Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.

BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.

Evaluation of a large-scale donation of Lifebox pulse oximeters to non-physician anaesthetists in Uganda.

Pulse oximetry is widely accepted as essential monitoring for safe anaesthesia, yet is frequently unavailable in resource-limited settings. The Lifebox pulse oximeter, and associated management training programme, was delivered to 79 non-physician anaesthetists attending the 2011 Uganda Society of Anaesthesia Annual Conference. Using a standardised assessment, recipients were tested for their knowledge of oximetry use and hypoxia management before, immediately following and 3-5 months after the training. Before the course, the median (IQR [range]) test score for the anaesthetists was 36 (34-39 [26-44]) out of a maximum of 50 points. Immediately following the course, the test score increased to 41 (38-43 [25-47]); p < 0.0001 and at the follow-up visit at 3-5 months it was 41 (39-44 [33-49]); p = 0.001 compared with immediate post-training test scores, and 75/79 (95%) oximeters were in routine clinical use. This method of introduction resulted in a high rate of uptake of oximeters into clinical practice and a demonstrable retention of knowledge in a resource-limited setting.

Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC. PATIENTS AND METHODS: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1:1. Patients received docetaxel (75 mg/m2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS). RESULTS: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P=0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n=34), outcomes appeared to favor ADP (median OS 19 versus 14 months). CONCLUSIONS: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients.

Sunitinib malate for metastatic castration-resistant prostate cancer following docetaxel-based chemotherapy.

BACKGROUND: Systemic therapy options are limited for metastatic castration-resistant prostate cancer (CRPC) patients who progress following docetaxel (Taxotere). This phase II trial evaluated sunitinib malate in patients with progressing metastatic CRPC following prior docetaxel. PATIENTS AND METHODS: Patients with metastatic CRPC progressing following one to two chemotherapy regimens including docetaxel were included. The primary end point was progression-free survival (PFS) per radiographic and clinical evaluations. Oral sunitinib was administered 50 mg/day 4-weeks on followed by 2-weeks off per cycle up to a maximum of eight cycles or until clinical progression or intolerable toxicity. RESULTS: Thirty-six patients with a median age of 69.5 years were accrued. The median PFS was 19.4 weeks with a 12-week PFS of 75.8%. Four patients (12.1%) had a > or =50% prostate-specific antigen (PSA) decline and seven (21.2%) had a > or =30% PSA decline. Two of 18 patients (11.1%) with measurable disease demonstrated 30% declines by RECIST and eight (44.4%) displayed some shrinkage. A decline in pain score > or =2 points occurred in 13.6% of 22 assessable patients. Drug discontinuation due to toxic effects occurred in 52.8% of patients. CONCLUSION: Sunitinib malate demonstrated promising activity in metastatic CRPC progressing after prior docetaxel.

Mediastinal bronchogenic cyst manifesting as a catastrophic myocardial infarction.

Congenital bronchogenic cysts of the lung and mediastinum develop from the ventral foregut during embryogenesis. These cysts are often incidental radiologic findings in adults, but patients can be seen with symptoms of chest pain, cough, dyspnea, or any combination of these. Acute presentations are unusual and have rarely been reported. We present the unique case of a 36-year-old man seen with an acute coronary syndrome and sudden hemodynamic collapse. The patient sustained a massive and ultimately fatal myocardial infarction, compression of the left main coronary artery by a bronchogenic cyst was demonstrated at postmortem examination. If detected, bronchogenic cysts should be surgically excised to limit associated morbidity and mortality.

Traumatic thoracobiliary fistula.

Thoracobiliary fistulas are a commonly reported complication of subphrenic or liver abscesses and biliary tract obstruction. However, they are a rare and unusual complication of traumatic thoracoabdominal wounds. Due to their rarity, the experience of any one surgeon is minimal, and there is a paucity of information available in the literature regarding their treatment. We describe a case of a traumatic thoracobiliary fistula, review the existing literature, and discuss the proper management of this potentially lethal sequela of trauma.

Comparison of blood reinfusion techniques used during coronary artery bypass grafting.

