Phase I pharmacokinetic study of chronomodulated dose-intensified combination of capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer

Purpose

To evaluate the maximum tolerated dose (MTD) and pharmacokinetic profile of a chronomodulated, dose-intensified regimen of capecitabine in combination with oxaliplatin (XELOX) in metastatic colorectal cancer (mCRC).

Methods

Patients (N?=?18) with 0 or 1 line of prior chemotherapy received oxaliplatin 100?mg/m² on day 1 from 1400 to 1800 hours with escalating dose levels of capecitabine (2,500, 3,000, 3,500, 4,000, 4,500, and 5,000?mg) once daily taken at 2400 hours on days 1?C5. Each cycle lasted 14?days.

Results

The MTD of capecitabine was 4,500?mg. Transaminitis and anemia were the commonest non-hematologic and hematologic toxicities, respectively. Toxicities were generally mild, with only five occurrences of grade 3 toxicity and none of grade 4. There were no dose-limiting toxicities, defined as specific grade 3 or 4 toxicities occurring in the first two cycles of treatment. The objective response rate was 33.3?%, and median overall survival was 16.3?months (95?% CI: 11.2?C18.2?months). The maximum plasma concentration (C _max) and area under plasma concentration?Ctime curve from time 0 to infinity (AUC_[0?C??]) of the capecitabine metabolites in our fixed-dosing chronomodulated regimen were comparable to values seen with comparably dose-intense regimens but associated with significantly reduced toxicity.

Conclusions

Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.     

Mid-term outcomes of patients undergoing adjustable pulmonary artery banding

ObjectiveThe adjustable pulmonary artery band (APAB) has been demonstrated by us earlier to be superior to the conventional pulmonary artery banding (CPAB), in terms of reduced early morbidity and mortality. In this study, we assessed the adequacy of the band and its complications over the mid-term.MethodsBetween 2002 and 2012, 73 patients underwent adjustable PAB, and their operative and follow-up data were collected and analyzed.ResultsThere was one early death following the APAB. Follow-up data were available for 57 patients of which 44 patients (61.7%) underwent definitive repair, 10 were awaiting definitive repair, and 3 patients were kept on medical follow-up because of inadequate fall in pulmonary artery (PA) pressures. 14 patients (19%) were lost to follow-up. Major PA distortion or stenosis was absent in the majority. 1 patient had pseudoaneurysm of the main pulmonary artery (MPA) with sternal sinus infection and required surgical reconstruction. 1 patient had infective endocarditis of the pulmonary valve managed medically. Band migration was not encountered. There were two deaths after definitive repair and one after APAB.ConclusionsPatients undergoing APAB fulfilled the desired objectives of the pulmonary artery banding (PAB) with minimum PA complications in the mid-term. This added to the early postoperative benefits, makes the APAB an attractive alternative to the CPAB.     

Fate of thrombectomized Bj?rk-Shiley valves. A long-term cinefluoroscopic, echocardiographic, and hemodynamic evaluation

Fourteen patients underwent thrombectomy for thrombosis of implanted Bj?rk-Shiley valves (13 in the mitral and one in the aortic position) between January, 1975, and July, 1984. There was no operative mortality or perioperative embolism. Over a follow-up period of 1 to 96 months (average 23.5 months), there was no late mortality. Serial evaluation of valve function by cinefluoroscopy and echocardiography has shown no evidence of rethrombosis or valve dysfunction in any of the patients. Cardiac catheterization and angiocardiography done in 10 patients at various intervals (1 month to 6 years) postoperatively have shown normal valve function in all and normalization of elevated preoperative intracardiac pressures in the majority. Our experience suggests that thrombectomy of thrombosed Bj?rk-Shiley valves provides excellent early and long-term results in terms of patient survival and valve function.     

Cardiopulmonary Bypass and Serum Thyroid Hormone Profile in Pediatric Patients with Congenital Heart Disease

Objective: To study the effect of cardiopulmonary bypass (CPB) on serum thyroid hormone profile in children undergoing open‐heart surgery. Design: Prospective cross‐sectional study. Setting: Multispecialty tertiary level referral center. Patients: One hundred consecutive patients (age 15.9 ± 14.6 months, weight 6.7 ± 2.5 kg) undergoing open‐heart surgery under CPB. Interventions: None. Outcome Measures: Levels and trends of serum total thyroxine (TT4), free thyroxine (FT4), total tri‐iodothyronine (TT3), free tri‐iodothyronine (FT3) and thyroid stimulating hormone (TSH), survival, inotropic score, duration of mechanical ventilation, postoperative complications. Results: TT4 levels were 9.08 ± 3.6, 6.4 ± 2.5, 6.24 ± 2.1, 6.43 ± 2.4, 7.20 ± 3.0 µg/dL at baseline and at 1, 24, 48 and 72 hours; FT4 levels were 1.82 ± 0.5, 1.49 ± 0.3, 1.29 ± 0.3, 1.32 ± 0.4, and 1.43 ± 0.5 ng/dL; TT3 levels were 1.81 ± 0.4, 1.31 ± 0.3, 0.99 ± 0.2, 1.0 ± 0.37, and 1.17 ± 0.48 ng/ml; FT3 levels were 4.09 ± 1.0, 3.02 ± 0.8, 2.21 ± 0.6, 2.22 ± 0.7, and 2.66 ± 1.05 pg/ml; TSH levels were 5.40 ± 3.8, 2.0 ± 3.1, 1.24 ± 1.1, 2.90 ± 3.3, and 4.03 ± 3.4 mIU/L. There was significant fall (29.1% for FT4, 32.1% for TT4, 77% for TSH, 46% for FT3 and 45% for TT3, p < 0.0001). When area under curve (AUC) TT4 was compared between survivors (n = 87) and nonsurvivors (n = 12), significantly larger AUC was seen in survivors (492.81 ± 158.6) than nonsurvivors (360.75 ± 179.6 p = 0.0125). In survivors >72 hours, AUC TT4 was larger in patients with uneventful postoperative course versus those with postoperative complications (516.48 ± 18.6 vs. 394.78 ± 29.9, p = 0.001). AUC TT4 showed significant inverse correlation with inotropic score and borderline inverse correlation with duration of mechanical ventilation. Conclusion: Children undergoing surgery under CPB showed significant fall in thyroid hormones. Because TT4 level is modifiable, prophylactic administration of TT4 for improving outcomes needs to be studied further.     

