Prognosis of mucinous histology for patients with radically resected stage II and III colon cancer.

BACKGROUND: Previous studies investigating the prognostic role of mucinous histology of colorectal cancer produced conflicting results. This retrospective analysis was carried out in order to explore whether mucinous adenocarcinoma (MC) is associated with a comparatively worse prognosis than that of nonmucinous adenocarcinoma (NMC) for patients undergoing curative resection for stage II and III colon cancer. PATIENTS AND METHODS: This study involved 1025 unselected patients who underwent curative surgery for sporadic colon cancer and follow-up procedures at six different oncology departments. RESULTS: MCs accounted for 17.4% (n=178) of tumours. Patients with MC had 5- and 8-year overall survival rates of 78.6% and 68.8%, respectively, compared with 72.3% and 63.8%, respectively, for patients with nonmucinous tumours. Multivariate analysis using the Cox proportional hazards model showed that the clinically significant prognostic factors were stage of disease and adjuvant chemotherapy. No statistically significant interaction between mucinous histology and adjuvant chemotherapy was found. CONCLUSIONS: For patients with stage II and III colon cancer who underwent curative surgery, mucinous histology has no significant correlation with prognosis compared with NMC. This retrospective analysis suggests a comparable benefit from adjuvant chemotherapy for MC compared with NMC.

Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy.

The objective of this study was to investigate the efficacy of first-line chemotherapy containing irinotecan and/or oxaliplatin in patients with advanced mucinous colorectal cancer. Prognostic factors associated with response rate and survival were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The population included 255 patients, of whom 49 (19%) had mucinous and 206 (81%) had non-mucinous colorectal cancer. The overall response rates for mucinous and non-mucinous tumours were 18.4 (95% CI, 7.5-29.2%) and 49% (95% CI, 42.2-55.8%), respectively (P=0.0002). After a median follow-up of 45 months, median overall survival for the mucinous patients was 14.0 months compared with 23.4 months for the non-mucinous group (hazard ratio (HR), 1.74; CI 95%, 1.27-3.31; P=0.0034). After adjustment for significant features by multivariate Cox regression analysis, mucinous histology was associated with poor overall survival (HR, 1.593, 95% CI, 1.05-2.40; P=0.0267), together with performance status ECOG 2, number of metastatic sites > or =2, and peritoneal metastases. This retrospective analysis shows that patients with mucinous colorectal cancer have poor responsiveness to oxaliplatin/irinotecan-based first-line combination chemotherapy and an unfavourable prognosis compared with non-mucinous colorectal cancer patients.

Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectal cancer.

The interleukin-1 receptor antagonist (IL-1RA) cytokine is thought to counteract tumor angiogenesis/metastasis. Two single nucleotide polymorphisms in the IL-1RA gene (rs4251961 T/C and rs579543 C/T) influence IL-1RA circulating levels with highest production in carriers of the homozygous rs4251961 T/T and rs579543 T/T genotypes. A total of 180 patients with metastatic colorectal cancer were categorized as high IL-1RA producers if they were carriers of at least one of the rs4251961 T/T or rs579543 T/T genotypes (T/T carriers). Median survival times were 35.8 months (95% confidence interval: 29.7-43.7 months) and 28.6 months (95% confidence interval: 25.6-30 months) in 56 T/T carriers and in 124 non-T/T carriers, respectively. The favorable association between T/T carriers' status and survival was significant in the multivariate analysis (P=0.018). Also, T/T carriers and non-T/T carriers were prevalent among patients with Karnofsky performance status 90-100 and 70-80, respectively (P=0.002). These findings encourage additional studies in this field and the evaluation of a recombinant-IL-1RA for anticancer activity.

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy.

