A preliminary evaluation of two different meshes in minimally invasive inguinal hernia surgery.

BACKGROUND: Many meshes are available for use in laparoscopic inguinal hernia repair. The surgeon must consider several factors when choosing a mesh for hernia repair including clinical outcomes, cost, and ease of use. The purpose of this study was to compare two different lightweight polypropylene meshes for laparoscopic and robotic inguinal hernia repairs. METHODS: Subjects were randomized immediately before surgery. Data were reported in N (%) and median [Q1-Q3], comparisons of mesh insertion time were tested using a 2 × 2 ANOVA on the ranked times, comparisons between categorical variables were tested with Fisher's Exact, and all data were analyzed using SAS® 9.4 (SAS Institute, Inc.). RESULTS: Between January 2015 and June 2016, 50 subjects were enrolled; two were excluded. Of 48 eligible subjects, most were Caucasian (N = 42, 88%), male (N = 37, 77%), with a median age of 63, and were randomized evenly between 3DMax™ mesh and Ultrapro® mesh. Robotic mesh placement significantly increased insertion time regardless of mesh type (p < .0001). When comparing NASA-TLX self-assessment surveys, there was no significant difference between the meshes in difficulty of placement. The type of mesh did not significantly impact the insertion time regardless of robot use (p = 0.523). CONCLUSION: Our data demonstrate that mesh insertion times comparing two different lightweight polypropylene meshes were not significantly different. Increased insertion times associated with robotic repair are likely due to the mechanics of robotic suturing and associated learning curve. Our data suggest that these meshes can be used interchangeably based on the surgeon's preference. CLINICAL TRIAL REGISTRATION NUMBER: NCT01825187.

A Preliminary Assessment of Abdominal Wall Tension in Patients Undergoing Retromuscular Hernia Repair.

A common technique for ventral and incisional hernia repair is the retrorectus repair (Rives-Stoppa). The posterior rectus sheath is incised bilaterally, and mesh is placed retromuscularly. There is little information on how this component separation technique affects abdominal wall tension. We evaluated abdominal wall tension in patients undergoing retrorectus repair of abdominal wall hernias. Patients undergoing retrorectus repair of their ventral hernias were enrolled in a prospective, Institutional Review Board-approved protocol to measure abdominal wall tension from 8/1/2013 to 8/2/2017. Demographic information and operative details were documented. Abdominal wall tensions were measured using scales attached to Kocher clamps that were clamped to the fascia and brought together in the midline. Measurements were made before and after incising the posterior rectus sheaths. Data were analyzed with a repeated measures analysis of variance (ANOVA), and differences between individual groups were analyzed by least square differences. Forty-five patients had tension measurements. Average age was 58 years (range 29-81)-78% Caucasian, 51% female, an average body mass index (BMI) of 35 kg/m2 (range 20-62), and 38% recurrent hernias. The average hernia defect was 121.9 cm2, and the average mesh size was 607.8 cm2. There was a significant reduction in tension after bilateral posterior rectus sheath incision (3.1 lbs vs. 5.6 lbs, p<0.0001). In this evaluation, abdominal wall tension measurements are shown to be a feasible adjunct during open hernia repair with retrorectus repair. Transection of the posterior rectus sheath decreases tension during hernia repair and may help guide surgeons regarding when to use this procedure.

A phase 1 study of KOS-862 (Epothilone D) co-administered with carboplatin (Paraplatin®) in patients with advanced solid tumors.

PURPOSE: To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m(2))/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3 + 3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. RESULTS: Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m(2) + carboplatin AUC = 6. CONCLUSIONS: The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations.

Comparison of risk-adjusted 30-day postoperative mortality and morbidity in Department of Veterans Affairs hospitals and selected university medical centers: vascular surgical operations in women.

