Vagal Nerve Stimulation Reduces Ventricular Arrhythmias and Mitigates Adverse Neural Cardiac Remodeling Post-Myocardial Infarction.

This study sought to evaluate the impact of chronic vagal nerve stimulation (cVNS) on cardiac and extracardiac neural structure/function after myocardial infarction (MI). Groups were control, MI, and MI + cVNS; cVNS was started 2 days post-MI. Terminal experiments were performed 6 weeks post-MI. MI impaired left ventricular mechanical function, evoked anisotropic electrical conduction, increased susceptibility to ventricular tachycardia and fibrillation, and altered neuronal and glial phenotypes in the stellate and dorsal root ganglia, including glial activation. cVNS improved cardiac mechanical function and reduced ventricular tachycardia/ventricular fibrillation post-MI, partly by stabilizing activation/repolarization in the border zone. MI-associated extracardiac neural remodeling, particularly glial activation, was mitigated with cVNS.

Ischemia-induced ventricular proarrhythmia and cardiovascular autonomic dysreflexia after cardioneuroablation.

BACKGROUND: Cardioneuroablation (CNA) is an attractive treatment of vasovagal syncope. Its long-term efficacy and safety remain unknown. OBJECTIVE: The purpose of this study was to develop a chronic porcine model of CNA to examine the susceptibility to ventricular tachyarrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]) and cardiac autonomic function after CNA. METHODS: A percutaneous CNA model was developed by ablation of left- and right-sided ganglionated plexi (n = 5), confirmed by histology. Reproducible bilateral vagal denervation was confirmed after CNA by extracardiac vagal nerve stimulation (VNS) and histology. Chronic studies included 16 pigs randomized to CNA (n = 8) and sham ablation (n = 8, Control). After 6 weeks, animals underwent hemodynamic studies, assessment of cardiac sympathetic and parasympathetic function using sympathetic chain stimulation and direct VNS, respectively, and proarrhythmic potential after left anterior descending (LAD) coronary artery ligation. RESULTS: After CNA, extracardiac VNS responses remained abolished for 6 weeks despite ganglia remaining in ablated ganglionated plexi. In the CNA group, direct VNS resulted in paradoxical increases in blood pressure, but not in sham-ablated animals (CNA group vs sham group: 8.36% ± 7.0% vs -4.83% ± 8.7%, respectively; P = .009). Left sympathetic chain stimulation (8 Hz) induced significant corrected QT interval prolongation in the CNA group vs the sham group (11.23% ± 4.0% vs 1.49% ± 4.0%, respectively; P < .001). VT/VF after LAD ligation was more prevalent and occurred earlier in the CNA group than in the control group (61.44 ± 73.7 seconds vs 245.11 ± 104.0 seconds, respectively; P = .002). CONCLUSION: Cardiac vagal denervation is maintained long-term after CNA in a porcine model. However, chronic CNA was associated with cardiovascular dysreflexia, diminished cardioprotective effects of cardiac vagal tone, and increased susceptibility to VT/VF in ischemia. These potential long-term negative effects of CNA suggest the need for rigorous clinical studies on CNA.

The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models.

The Wnt/ß-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066).

Outcomes of open and endovascular repair for ruptured and nonruptured internal iliac artery aneurysms.

OBJECTIVE: To evaluate outcomes of open (OR) and endovascular repair (II-EVAR) of internal iliac artery aneurysms (IIAAs) with or without preservation of internal iliac artery (IIA) flow. METHODS: We reviewed the clinical data of consecutive patients treated for IIAAs between 2001 and 2012. End-points were morbidity, mortality, graft patency, and freedom from pelvic ischemic symptoms (buttock claudication, ischemic colitis, and spinal cord injury). RESULTS: There were 97 patients, 87 male and 10 female, with mean age of 74 ± 8 years. A total of 125 IIAAs (71 unilateral and 27 bilateral) with mean diameter of 3.6 ± 2 cm were treated. Eighty-two patients (86%) had elective repair and 15 (14%) required emergent repair (mean size, 6.7 ± 2.4 cm; range, 3.6-10 cm). OR in 60 patients (62%; 49 elective, 11 emergent) included IIA bypass in 36 (60%) patients and endoaneurysmorrhaphy in 24 (40%). II-EVAR in 37 patients (38%; 30 elective, 4 emergent) required IIA embolization in 29, iliac branch device in five or open IIA bypass in three, combined with bifurcated aortic stent grafts in 17. Early mortality was 1% for elective (1/49 open, 0/33 endovascular) and 7% for emergent repair (1/11 open, 0/4 endovascular). Early morbidity (43% vs 8%; P < .001) and length of stay (9 vs 1 day; P < .001) were significantly higher for OR as compared with II-EVAR. Pelvic ischemic complications occurred in 25 patients (26%), including hip claudication in 23, ischemic colitis in two, and paraplegia in one. Freedom from buttock claudication at 2 years was 25% in patients with no IIA preserved, 68% with preservation of one, and 95% with preservation of both IIAs (P = .002). Freedom from buttock claudication was higher after OR than after II-EVAR (79% vs 59%; P = .05). Primary and secondary patency rates of IIAA bypasses were 95%, and 80% at 1 and 3 years, respectively. CONCLUSIONS: II-EVAR of IIAAs is associated with fewer complications and shorter hospital stay compared with OR. Open and endovascular IIA reconstructions have very good long-term patency, and preservation of IIA flow is associated with higher freedom from buttock claudication.