We investigated the association between thymidylate synthase (TS) germline polymorphisms and response to 5-fluorouracil-based chemotherapy in 80 patients with liver-only metastatic colorectal cancer (MCRC). The tandem repeat polymorphism (VNTR) in TS 5'-untranslated region (5'-UTR), which consists of two (2R) or three (3R) 28-bp repeated sequences, with or without a G/C nucleotide change in 3R carriers (3G or 3C) and a 6-bp insertion/deletion (6+/6-) in the TS 3'-UTR, was studied. The distinction between high (2R/3G, 3C/3G and 3G/3G) and low (2R/2R, 2R/3C and 3C/3C) TS expression genotypes according to the 5'-UTR VNTR+G/C nucleotide change showed significant association with tumour response (P=0.01). In particular, high TS expression genotypes were found in 8 out of 34 patients (23.5%) with complete or partial response and in 24 out of 46 patients (52%) with stable disease and disease progression. Liver-only MCRC patients are a homogeneous and clinical relevant subgroup that may represent an ideal setting for studying the actual influence of TS polymorphisms.

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy.

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.

Urinary excretion of L-carnitine and its short-chain acetyl-L-carnitine in patients undergoing carboplatin treatment.

PURPOSE: To evaluate the effect of the anti-cancer drug carboplatin on plasma concentrations and urinary excretion of L-carnitine (LC) and its main ester, acetyl-L-carnitine (ALC), in cancer patients. METHODS: Plasma and urine concentrations of LC and ALC from 11 patients on carboplatin therapy (1 h intravenous infusion; AUC dose 4.8 +/- 1.1 mg/ml min) in combination with docetaxel, paclitaxel or vinorelbine, were determined by high-performance liquid chromatography with fluorimetric detection. RESULTS: Before carboplatin therapy, the mean +/- SD plasma concentrations of LC and ALC were 47.8 +/- 10.9 and 7.04 +/- 1.04 nmoles/ml, respectively, and remained constant throughout the entire study period. In contrast, urinary excretion of LC and ALC, increased significantly during the chemotherapy from 115 +/- 105 to 480 +/- 348 micromoles/day (P < 0.01) and from 41 +/- 41 to 89 +/- 52 micromoles/day (P < 0.05) for LC and ALC, respectively, subsequently reverting to normal 6 days after the end of chemotherapy. Similarly, the renal clearance of LC and ALC increased substantially during chemotherapy from 1.67 +/- 1.43 to 9.05 +/- 9.52 ml/min (P < 0.05) and from 4.02 +/- 4.51 to 7.97 +/- 5.05 ml/min (P = not significant) for LC and ALC, respectively, reverting to normal 6 days after the end of chemotherapy. Plasma concentrations and urinary excretion of glucose, phosphate and urea nitrogen and creatinine clearance, however, were not affected by carboplatin therapy, indicating no impaired kidney function. CONCLUSION: Treatment with carboplatin was associated with a marked urinary loss of LC and ALC, most likely due to inhibition of carnitine reabsorption in the kidney.

Long-survival in responding patients with metastatic breast cancer treated with doxorubicin-docetaxel combination. A multicentre phase II trial.

BACKGROUND: The doxorubicin-docetaxel combination is active in breast cancer; the aim of the present study was to evaluate the complete response rate and safety profile of the doxorubicin and docetaxel regimen as first-line chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: Forty-three patients entered the study. Treatment plan was: doxorubicin (50 mg/m2, i.v. bolus) followed 1 hour later by docetaxel (75 mg/m2 i.v. infusion over 1 hour), q 3 weeks, for up to six courses. The patients achieving a response or a stabilisation of disease after 6 courses were allowed to intensify the treatment with docetaxel (100 mg/m2, q 3 weeks) for up to 2 courses. G-CSF (or GM-CSF) was administered if clinically indicated. RESULTS: Patients' median age was 57years (range 32-75) and 72% of them had visceral disease. A total of 217 doxorubicin-docetaxel courses were delivered, with 70% of patients receiving all the 6 planned cycles. Among the 40 patients assessable for response (WHO criteria), 7 (16%) achieved a complete remission and 22 (51%) a partial remission, for an overall response rate (intent-to-treat) of 67% (95% C.I. =53% to 81%). In 19 patients, the treatment was intensified with two more single-agent docetaxel cycles, without ameliorating the response. Twenty-seven patients with oestrogen receptor-positive received hormonal therapy as 'maintenance' after completing chemotherapy treatment. NCIC G3-G4 neutropenia was recorded in 58% of patients, with G/GM-CSF used in 23 (53%) patients and 91 (38%) cycles. No patients experienced severe cardiac or neurological toxicity. No toxic death occurred. With a median follow-up of 41 months among alive patients, we observed in responder patients an overall median time to progression and survival of 18 and 33 months respectively, with ten long-survivors still alive. CONCLUSION: This study confirmed the combination doxorubicin-docetaxel as a very active regimen for metastatic breast cancer. Remarkably long survival times were observed not only in complete responders, but also in those patients who responded partially. This might be equally attributed to first-line treatment and sequential maintenance hormonal therapy.

Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients.

Ifosfamide and cisplatin cause urinary loss of carnitine, which is a fundamental molecule for energy production in mammalian cells. We investigated whether restoration of the carnitine pool might improve chemotherapy-induced fatigue in non-anaemic cancer patients. Consecutive patients with low plasma carnitine levels who experienced fatigue during chemotherapy were considered eligible for study entry. Patients were excluded if they had anaemia or other conditions thought to be causing asthenia. Fatigue was assessed by the Functional Assessment of Cancer Therapy-Fatigue quality of life questionnaire. Treatment consisted of oral levocarnitine 4 g daily, for 7 days. Fifty patients were enrolled; chemotherapy was cisplatin-based in 44 patients and ifosfamide-based in six patients. In the whole group, baseline mean Functional Assessment of Cancer Therapy-Fatigue score was 19.7 (+/-6.4; standard deviation) and the mean plasma carnitine value was 20.9 microM (+/-6.8; standard deviation). After 1 week, fatigue ameliorated in 45 patients and the mean Functional Assessment of Cancer Therapy-Fatigue score was 34.9 (+/-5.4; standard deviation) (P<.001). All patients achieved normal plasma carnitine levels. Patients maintained the improved Functional Assessment of Cancer Therapy-Fatigue score until the next cycle of chemotherapy. In selected patients, levocarnitine supplementation may be effective in alleviating chemotherapy-induced fatigue. This compound deserves further investigations in a randomised, placebo-controlled study.

Advanced non-small cell lung cancer in the elderly: effective and well tolerated weekly gemcitabine and cisplatin regimen. A pilot study.

BACKGROUND: The frequency of advanced non-small cell lung cancer (NSCLC) increases with age and more effective and less toxic chemotherapy schedules are needed in elderly patients. Cisplatin-based regimens are considered the best treatment for advanced NSCLC, although they produce only a modest advantage in overall survival with considerable toxicity. METHODS: In the present study the activity and toxicity of a weekly gemcitabine and cisplatin schedule was evaluated in a small group of advanced NSCLC patients aged 68 years or more. Treatment consisted of gemcitabine 1000 mg/m2 i.v. and cisplatin 35 mg/m2 i.v., both given weekly on days 1, 8, 15 followed by 1 week of rest. RESULTS: Fifteen previously untreated patients entered the study; their median age was 72 years (range 68-76). One hundred and sixteen weekly administrations were delivered. The median dose-intensity was 614.5 mg/m2 per week for gemcitabine (82%) and 21 mg/m2 per week for cisplatin (80%). All the 15 patients were evaluable for response and toxicity. The overall response rate was 40% [95% CI = 16-68%]. The main toxicity was WHO grade III-IV thrombocytopenia that was recorded in 6 patients (40%). Other major toxicities were very low and no treatment-related deaths were reported. CONCLUSIONS: This schedule appears to be active, to have a favourable toxicity profile and can be considered in advanced NSCLC elderly patients. Of interest, the patients enrolled received high dose intensities of both drugs.

Hypertension management: relationship between visit interval and control.

OBJECTIVE: Hypertension is one of the most common diagnoses resulting in an office visit to the physician. We examined the relationship between the variation in the interval between follow-up visits for hypertensive patients and the control of blood pressure. METHODS: The sample consisted of 113 patients who made 399 visits. Data included current medical problems, medications, type of health insurance, and socioeconomic status for each patient. RESULTS: The mean number of days between visits was 70.6 with a standard deviation of 76.3. No significant relationship was found between visit interval and severity of hypertension (p = 0.14). Sample size made it possible to detect a 20% difference with a likelihood of 0.80 at a significance level of 0.05. CONCLUSIONS: Our findings are limited by our focus on patient behavior rather than physician recommendation concerning the interval between visits, and by the distinct possibility that many of the visits were made for reasons other than follow-up of hypertension.