BACKGROUND: Women with peripheral vascular disease requiring vascular operations are less well studied than their male counterparts. The surgical outcomes of female vascular patients in the Department of Veterans Affairs (VA) and private sector hospitals have not previously been compared, and their preoperative risk profile, postoperative morbidity, and mortality need to be better elucidated. STUDY DESIGN: Patients undergoing vascular operations at 14 private sector and 128 VA hospitals, from October 2001 through September 2004, had their preoperative characteristics, operative data, and 30-day postoperative morbidity and mortality compared, as part of the Patient Safety in Surgery (PSS) Study. Logistic regression analysis was performed to develop predictive models for morbidity and mortality, which allowed for a comparison of risk-adjusted outcomes between the two hospital groups. RESULTS: There were 458 vascular surgical operations performed in women in the VA, and 3,535 vascular operations were performed in women in the private sector. Eighteen of 45 preoperative comorbidities and laboratory variables differed considerably between the institutions, and 16 of 18 were adverse among the private sector patients. The unadjusted 30-day mortality rate was higher in the private sector compared with the VA (5.2% versus 2.4%, p=0.008); the unadjusted morbidity rate was higher in the private sector compared with the VA sector (23.4% versus 13.3%, p < 0.0001). After risk adjustment, there was no marked difference between the VA and the private sector in mortality (p=0.12), but the difference in morbidity rates remained pronounced, with an odds ratio of 0.60 for VA versus private sector (95% CI=0.44, 0.81). CONCLUSIONS: Compared with their VA counterparts, women undergoing vascular operations at private sector hospitals had a higher incidence of preoperative comorbidities; after risk adjustment, mortality did not differ substantially. Despite risk adjustment, the incidence of postoperative morbidity in the VA patients was considerably lower, suggesting unidentified differences in the hospital populations, their processes of care, or both.

Multivariable predictors of postoperative respiratory failure after general and vascular surgery: results from the patient safety in surgery study.

BACKGROUND: Postoperative respiratory failure (RF) is associated with an increase in hospital morbidity, mortality, cost, and late mortality. We developed and tested a model to predict the risk of postoperative RF in patients undergoing major vascular and general surgical operations. This model is an extension of an earlier model that was derived and tested exclusively from a population of male patients from the Veterans Affairs National Surgical Quality Improvement Program. METHODS: Patients undergoing vascular and general surgical procedures at 14 academic and 128 Veterans Affairs Medical Centers from October 2001 through September 2004 were used to develop and test a predictive model of postoperative RF using logistic regression analyses. RF was defined as postoperative mechanical ventilation for longer than 48 hours or unanticipated reintubation. RESULTS: Of 180,359 patients, 5,389 (3.0%) experienced postoperative RF. Twenty-eight variables were found to be independently associated with RF. Current procedural terminology group, patients with a higher American Society of Anesthesiologists classification, emergency operations, more complex operation (work relative value units), preoperative sepsis, and elevated creatinine were more likely to experience RF. Older patients, male patients, smokers, and those with a history of congestive heart failure or COPD, or both, were also predisposed. The model's discrimination (c-statistic) was excellent, with no decrement from development (0.856) to validation (0.863) samples. CONCLUSIONS: This model updates a previously validated one and is more broadly applicable. Its use to predict postoperative RF risk enables the study of preventative measures or preoperative risk adjustment and intervention to improve outcomes.

Comparison of risk-adjusted 30-day postoperative mortality and morbidity in Department of Veterans Affairs hospitals and selected university medical centers: vascular surgical operations in men.