Beyond the square knot: a novel knotting technique for surgical use.

BACKGROUND: Knot holding strength is essential to maintain wound closure and ensure tissue contact for healing. Knot unraveling can lead to severe complications, especially for high-tension closures such as tendon repairs, which have recently been reported to have knot unraveling rates as high as 86%. In the current study, a novel surgical knot, the two-strand-overhand locking (TSOL) knot, was designed and mechanically evaluated with use of different suture materials and knot configurations and in actual tendon repairs. METHODS: The knot holding strength of the TSOL knot was compared with that of a 4-throw square knot with use of three different suture materials that are in common clinical use. With use of braided polyblend suture, the TSOL knot was also compared with five other surgical knot configurations. Finally, the strength of tendon repairs performed with use of the TSOL knot and a 4-throw square knot was studied. RESULTS: Compared with the 4-throw square knot, the holding strength of the TSOL knot was 143% greater for braided polyblend, 216% greater for polydioxanone, and 118% greater for polyester suture, with a significantly lower knot unraveling rate compared with that of the 4-throw square knot regardless of suture material. The TSOL knot holding strength was also greater than that of the other surgical knot configurations. The strength and stiffness of tendon repairs with a TSOL knot were significantly increased over those of repairs with a 4-throw square knot. CONCLUSIONS: The TSOL knot provided superior knot holding strength compared with some commonly used surgical knots. CLINICAL RELEVANCE: The TSOL knot has potential clinical applications, especially when knot security is important and high loads are expected, as in tendon or ligament repairs.

Do timely outpatient follow-up visits decrease hospital readmission rates?

It is widely believed that timely follow-up decreases hospital readmissions; however, the literature evaluating time to follow-up is limited. The authors conducted a retrospective analysis of patients discharged from a tertiary care academic medical center and evaluated the relationship between outpatient follow-up appointments made and 30-day unplanned readmissions. Of 1044 patients discharged home, 518 (49.6%) patients had scheduled follow-up ≤14 days after discharge, 52 (4.9%) patients were scheduled ≥15 days after discharge, and 474 (45.4%) had no scheduled follow-up. There was no statistical difference in 30-day readmissions between patients with follow-up within 14 days and those with follow-up 15 days or longer from discharge (P = .36) or between patients with follow-up within 14 days and those without scheduled follow-up (P = .75). The timing of postdischarge follow-up did not affect readmissions. Further research is needed to determine such factors and to prospectively study time to outpatient follow-up after discharge and the decrease in readmission rates.

Long-term outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells.

Metastatic breast cancer remains a major treatment challenge. The use of high-dose chemotherapy (HDCT) with rescue by autologous mobilized peripheral blood (MPB) is controversial, in part because of contamination of MPB by circulating tumor cells. CD34(+)Thy-1(+) selected hematopoietic stem cells (HSC) represent a graft source with a greater than 250,000-fold reduction in cancer cells. Here, we present the long-term outcome of a pilot study to determine feasibility and engraftment using HDCT and purified HSC in patients with metastatic breast cancer. Twenty-two patients who had been treated with standard chemotherapy were enrolled into a phase I/II trial between December 1996 and February 1998, and underwent HDCT followed by rescue with CD34(+)Thy-1(+) HSC isolated from autologous MPB. More than 12 years after the end of the study, 23% (5 of 22) of HSC recipients are alive, and 18% (4 of 22) are free of recurrence with normal hematopoietic function. Median progression-free survival (PFS) was 16 months, and median overall survival (OS) was 60 months. Retrospective comparison with 74 patients transplanted between February 1995 and June 1999 with the identical HDCT regimen but rescue with unmanipulated MPB indicated that 9% of patients are alive, and 7% are without disease. Median PFS was 10 months, and median OS was 28 months. In conclusion, cancer-depleted HSC following HDCT resulted in better than expected 12- to 14-year PFS and OS in a cohort of metastatic breast cancer patients. These data prompt us to look once again at purified HSC transplantation in a protocol powered to test for efficacy in advanced-stage breast cancer patients.