Bidirectional superior cavo-pulmonary anastomosis without cardiopulmonary bypass

The bidirectional superior cavopulmonary anastomosis is an important intermediate palliation in patients with a structurally or functionally univentricular heart. There is an increasing trend to perform this anastomosis without cardiopulmonary bypass. In this review, we present our preferred technique of performing this operation in a safe, simple, inexpensive and reproducible manner.     

Inflammatory Markers Are Elevated in Eisenmenger Syndrome

Inflammation may be an important contributing factor to the progression of Eisenmenger syndrome (ES). Markers of systemic inflammation in ES have not been systematically studied. Inflammatory markers including high-sensitivity C-reactive protein (hs-CRP), interleukin-2 (IL-2), IL-6, and interferon-γ (IFN-γ) were measured in 42 consecutive ES patients (mean age, 24.3 ± 10.6 years) compared with their levels in 22 healthy control subjects. The patients were followed up for a mean duration of 16.3 ± 13.7 months. The levels of inflammatory markers were correlated with clinical and hemodynamic variables at baseline and the outcomes of death, hospitalization, and worsening World Health Organization (WHO) functional class at follow-up evaluation. Compared with the control subjects, ES patients showed a significant elevation in hs-CRP (2.99 ± 3.5 vs 1.1 ± 0.9 mg/dl; p = 0.002) and IFN-γ (41.3 ± 43.6 vs 10.4 ± 6.9 pg/ml; p < 0.001) levels. The levels of IL-2 and IL-6 also were elevated but did not differ significantly from those in the control subjects. The patients with hs-CRP levels higher than 3 mg/dl were significantly older (28.9 ± 10.6 vs 21.5 ± 9.8 years) and had a significantly shorter 6-min walk distance (421.5 ± 133.2 vs 493.3 ± 74.8 m). The levels of inflammatory markers did not correlate with baseline parameters or clinical outcomes. To conclude, the levels of hs-CRP and IFN-γ are significantly elevated in ES. Elevated hs-CRP in ES was associated with older age and shorter 6-min walk distance, but the levels of inflammatory markers were not predictive of clinical events.     

Viable extracardiac total right heart bypass: technical considerations and mid-term results

BACKGROUND: Direct connection of both caval veins to the pulmonary arterial system would be the ideal right heart bypass by virtue of elimination of prosthetic material and extensive atrial suture lines. However, it can be applied only to selected patients with peculiar anatomical arrangements. We decided to perform total extracardiac right heart bypass using pedicled in situ pericardium in situations when a direct connection was not possible. METHODS: A cohort of five patients, aged 3.5, 4, 10, 10 and 31 years, respectively, with complex cyanotic congenital heart diseases were candidated to extracardiac total cavopulmonary connection using viable in situ pericardium. Aortic cross-clamp was completely avoided in all patients. RESULTS: There was no early or late death. Postoperatively, all patients are in functional class I and in normal sinus rhythm at a mean follow-up of 30 months (S.D.=+/-19 months). Postoperative serial echocardiograms revealed wide, unrestricted anastomoses, unobstructed venous flow to both pulmonary arteries with cardiac pulsations and respiratory variations in the pulmonary arteries due to compressible lateral tunnel. Cavopulmonary angiograms (n=5) in late postoperative period have demonstrated a smooth, nonturbulent, somewhat pulsatile flow without pressure gradient. CONCLUSIONS: The technical advantages and haemodynamic benefits of this operation are encouraging. A longer follow-up is needed to confirm the early results, especially late atrial dysrrhythmias, pulmonary venous obstruction, thromboembolic complications and growth of the conduit.     

Co-teaching: Exploring an Alternative for Integrated Curriculum

Purpose

Currently, the curriculum of medical education is compartmentalized which makes achieving the expected outcome, a real challenge. Co-teaching, an existing concept in education, however, may be used in medical education for integrating the applied component while basic concepts are being taught. The hypothesis, “can co-teaching be an alternate for an integrated curriculum?” was explored in this study. Therefore, the present study was designed to compare the outcomes of co-teaching with the existing teaching methodology owing to the absence of integrated curriculum.