BACKGROUND: In response to a Congressional mandate to compare risk-adjusted surgical outcomes from Department of Veterans Affairs (VA) hospitals with those from private-sector hospitals, the National Surgical Quality Improvement Program was initiated in the VA system and then was developed in a select group of university medical centers in the private sector. This article analyzes risk-adjusted outcomes after vascular surgical operations in men performed at VA hospitals as compared with private-sector hospitals. STUDY DESIGN: This is a prospective cohort study of a sample of vascular surgical operations in men performed at 128 VA medical centers as compared with 14 university medical centers from October 1, 2001 to September 30, 2004. Patient and operative characteristics, and both unadjusted and risk-adjusted 30-day postoperative morbidity and mortality outcomes were compared. RESULTS: Data from 30,058 vascular operations in men at VA hospitals were compared with 5,174 cases performed at private-sector hospitals. The unadjusted 30-day mortality rate was notably lower in the VA system as compared with the private-sector group (3.4% versus 4.2%, p = 0.004). After risk-adjustment, there was no marked difference in mortality between the two hospital types. The unadjusted 30-day morbidity rate was also considerably lower in the VA hospitals as compared with the private sector (17.3% versus 22.3%, p < 0.0001). After risk-adjustment, morbidity in the VA system remained considerably lower than in the private sector, with an odds ratio of 0.84 (95% CI, 0.78 to 0.92). CONCLUSIONS: In vascular surgical operations in men, the VA hospitals demonstrated a lower risk-adjusted 30-day morbidity rate than the private-sector group. There is no marked difference in adjusted mortality rates between the two types of institutions.

T-Coupler: a method of in situ coupling of plate-plate and rod-plate: a technical report.

BACKGROUND CONTEXT: With the existing VSP plate using "no-cut," or low profile screws, with a 5-mm spacer on the screw, it is difficult or impossible to stack a second plate onto the existing in situ plate. In order to extend a fusion above or below, the plate must be explanted and replaced with a longer plate. PURPOSE: Situations exist where it would be advantageous to leave an existing plate in situ and couple a second plate onto the existing plate. A new device is described for in situ coupling of a plate to plate and a rod to plate using the VSP and lsola systems. STUDY DESIGN: A T-Coupler was designed to permit coupling of plate-to-plate and rod-to-plate. The T-Coupler was implanted into patients who were prospectively followed clinically and radiographically for a minimum of 2 years. PATIENT SAMPLE: Seventeen patients were selected who were deemed candidates for the above procedure. In each case, the patient had an existing fusion with Steffee plate and required extension of the fusion above or below the existing plate. OUTCOME MEASURES: The patients were followed clinically and radiographically for a minimum 2 years. METHODS: After obtaining FDA 510K clearance and appropriate mechanical testing, the T-Coupler was implanted into patients who were deemed appropriate candidates. In each case the patient had an existing fusion with a Steffee plate and required an extension of the fusion above or below. The patients were followed with anterior-posterior and flexion/extension lateral films every 3 months for 2 years and then every 6 months. The patient's clinical progress was also evaluated. RESULTS: The T-Coupler was used in 18 operations in 17 patients with a minimum follow-up of 24 months, an average follow-up of 49.6 months with a range of 24 to 84 months. Three patients underwent reexploration with direct visualization of the T-Coupler. There was no evidence of loosening or breakage, and radiographically all patients went on to solid fusions. CONCLUSIONS: The T-Coupler is a safe and effective device for the stacking of plates or rods onto an existing plate in selected patients. The T-Coupler may improve patient care by reducing the need to explant long constructs thereby reducing operating time, blood loss, and risk of infection.

Clinical and economic outcomes of multivessel coronary stenting compared with bypass surgery: a single-center US experience.

BACKGROUND: Randomized trials comparing multivessel stenting with coronary artery bypass surgery (CABG) have demonstrated similar rates of death and myocardial infarction but higher rates of repeat revascularization after stenting. The impact of these alternative strategies on overall medical care costs is uncertain, particularly within the US health care system. METHODS: We performed a retrospective, matched cohort study to compare the clinical and economic outcomes of multivessel stenting and bypass surgery. The stent group consisted of 100 consecutive patients who underwent stenting of >or=2 major native coronary arteries at our institution. The CABG group consisted of 200 patients who underwent nonemergent isolated bypass surgery during the same time frame, matched (2:1) for age, sex, ejection fraction, diabetes mellitus, and extent of coronary disease. Detailed clinical follow-up and resource utilization data were collected for a minimum of 2 years. Total costs were calculated by use of year 2000 unit prices. RESULTS: Over a median follow up period of 2.8 years, there were no significant differences in all-cause mortality rates (3.0% vs 3.0%), Q-wave myocardial infarction (5.1% vs 4.0%), or the composite of death or myocardial infarction (7.1% vs 7.0%) between the stent and CABG groups (P = not significant for all comparisons). However, at 2-year follow up, patients with stents were more likely to require >or=1 repeat revascularization procedure (32.0% vs 4.5%, P <.001). The initial cost of multivessel stenting was 43% less than the cost of CABG (11,810 dollars vs 20,574 dollars, P <.001) and remained 27% less (17,634 dollars vs 24,288 dollars, P =.005) at 2 years. CONCLUSIONS: Multivessel stenting and CABG result in comparable risks of death and myocardial infarction. Despite a higher rate of repeat revascularization, multivessel stenting was significantly less costly than CABG through the first 2 years of follow-up.