Renal impairment, hemoglobinuria, and hemoglobinemia among patients with idiopathic thrombocytopenic purpura.

Renal impairment (RI) and events potentially leading to RI were reported in idiopathic thrombocytopenic purpura (ITP) patients with specific medications. This study was conducted to estimate the incidence rate (IR) of RI, hemoglobinuria and hemoglobinemia (HE) and characterize baseline risk factors in ITP and ITP-free patients. Incident ITP and matched non-ITP patients were identified from an electronic medical record database from 1990 to 2002. ITP patients were classified by the treatment first received (initiators) or ever received (users). All cohorts were followed for study outcomes. IRs were calculated and standardized by age and gender. A total of 881 ITP and 4,496 ITP-free patients yielded 3,044 and 16,006 person-years, respectively. The ITP cohort had a slightly higher prevalence of autoimmune diseases and infections than the ITP-free cohort. The IR (/10,000 person-years) for RI, hemoglobinuria and HE was 14.2, 35.7, and 7.1 in the ITP cohort; 10.0, 48.8, and 0 in the ITP-free cohort; and 18.3, 37.1, and 6.1 in untreated ITP patients, respectively. The risk of RI, HE or hemoglobinuria was not found to differ substantially between ITP and non-ITP patients or across ITP treatments.

Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study.

Few data exist on the long-term prognosis of patients with chronic primary chronic immune thrombocytopenia (ITP). We examined the risk of infections, hemorrhage resulting in hospitalization, hematologic malignancies, and total and cause-specific mortality among patients with ITP compared with the general population. We used population-based medical databases to identify 407 patients with primary chronic ITP diagnosed during 1996 to 2007 and 4069 general population members individually matched on age, sex, and comorbidity level. We used Cox regression analysis to estimate rate ratios (RRs) adjusted for age (≤ 60 or > 60 years), sex, calendar year, and level of comorbidity. The adjusted 1-year RR of infection was 4.5 (95% confidence interval [CI], 3.3-6.1) for patients with chronic ITP compared with the general population cohort. The adjusted RR decreased to 1.8 (95% CI, 1.3-2.5) for the second to fifth year of follow-up. The adjusted 5-year RR was 3.2 (95% CI, 1.2-9.0) for hospitalized intracranial hemorrhage, 4.4 (95% CI, 2.3-8.3) for other hospitalized hemorrhages, and 4.7 (95% CI, 1.7-12.7) for hematologic malignancy. The 5-year all-cause mortality RR was 2.3 (95% CI, 1.8-3.0). In summary, primary chronic ITP was associated with substantially increased long-term risk of infections, hemorrhagic episodes requiring hospitalization, hematologic malignancies, and mortality.

Are e-health web users looking for different symptom information than callers to triage centers?

INTRODUCTION: Telemedicine options for symptom assessment include both telephonic means (call centers) and Internet sites. Although symptom assessment call centers have been available for decades, symptom assessment over the Internet is relatively new. It is not well known what types of symptoms Internet users are seeking assessment for and whether extant telephone triage algorithms would be applicable to Internet users. METHODS: Symptom assessments on a heavily used Internet site (MayoClinic.com) were compared with symptom calls to a U.S. call center (Ask Mayo Clinic). RESULTS: Internet users sought symptom assessments about adult symptoms 13 times more often than children's symptoms. In contrast, over the telephone, adult symptoms were addressed 2.1 times more frequently than children's symptoms. Despite the differences in frequencies of adult and child symptom assessments, users of the Internet and telephone callers asked about specific symptoms with similar relative frequencies. Analysis of 20 adult symptom types shared by the Web and call center revealed that by excluding only 2 assessments (nasal symptoms and leg pain) the remaining 18 showed a significant correlation in counts of use (r(2) = 0.68, p < 0.001 for linear trend). CONCLUSIONS: Internet users have symptoms assessed in similar proportions to callers, with a few exceptions. Compared with callers, Web users are much more likely looking for information about adult symptoms. Callers are proportionally asking more about acute symptoms, whereas Internet users appear more interested in symptom assessment of chronic conditions.

