent metformin is associated with a reduced incidence of cancer-related deaths. METHODS: We retrospectively evaluated the medical records of 4758 patients seen at a single institution and determined that 424 patients were identified by their physicians as having type II DM and CRC cancer. Data were subsequently acquired determining the subject's age, body mass index (BMI), and disease date of diagnosis, stage, site of cancer, treatment, and survival. RESULTS: Patients with type II DM and CRC cancer treated with metformin as one of their diabetic medications had a survival of 76.9 months (95% CI=61.4-102.4) as compared with 56.9 months in those patients not treated with metformin (95% CI=44.8-68.8), P=0.048. By using a multivariable Cox regression model adjusted for age, sex, race, BMI, and initial stage of disease, we demonstrated that type II diabetic patients treated with metformin had a 30% improvement in overall survival (OS) when compared with diabetic patients treated with other diabetic agents. CONCLUSION: Colorectal cancer patients with DM treated with metformin as part of their diabetic therapy appear to have a superior OS.

Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy.

BACKGROUND: The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies. METHODS: Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m(-2) loading dose then 250 mg m(-2) weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses. RESULTS: Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months. CONCLUSIONS: The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

Barriers to health care for immigrants and nonimmigrants: a comparative study.

A survey asked medical social workers and visiting public health nurses to identify health problems and to compare barriers to health care experienced by immigrants and nonimmigrants in the Twin Cities area. Respondents considered infectious diseases a more significant problem for immigrants; they saw alcohol and chemical dependency as more problematic for nonimmigrants. Survey respondents thought that both groups experienced many of the same logistical barriers, including inadequate insurance coverage, transportation, mental stress, time constraints, and distance to their health care facilities. They identified language barriers and the need for trained interpreters as barriers for immigrants only. The survey confirmed widely held assumptions that cultural barriers are more problematic for immigrants, although these barriers were also perceived for nonimmigrants. Participants identified 16 of 18 health services as more available for nonimmigrants. Emergency and obstetrical services are equally available to the two groups, according to survey respondents.

Monitoring blood levels of selected drugs. Remember to factor in the many confounding variables.

Appropriate use of various pharmacologic agents involves not only awareness of therapeutic indications and side effects but also familiarity with clinical use and timing of blood level monitoring. The effective as well as the toxic level of antiepileptic drugs varies widely among patients, so the patient's response is more important than the serum drug level. These agents may interact with other disease states, other drugs, and even other antiepileptic agents. Because of digoxin's long half-life and the effect of physical exercise on serum concentration, the timing of serum collection is important. The usefulness of measuring amiodarone serum concentrations is controversial, but findings may help identify patients at risk for side effects related to the drug. Procainamide has a very short half-life and concentrations change over a short period, so blood levels of this agent should be measured before administration of a dose. The dose of levothyroxine required to restore a normal thyroid hormone level varies with age, coexistent conditions, and use of other medications. After the appropriate dose is determined, follow-up monitoring yearly is necessary (more often in the elderly). Efficacy and toxicity of theophylline are directly related to serum concentrations, and a reduced target level of 5 to 15 micrograms/mL has recently been suggested. Proper monitoring is important, because metabolic changes and drug interactions can cause either subtherapeutic or toxic levels.

Skin necrosis secondary to low-molecular weight heparin in a patient with antiphospholipid antibody syndrome.

Skin necrosis is a rare complication of subcutaneous heparin therapy that usually occurs at injection sites. It occasionally accompanies the heparin-associated thrombocytopenia and thrombosis syndrome. We describe a patient with the antiphospholipid syndrome who had skin necrosis develop from low-molecular weight heparin therapy at sites distant from injection sites.

Covert hypothyroidism presenting as a cardiovascular event.

Hypothyroidism presenting with classic signs and symptoms is generally easily recognized. Less often, patients with hypothyroidism may present with symptoms and laboratory abnormalities suggestive of cardiovascular disease. In this article, we describe six such patients. Hypothyroidism was suspected when creatine phosphokinase (CPK) levels were persistently elevated. The diagnosis was confirmed by thyroid function tests, and thyroid hormone therapy resulted in resolution of symptoms and CPK elevations. Persistently elevated CPK levels associated with cardiovascular symptoms but without demonstrable myocardial damage should prompt consideration of covert hypothyroidism.

Detection of Clostridium difficile toxins A (enterotoxin) and B (cytotoxin) in clinical specimens. Evaluation of a latex agglutination test.

A new latex test, Culturette Brand Rapid Latex Test for detection of Clostridium difficile toxin A, was tested on 408 stool samples. In 247 frozen tissue culture supernate specimens previously obtained from patients with C. difficile-associated diarrhea (CAD), the latex test (enterotoxin) was positive in 182 (74%) as compared with 194 (79%) for the repeat tissue culture (P greater than 0.1) cytotoxin (toxin B) test. Testing of 161 fresh stool samples found the latex test superior to tissue culture (P less than 0.05) in cases of CAD (90% positivity vs. 70%), with the two tests being equal in both non-CAD diarrheal and non-diarrheal control groups. In vitro evaluation of 61 C. difficile isolates found all (100%) to be producers of enterotoxin A, while only 53 (87%) produced toxin B. The latex test for C. difficile toxin detection is a rapid, simple test for use in the diagnosis in CAD.

Frequency of aminoglycoside 6'-N-acetyltransferase among Serratia species during increased use of amikacin in the hospital.

The incidence of tobramycin-resistant, gentamicin-susceptible Serratia species at the Minneapolis Veterans Administration Medical Center decreased from an average 42.1 to 2.5% (P less than 0.001) during a 4.5-year period despite the predominant use of amikacin. These organisms were shown to express a 6'-N-acetyltransferase-modifying enzyme (EC 2.3.1.82). Resistance was not shown to be plasmid mediated.

Evaluation of the 24-h API 20A anaerobe system for identification of Clostridium difficile.

Accurate identification of Clostridium difficile is important when antibiotic-associated diarrhea or pseudomembranous colitis is suspected. Presumptive identification of C. difficile was made on the basis of microscopic features and colony characteristics on cycloserine, cefoxitin, fructose, and egg yolk agar medium. We studied the reliability of the 24-h API 20A anaerobe system for definitive identification of C. difficile. This system showed low dependability after the recommended 24 h of incubation by confirming the identity of only 54% of the isolates presumptively identified as C. difficile. There was a marked improvement in the system's capability after 48 h of incubation, when the identity of 95% of the isolates was confirmed.