Transurethral prostatectomy versus transurethral dilatation of the prostatic urethra for benign prostatic hyperplasia: a cost-utility analysis.

Transurethral prostatectomy is the treatment currently preferred for benign prostatic hyperplasia. A new procedure, transurethral dilatation of the prostatic urethra, has lower costs and mortality and complication rates but may be less effective. These two strategies were evaluated by using cost-utility analysis, a form of cost-effectiveness analysis in which the benefit is defined in terms of individual preferences. Under the model assumptions, the cost of transurethral dilatation is less than the cost of transurethral prostatectomy for patients with benign prostatic hyperplasia ($7084 versus $8647) and slightly more effective: 11.787 quality adjusted life years versus 11.766. Thus, transurethral prostatectomy is said to be dominated. Results indicate that if patients are rigorously selected, and if balloon catheters of 30-35mm in size are utilized, transurethral dilatation could be the initial treatment of choice for eligible patients with benign prostatic hyperplasia.

Human ehrlichiosis--an overview.

Canine ehrlichiosis, previously thought to be restricted to dogs, has gained prominence in the human population since 1986. In the United States, human ehrlichiosis is a newly recognized disease ranging from a mild infection to a severe life threatening or fatal disease. Since antibody titers were found to be highest to E. canis in human ehrlichiosis patients, it was believed that E. canis or a closely related species was the etiologic agent. Investigators from the Centers for Disease Control recently have isolated a bacterium believed to be the etiologic agent of human ehrlichiosis and proposed the name Ehrlichia chaffeensis. Human cases of the disease have been identified primarily in the southeastern and south-central areas of the United States. Although relatively few cases are diagnosed, Oklahoma, according to one source, has been found to have the highest incidence rate. The human disease could be misdiagnosed as Rocky Mountain spotted fever, murine typhus fever, or Q fever.

The evaluation and treatment of men with asymptomatic prostate nodules in primary care: a decision analysis.

BACKGROUND: Whether to perform periodic rectal examinations in asymptomatic men as a screening test for prostatic cancer remains controversial. A randomized clinical trial that tests the efficacy of further evaluation and treatment of men who have been found to have asymptomatic prostate nodules may never be carried out. Decision analysis was therefore used to further investigate this clinical issue. METHODS: A decision tree was developed to model the decision of whether to biopsy an asymptomatic prostate nodule found by digital rectal examination in a 65-year-old man by his primary care physician. Test operating characteristics, probabilities of disease at different stages, probabilities of side effects from various treatments, and average life expectancies were obtained from the medical literature. Utilities for the various possible health outcome states were obtained from ratings by two experienced primary care physicians using the Kaplan-Anderson Quality of Well-Being Scale. These were used to adjust the quality-of-life expectancies for each outcome state. Multiple sensitivity analyses were performed to assess the robustness of the conclusions. RESULTS: Disregarding patient utilities, the average survival benefit of evaluation and treatment is 1.1 months. When quality-of-life adjustments are included in the analysis, evaluation and treatment results in an average loss of 3.5 quality-adjusted months of life. Factors that shift the decision toward evaluation and treatment include a positive predictive value of a prostate nodule for cancer of 49% or greater, specificity of prostate biopsy of 98.3% or greater, and the availability of much more effective treatment for stage D cancers. Factors that do not substantially affect the decision are cancer-free life expectancy, the percentage of cancers that are stage B at time of discovery, the sensitivity of prostate biopsy, and more effective treatment for stage C cancer, assuming the same rate of adverse consequences from treatment. CONCLUSIONS: The evaluation and treatment of prostatic nodules found by digital rectal examination in asymptomatic men in the primary care setting does not lead to significant improvement in life expectancy and adversely affects quality of life. Digital rectal examination should not be performed by primary care physicians as a screening test for prostate cancer.

Recurrent otitis media: a cost-utility analysis of simulated treatment using tympanostomy tubes vs antibiotic prophylaxis.