Risk of adverse events after coronary artery bypass graft and subsequent noncardiac surgery.

AIMS: Coronary artery bypass grafts (CABGs) are increasingly performed in elderly patients. Risk factors and outcomes are poorly described for those undergoing noncardiac surgery within 1 year after CABG. Our objectives were to assess the risk and predictors of major adverse events associated with noncardiac surgery within 1 year after CABG. METHODS: In a retrospective review of medical records at Mayo Clinic (Rochester, MN, USA), over a period of 5 years, we identified patients who underwent noncardiac procedures within 1 year post-CABG. All events that occurred within 30 days after noncardiac surgery and deaths within 1 year after noncardiac surgery were considered to be related to CABG. RESULTS: We identified 211 patients; of these, 21 patients had 24 adverse events. Within 1 year, 11 died, and within the first 30 days, three myocardial infarctions, six acute congestive heart failure episodes, three cerebrovascular accidents and one deep vein thrombosis episode had occurred. Predictors of an adverse event included emergency operation (odds ratio: 6.8), ejection fraction less than 45% (p < 0.001) and elevated right ventricular systolic pressure by 40 mmHg or more (p = 0.03). After the noncardiac procedure, patients requiring dialysis (p = 0.02), ventilatory support (p = 0.03) and longer hospital stay (p = 0.03) had greater rates of adverse outcomes. CONCLUSION: Post-CABG, preoperative ejection fraction less than 45%, right ventricular systolic pressure of 40 mmHg or more, as well as emergent noncardiac surgery, were predictors of adverse outcomes after the noncardiac procedure. Longer postoperative hospital stay, dialysis, as well as ventilatory support, were predictors of adverse outcomes after CABG.

Bone marrow reticulin and collagen content in patients with adult chronic immune thrombocytopenic purpura: a Danish nationwide study.

We quantified and differentiated reticulin and collagen content in bone marrow specimens from chronic immune thrombocytopenic (ITP) patients and examined the correlation between some clinical characteristics and the fibrosis grading. Through the Danish National Patient Registry, we identified 378 patients with chronic ITP from 1997 until 2007. Of these, 253 (67%) had undergone at least one bone marrow biopsy, and we retrieved the bone marrow specimens from 187 (74%). We graded the bone marrow content of reticulin and collagen according to the Thiele scale (Grade 0-3). We also retrieved information on patients' clinical characteristics. We examined the prevalence of bone marrow fibrosis grading > 0 by patients' age (≤ 75 years and > 75 years), sex, platelet count at baseline (< 30 × 109/L, and ≥ 30 × 109/L), splenomegaly, hepatomegaly, and medications. In total 75 chronic ITP patients (40%) had a bone marrow grading >0. Of these, 72 (39%) had Grade 1 reticulin fibers present. Only three patients (< 2%) had collagen fibers present: two had Grade 2 and one had Grade 3. The prevalence of bone marrow grading > 0 was lower in patients aged > 75 years than ≤ 75 years (prevalence ratio = 0.64, 95% CI: 0.36-1.15) and lower in men than women (prevalence ratio = 0.70, 95% CI: 0.45-1.09), while a baseline platelet count ≥ 30 × 109/L was associated with a higher prevalence of grading > 0 (prevalence ratio = 1.24, 95% CI: 0.81-1.86). Thus, bone marrow reticulin and collagen content in chronic ITP patients may be associated with some clinical characteristics.

Questioning the role of abuse in behavioral spells and epilepsy.

Past sexual trauma is frequently linked to the development of behavioral spells, present among 30% of patients admitted for video/EEG monitoring. Current attempts to verify and explore mechanisms in this reported association revealed that patients with epilepsy (n=58) and those with behavioral spells (n=38) did not differ in their self-report of past sexual trauma (among approximately 38% in each group). Ninety percent (90%) of men with behavioral spells endorsed past physical abuse, however, compared with 45% of men with epilepsy, and 40% of men with spells likely met current criteria for posttraumatic stress disorder. Among all patients, the presence of past physical, but not sexual, abuse positively predicted the diagnosis of spells rather than epilepsy. Current findings do not support a preponderance of sexual trauma in behavioral spells, yet within the subset of men with spells, greater exposure to physical abuse and current symptoms of posttraumatic stress disorder may be important etiological and sustaining factors.