Internal thoracic artery flow competition: studies in a canine H-graft model.

OBJECTIVE: Internal thoracic artery (ITA) flow competition is a diversion of graft flow through intact ITA branches with a net decrease in perfusion to the grafted coronary. Although a widely acknowledged phenomenon, the conditions under which flow competition occurs have not been established. This is examined in a canine H-graft model. METHODS: Eight dogs had a right ITA segment interposed (H-graft) between their in situ left ITA (LITA) and the snared left anterior descending (LAD) coronary artery. Proximal LITA and H-graft flows were measured at baseline and during pacing-induced tachycardia, phenylephrine-induced hypertension, and nitroprusside-induced hypotension. Flows were measured with the distal LITA open and occluded. Two additional animals were subjected to eight separate 2-min periods of LAD ischemia, after which post-ischemic H-graft flow measurements were obtained with and without distal LIMA occlusion. RESULTS: During baseline conditions, proximal LITA flow was greater when the distal LITA was open rather than occluded (46+/-15 versus 35+/-12 ml/min, respectively; P=0.002), but H-graft flow did not change significantly (32+/-18 versus 35+/-18 ml/min, respectively; P=0.21). Similarly, occlusion of the distal LITA had no impact on H-graft flow during tachycardia, hypertension, or hypotension. Only in animals subjected to transient LAD ischemia did H-graft flow increase with distal LITA occlusion, albeit marginally (65+/-7-70+/-9 ml/min, occluded versus open, respectively; P=0.04). CONCLUSIONS: Mild diversion of flow from the LAD was demonstrated during immediate post-ischemic coronary reperfusion only, and could not be elicited under any other physiologic condition. These data suggest that flow competition is unlikely to constitute a clinically significant limitation to the use of H-grafts or other modalities that leave ITA branches patent.

Cardiac surgery in the newborn: improved results in the current era.

Pediatric cardiovascular surgeons can now safely operate on newborns to palliate or completely correct congenital heart defects in babies as small as 1.5-2.0 kilograms. The various cardiac anomalies treated can be categorized with respect to their dependency on a patent ductus arteriosus for systemic or pulmonary blood flow. The early results are directly linked to the complexity of the congenital defect, but are generally good so long as the intervention can provide two functional ventricular chambers. Although great strides have been made, continued progress in the treatment of neonates with congenital heart defects remains challenging and requires the collaborative effort between pediatricians, perinatologists, neonatologists, interventional cardiologists, pediatric cardiovascular surgeons and intensive care unit nurses.

Bone marrow concentrate with allograft equivalent to autograft in lumbar fusions.

STUDY DESIGN: Prospective randomized study. OBJECTIVE: To compare autologous bone marrow concentrate mixed with allograft cancellous bone to iliac crest autograft in lumbar fusions. SUMMARY OF BACKGROUND DATA: Bone marrow has been shown to be a rich source of osteoprogenitor cells. Osteoprogenitor cells have been shown in animals, and some human studies, to have potential in use as a bone graft substitute. METHODS: Twenty-five patients underwent from 1- to 3-level lumbar fusions. One patient was lost to follow-up. On one half of the spine, allograft plus autologous bone marrow concentrate was used, whereas on the other half, autologous iliac crest bone was used. Cellular analysis, consisting of nucleated cell count, mononuclear cell count, CD34+ count, and colony-forming-units-fibroblast count, was done on marrow aspirates and concentrates. At 1 year postoperation, computed tomographic scans of the fusions were evaluated on a blinded basis by 2 neuroradiologists independent of each other. Radiographical fusion was the primary outcome measure. RESULTS: There was no statistical difference in fusion scores between allograft and autograft in the lateral gutters, interbody cages, or facet joints. There was a positive trend between CD34+ counts and radiographical fusion. CONCLUSION: The study shows equivalence between cancellous allograft mixed with bone marrow concentrate and autologous iliac crest bone for lumbar fusions. LEVEL OF EVIDENCE: 2.