Using a cost-utility analysis, the effectiveness of tympanostomy tubes was compared to that of antibiotic chemoprophylaxis in young patients with recurrent otitis media. The tympanostomy approach (T-tubes) consisted of placement of a polyethylene grommet in the tympanic membrane, with systemic and local antibiotics administered for one week. The chemoprophylaxis approach consisted of antibiotics in full doses for seven to ten days, followed by continuous antibiotic chemoprophylaxis for six months. Because the T-tube strategy under the model assumptions was more expensive ($396.44 vs $281.30) and yielded slightly less benefit (net utility of .9325 vs. .9476 for initial antibiotic therapy), the chemoprophylaxis option was preferred. We conclude that the initial treatment for recurrent otitis media should consist of acute antibiotics followed by chemoprophylaxis, with T-tubes reserved for treatment failure. Extreme changes in the baseline probabilities of cure or recurrence with antibiotic therapy or in the cost of antibiotic therapy or tympanostomy surgery were required to alter this conclusion. Varying therapy preference (utility) values did not materially alter the conclusions.

Circumcision: a decision analysis of its medical value.

Routine neonatal circumcision has long been controversial. Presented here is a cost-effectiveness analysis of the consequences of the treatment choices (circumcision versus no circumcision) using a decision tree model. For a simulated 85-year life expectancy, routine neonatal circumcision had an expected lifetime cost of $164.61 per patient circumcised and a quality-adjusted survival of 84.999 years. Conversely, for the noncircumcision approach, the expected average lifetime cost was $139.26 per patient, and the quality-adjusted survival was 84.971 years. The net cost-effectiveness ($919.87 per quality-adjusted life year) is within the range usually considered worthwhile for public health policy. However, because of the minor differences in lifetime cost ($25) and benefit (10 days of life) for an individual and the tenuous values available for disease incidence and surgical risk, we conclude that there is no medical indication for or against circumcision. Additional analyses suggested that reported benefits in preventing penile cancer and infant urinary tract infections are insignificant compared to the surgical risks of post neonatal circumcision. The decision regarding circumcision may most reasonably be made on nonmedical factors such as parent preference or religious convictions.

Colloids versus crystalloids in fluid resuscitation: an analysis of randomized controlled trials.

BACKGROUND: Controversy about fluid therapy in resuscitation has existed since the 1960s. The difficulty could be that fluid behavior at the lung capillary membrane level may vary depending on the patient's particular pathology. METHODS: Mortality rates taken from randomized controlled trials were analyzed to compare colloidal and crystalloidal fluid for resuscitation efforts. We controlled for the underlying pathological process by categorizing subjects into three groups: (1) surgical stress, (2) hypovolemia, and (3) severe pulmonary failure. A cost-effectiveness analysis also was performed. RESULTS: No statistically significant differences in mortality rates were found. The cost of each life saved using crystalloids is $45.13, and the cost of each life saved using colloidal solutions is $1493.60. CONCLUSIONS: Because there is no significant mortality-rate advantage to using colloids, and because the cost-effectiveness ratio for crystalloids is much lower than for colloids, it is concluded that crystalloids should always be used in resuscitation efforts.

Documentation of referrals: recording bias due to patient insurance type.

This study explores a possible association between the propensity of primary care physicians to record referrals on special referral forms and the source/mechanism of payment for services. Using a randomly selected sample of visits to University faculty family physicians over a 12-month period, referrals were identified from three sources: progress notes, a special form that was included in the patient's chart, and a computerized list that was generated from the special referral form. A notation in one or more of these sources constituted a referral. Using all three sources, the referral rates were 13.8 referrals per 100 patient encounters for Health Maintenance Organization (HMO) patients, compared with 14.1 for Preferred Provider Organization (PPO) patients and 10.4 for patients with other insurance (p = .83). The progress note in the patient chart was the best source for determining whether a referral had been requested, with approximately 85% documentation. Special forms were not likely to be completed for referrals, especially for non-HMO patients (less than 30% documentation). Thus, reliance on a special form for documentation of referrals would have led to the erroneous conclusion of higher referral rates for HMO patients. The tendency of providers to be more complete in recording referrals of HMO patients (a recording bias) may account for the observed higher rate of referral of such patients in other studies.