Minimum vs. maximum left atrial volume for prediction of first atrial fibrillation or flutter in an elderly cohort: a prospective study.

AIMS: We sought to compare the predictive power and reproducibility between minimum and maximum left atrial (LA) volume for the development of first atrial fibrillation (AF)/flutter. METHODS AND RESULTS: This prospective study included 574 adults, mean age 74+/-6 years, in sinus rhythm, and had no history or evidence of prior atrial arrhythmias. During a mean follow-up of 1.9+/-1.2 years, 30 (5.2%) developed first AF/flutter. The 3-year risk estimates of freedom from AF/flutter by tertiles of minimum and maximum LA volumes were, respectively, 97, 87, and 74% (P<0.0006) and 94, 85, and 78% (P=0.03). Minimum LA volume was incremental to clinical and other echocardiographic parameters of AF/flutter prediction [per tertile, hazard ratio (HR) 2.4], as was maximum LA volume (per tertile, HR 1.8) in a separate model. When both volumes were entered into the same model and adjusting for covariates, minimum but not maximum LA volume retained significance. However, in terms of interobserver reproducibility, maximum LA volume compared more favourably (mean difference 3.1+/-7.1 vs. 7.4+/-7.3 mL/m(2)). CONCLUSION: Minimal LA volume was an independent predictor of first AF/flutter. Although it was marginally superior to maximal LA volume in terms of predictive ability, the interobserver variability was greater.

Comparison of polymerase chain reaction of polymorphonuclear leukocytes and plasma identifies patients who control cytomegalovirus infection after hematopoietic cell transplantation.

By use of an automated polymerase chain reaction test of plasma and a qualitative polymerase chain reaction assay on polymorphonuclear leukocytes, we identified a subgroup of hematopoietic cell transplant recipients who were able to control cytomegalovirus infection early after hematopoietic cell transplantation without antiviral therapy. Thirty-one percent of patients had cytomegalovirus DNA detected by qualitative polymerase chain reaction assay but had no cytomegalovirus DNA detected by the automated test; this group maintained a lower peak cytomegalovirus load, compared with the group of patients who had cytomegalovirus DNA detected by both tests (P = .03), suggesting a greater degree of functional immune reconstitution.

Effects of quinapril on left atrial structural remodeling and arterial stiffness.

Left atrial (LA) enlargement, left ventricular (LV) diastolic dysfunction, and increased arterial stiffness are all associated with adverse cardiovascular outcomes. The rate, magnitude, and concordance of modifiability of these risk markers have not been well characterized. Twenty-one patients (mean age 69 +/- 8 years; 52% women) with isolated diastolic dysfunction and indexed LA volumes > or =32 ml/m(2) were randomly assigned to receive either quinapril at a target dose of 60 mg/day or matching placebo for 12 months. Echocardiographic maximum LA volume and LV diastolic function and arterial stiffness by the augmentation index were measured at baseline and 6 and 12 months. Analysis was based on intention to treat. Baseline characteristics were comparable between the treatment (n = 9) and placebo (n = 12) groups. The mean reduction in LA volume of 4.2 +/- 7.8 ml/m(2) in the quinapril group was significant (p = 0.01) compared with the increase in LA volume in the placebo group (5.5 +/- 8.1 ml/m(2)). This represents a relative improvement of 9.7 ml/m(2). Change in LV filling pressure in terms of E/e' and diastolic function grade did not reach significance. A reduction in the augmentation index was associated with a decrease in indexed LA volume (odds ratio 11, p = 0.046), independent of changes in systolic blood pressure. In conclusion, LA structural remodeling appeared reversible with quinapril, which occurred in parallel with an improvement in arterial stiffness but independent of blood pressure changes.

Risk factors for recurrence and death after primary surgical treatment of malignant phyllodes tumors.