Phase I dose escalation study of KOS-1584, a novel epothilone, in patients with advanced solid tumors.

PURPOSE: First-in-man study of KOS-1584, a second generation epothilone. METHODS: Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized. RESULTS: Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m(2). Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m(2). At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m(2), 327 ± 161 L/m(2), and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m(2). Two patients achieved partial responses and 24 patients had stable disease (SD). CONCLUSIONS: The RP2D of KOS-1584 is 36 mg/m(2). The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.

Selective use of left heart bypass for aortic coarctation.

BACKGROUND: We evaluated left heart bypass (LHB) for spinal cord protection during aortic coarctation repair in patients with mild (primary, postsurgical, or intervention) and complex coarctation. METHODS: Between 1990 and 2008, 19 patients (mean age, 21 years; weight, 70 +/- 16 kg) using LHB were compared with 27 patients (mean age, 16 years; weight, 65 +/- 8 kg) undergoing coarctation repair without LHB (non-LHB). Follow-up was similar (LHB, 5 +/- 4 vs non-LHB 4 +/- 3 years; p = 0.81). RESULTS: Cohorts were similar in age and body surface area. No non-LHB patient lost somatosensory evoked potential or had a femoral artery pressure below 45 mm Hg with test clamping. LHB more often allowed graft interposition (18 of 19 [95%] vs non-LHB, 7 of 27 [26%]; p < 0.003) and a longer clamp time (LHB 44 +/- 16 vs non-LHB 31 +/- 12 minutes p < 0.003) without spinal cord ischemia. Two non-LHB patients had temporary spinal cord paresis. No early or late deaths occurred. Reintervention (LHB, 2 of 19 [11%] vs non-LHB, 2 of 27 [7%]; p = 0.82) and antihypertensive requirements were similar (LHB, 9 of 19 [40%] vs non-LHB, 8 of 27 [30%]; p = 0.35). The late peak transcoarctation gradient was 8 +/- 6 mm Hg in the LBH cohort vs 18 +/- 11 mm Hg in non-LBH patients (p= 0.001). CONCLUSIONS: Although the adequacy of spinal cord collateral assessment in coarctation repair is imperfect, no spinal cord ischemia occurred with coarctation repair and LHB. We recommend LHB in patients with mild or complex coarctation.

Depression increases risk of incident myocardial infarction among Veterans Administration patients with rheumatoid arthritis.

OBJECTIVE: This study evaluates whether depression is a risk factor for incident myocardial infarction (MI) in Department of Veterans Affairs (VA) patients with rheumatoid arthritis (RA) between 30 and 79 years of age. METHODS: We used a retrospective cohort study of 15,634 patients with RA. Diagnoses and sociodemographic data were obtained from VA administrative and pharmacy databases between fiscal years 1999 and 2006. Entry into the cohort required 2 years of patient time with no evidence of cardiovascular disease. Cox proportional hazard models with time-dependent covariates were computed to determine whether RA patients with depression as compared to RA patients without depression were at increased risk for MI during the maximum 6-year follow-up period. RESULTS: Unadjusted analyses indicated depressed RA patients were 1.4 times more likely than nondepressed RA patients to have an MI during follow-up. These results remained significant (HR=1.4; 95% CI: 1.1-1.8) in the adjusted Cox proportional hazards model which included the effects of sociodemographics and known physical risks (e.g., diabetes) for MI. CONCLUSIONS: Depressed RA patients, without a history of cardiovascular disease, are 40% more likely to have a heart attack as compared to those without depression. These data demonstrate a rapid (within 6 years) transition to MI following onset of depression in RA patients. Increased monitoring of depression and heart disease status in this patient population may be warranted which in turn may result in longer duration of life.