BACKGROUND: Malignant phyllodes tumor (MPT) is a rare but aggressive breast malignancy. The aim of this study was to evaluate parameters that influence outcome in patients with MPT. METHODS: Fifty women were diagnosed with MPT of the breast and treated between August 1971 and July 2000. All medical records were reviewed retrospectively. The Cox regression model was used for multivariate analysis. RESULTS: Tumors were classified as borderline (6%), low grade (32%), or high grade (62%). The median patient age was 46 years (range, 14-77 years). The median tumor diameter was 3.5 cm (range, 1.5-18 cm). Twenty-two patients had wide local excision (WLE), and 28 patients had mastectomy. The median follow-up was 91 months (range, 12-360 months). Local recurrence (LR) occurred in 16 patients (32%) an average of 26 months after surgery (median, 17 months; range, 3-72 months). Distant metastasis occurred in 13 patients (26%) at an average of 53.4 months (median, 36 months; range, 4-177 months). Sixteen (32%) patients have died of their disease. LR was significantly increased with stromal overgrowth (P < .0001), large tumor size (P = .0177), and surgical margins <1 cm (P = .0120), but not with WLE (P = .5099). Stromal overgrowth was the only independent variable predictive of systemic metastasis (P < .0001) and patient survival (P < .0001). CONCLUSIONS: Stromal overgrowth in MPT carries a grave prognosis. Close surgical margins and large tumor size, but not type of operation, significantly increased LR. Either WLE with adequate margins or mastectomy is an appropriate treatment for patients with MPT.

Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer.

PURPOSE: The toxicity profile of fluorouracil (5-FU)-based chemotherapy given on 5 consecutive days at doses of 370 to 450 mg/m(2) has been well documented. A meta-analysis of six North Central Cancer Treatment Group (NCCTG) cancer control trials involving 786 patients indicated that women treated with this type of regimen experienced more severe stomatitis and leukopenia than men. After these findings, an additional meta-analysis of the toxicity profiles on five NCCTG colorectal cancer treatment trials was undertaken. METHODS: Data for 1,093 women and 1,355 men from 12 different treatment arms were included. The primary end points were the incidence of stomatitis, leukopenia, alopecia, diarrhea, nausea, and vomiting, recorded with standard National Cancer Institute common toxicity criteria. Fisher's exact test was used to compare incidence and severity across sexes, supplemented by Forrest meta-analysis plots and logistic regression. RESULTS: The incidence of four out of six toxicities studied was significantly greater for women than men; the exceptions were severe nausea and vomiting. Overall, almost half of the women compared with a third of the men experienced severe toxicity (P <.0001). Logistic regression confirmed the univariate findings while adjusting for the effects of study, dose, body mass index, and age. The differences were consistent across treatment cycles. Response rates and survival distributions were the same for both sexes. CONCLUSION: This study confirms an earlier finding that women receiving 5-FU-based chemotherapy in a 5-day bolus schedule experience toxicity more frequently and with more severity than men. These data raise the question of whether the recommended initial dose of 5-FU-based chemotherapy for women should be lower than that for men.

A phase II trial of docetaxel and CPT-11 in patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, and gastric cardia.

PURPOSE: The incidence of adenocarcinoma of the lower third of the esophagus, esophagogastric junction, and gastric cardia has been rising in the face of limited treatment options for patients with metastatic disease. With the emergence of data to suggest that single agent docetaxel and irinotecan carry antineoplastic effects in this setting, we determined the response rate of these agents when given in combination. PATIENTS AND METHODS: Forty-six patients with metastatic adenocarcinoma of the lower third of the esophagus, esophagogastric junction, and gastric cardia were evaluated. Patients received docetaxel 50 mg/m2/d and irinotecan 130 mg/m2/d intravenously at 21-d intervals with a tumor assessment after 2 cycles. Because of unacceptable toxicity among the first 13 patients, dosing was reduced to docetaxel 40 mg/m2/d and irinotecan 100 mg/m2/d intravenously at 21-d intervals. RESULTS: The response rate for the entire cohort was 26% (95% confidence interval: 14%, 41%) with 12 confirmed partial responses. Five of these 12 responses were observed in patients treated at the higher chemotherapy dose. However, because 8 of 13 patients suffered grade 4 neutropenia and fevers, a dose reduction was incorporated into the protocol, and the remainder of the cohort was treated at the lower dose. All except 4 of the 15 observed grade 4 toxicities occurred at the higher dose, and these toxicities included nausea and vomiting, dyspnea, hypotension, dysrhythmias, and diarrhea in addition to neutropenia and fevers. There were no grade 5 toxicities. The median survival for the entire cohort was 7.3 mo. CONCLUSION: The combination of docetaxel and irinotecan provides modest antineoplastic activity among patients with adenocarcinoma of the esophagus, esophagogastric junction, and gastric cardia. Doses of docetaxel 40 mg/m2/d and irinotecan 100 mg/m2/d at 21-d intervals provide an acceptable safety profile, but higher doses appear to result in unacceptable toxicity.