Preoperative noncontrast chest computed tomography identifies potential aortic emboli.

BACKGROUND: Intraoperative epiaortic scanning identifies aortic atheroma. Avoiding atheroma manipulation reduces cerebral vascular accidents (CVA). Unfortunately, epiaortic scanning can only be performed after the time of sternotomy. We sought to determine whether (1) preoperative noncontrast chest computed tomography (CT) identifies areas of aorta at risk for embolization in high-risk patients, and (2) operative strategies designed at the reduction of aortic manipulation of these areas can reduce permanent strokes. METHODS: The rate of permanent strokes was examined at a single institution between two time periods using the chi2 method. From January 2002 through June 2003 (pre-CT) 230 patients underwent elective cardiac procedures. All patients received routine intraoperative transesophageal echocardiography but only selective epiaortic scanning. From July 2003 through December 2005 (post-CT), 273 patients underwent cardiac operations and 114 patients at high risk for a stroke (history of CVA or transient ischemic attack, peripheral vascular disease, end-stage renal disease, age >70 years old or calcifications on cardiac catheterization) also received a preoperative noncontrast chest CT. RESULTS: In the pre-CT period, 7 patients received epiaortic scans that resulted in a change in operative strategy in only 1 patient. In the post-CT period, the 114 CT scans identified 20 patients with significant calcifications in the ascending aorta. Operative strategy was altered in 19 patients, including 12 axillary artery cannulations, four off-pump, no-touch aorta coronary bypasses, and three ascending aortic replacements. The CVA rate was 3.04% in the pre-CT period and 0.73% in the post-CT period (p = 0.05). CONCLUSIONS: Aggressive screening and avoidance of ascending aortic atheroma reduces stroke. Preoperative CT scans in patients at high risk may help identify aortic areas at risk before entering the operating room, lead to more thorough screening in the operating room, and result in a more aggressive strategy to avoid calcified areas.

Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer: a phase I dose-escalation study.

PURPOSE: This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes. PATIENTS AND METHODS: Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels. RESULTS: Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease > or = 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. CONCLUSION: Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.

Comparison of angioplasty and surgery for neonatal aortic coarctation.

BACKGROUND: The efficacy of balloon dilatation as primary treatment for neonatal aortic coarctation remains controversial. METHODS: A retrospective comparison between balloon angioplasty and surgery for the treatment of neonatal aortic coarctation was undertaken on 57 neonates younger than 40 days of age (angioplasty, 23 patients; surgery, 34 patients) treated between 1994 and 2004. RESULTS: Cohorts were similar with respect to the preinterventional variables of age, weight, upper extremity systolic blood pressure, coarctation gradient, degree of aortic arch hypoplasia, associated conditions, and mean follow-up (angioplasty, 36 months; surgery, 38 months). Among the angioplasty group, 13 patients (57%) required surgery, and 8 required a second balloon dilatation, of whom 3 patients had an aortic aneurysm. Among the surgery cohort, 6 patients experienced recurrence (18%) after either SFA (3) or XETE anastomosis repair (3). All were successfully treated with balloon angioplasty. Actuarial freedom from any intervention was significantly greater in the surgery cohort as was the degree of aortic arch growth. At latest follow-up, antihypertensive medication was required in 3 of 9 angioplasty patients (33%) and 2 of 27 surgery patients (7%). No repeat intervention was required in the 13 patients who underwent angioplasty followed by surgery. CONCLUSIONS: Primary angioplasty is palliative treatment for neonatal aortic coarctation, but it is the treatment of choice for recurrence after surgery. Surgery for neonatal aortic coarctation is associated with fewer reinterventions, improved aortic arch growth, no aortic aneurysm formation, and decreased need for antihypertensive medication when compared with neonates treated primarily with balloon angioplasty.