A comparison of intraoperative autologous blood conservation techniques was carried out in 100 patients undergoing coronary artery bypass grafting. To facilitate comparisons of similar groups, patients were stratified into high-risk and low-risk groups based on the ratio of preoperative bleeding time to preoperative red blood cell volume. Our previous work suggested that patients with an elevated ratio have increased risk of excessive post-operative blood transfusion. We used this ratio to stratify the 100 patients to either the high-risk (39 patients) or low-risk (61 patients) strata. Within each stratum, patients were randomized to one of three groups: no intraoperative autologous blood conservation (control group), infusion of autologous platelet-rich plasma obtained from intraoperative plasmapheresis (PRP group), and infusion of autologous whole blood harvested immediately before cardiopulmonary bypass (whole blood group). Variables of postoperative blood loss and transfusion requirements were measured in each patient. Analysis of variance showed significant differences in blood product transfusions between groups. Patients in the high-risk stratum required significantly more blood product transfusions than those in the low-risk stratum (5.4 +/- 0.7 versus 2.0 +/- 0.6 units per patient; p < 0.001). In the high-risk stratum, PRP patients required significantly less postoperative blood transfusion compared with patients in the high-risk control group (2.9 +/- 2.1 versus 8.1 +/- 2.2 units per patient; p = 0.05). In the low-risk stratum, no intraoperative blood infusion method resulted in significant improvement in postoperative blood use.(ABSTRACT TRUNCATED AT 250 WORDS)

Alternative conduits for coronary revascularization: a novel approach for harvest of the lesser saphenous vein.

Previous use of the greater saphenous vein limits the subsequent availability of conduit for coronary artery bypass grafting (CABG). One readily available alternative conduit is the lesser saphenous vein (LSV). During a 4-year period, 34 LSVs were explored in 23 patients using a novel surgical approach. The incision used for LSV harvest was carried through and deep into the muscular fascia, posterior to the tibia, along the length of the leg, developing a fascial-cutaneous flap. The LSV in all patients was imaged before operation by venous duplex scanning. Important anatomic details were mapped on the patient's leg before surgery using indelible ink. Findings at operation correlated well with the duplex imaging results. Of the 34 LSVs explored 31 were judged usable by the operating surgeon. In eight patients bilateral LSVs were used and in two this vein was the only conduit available. Among patients undergoing LSV harvest there was no operative mortality and minimal operative morbidity related to harvesting. Only one wound infection developed at the incision site. There were no documented cases of deep vein thrombosis. A case-control study was performed in which a control group of 25 patients undergoing CABG without use of the LSV were compared with the 23 who had LSVs harvested; patients in both groups underwent preoperative venous duplex studies. There were no significant differences in operative mortality or morbidity rate between groups (statistical power > 0.8 for these negative observations), suggesting that harvest of the LSV is usually successful when used in conjunction with preoperative venous duplex scanning.(ABSTRACT TRUNCATED AT 250 WORDS)

Pericardial closure without pericardial substitute.

Primary closure of the native pericardium is recommended whenever possible, and pericardial substitutes are advocated when primary closure is not feasible. To avoid foreign material, we have employed a unique method of dissection to allow mediastinal coverage without tension.

Results of a compassionate-use program using intravenous ondansetron to prevent nausea and vomiting in patients receiving emetogenic cancer chemotherapy.

This study reports the effectiveness and side effects of intravenous ondansetron as a single-agent antiemetic therapy for patients receiving emetogenic cancer chemotherapy under a compassionate-use program for patients not enrolled in controlled clinical trials. Patients were > or = 7 years old and had uncontrolled nausea and vomiting or intolerable side effects with standard antiemetics administered with previous cancer chemotherapy. All patients received ondansetron 0.15 mg/kg every 4 hours x 3 daily doses beginning 30 minutes prior to emetogenic chemotherapy. Patients could receive ondansetron for up to 5 consecutive days of chemotherapy. One hundred ninety patients received ondansetron during chemotherapy treatments that were similar to previous cycles of chemotherapy during which the patients had received standard antiemetics (identical chemotherapy or differing only by addition/deletion of chemotherapy agents of low emetogenicity). Chemotherapy regimens included cisplatin (n = 99; 52%), doxorubicin (without cisplatin, n = 52; 27%), and other drugs (n = 39; 21%). Patient experiences with nausea and vomiting and side effects with ondansetron and with previous standard antiemetics were rated on a scale of 1 to 10 (1, did not experience; 10, as bad as could be). On the nausea and vomiting scale, 74% of patients improved on ondansetron relative to standard antiemetics. Mean nausea and vomiting scales were 3.9 for ondansetron and 7.7 for standard antiemetics (P < .001). On the side effects scale, 62% of patients improved with ondansetron. Mean side effect scores were 1.8 for ondansetron and 4.5 for standard antiemetics (P < .001). One hundred nine patients assessed the effect of nausea and vomiting on their quality of life by means of the Functional Living Index-Emesis. On a 100-point scale (100=best quality of life), quality of life scores were 65.5 for ondansetron and 39.5 for standard antiemetics (P < .01). Functional Living Index-Emesis scores were higher for 76% of patients during ondansetron treatment as compared with previous chemotherapy with standard antiemetic regimens. Twenty-eight patients (15%) were withdrawn from the study because of nausea and vomiting. Forty-four patients (23%) experienced other adverse effects (headache, 17 patients; diarrhea, eight patients; all other events occurred in two or fewer patients). Only six patients were withdrawn due to adverse effects. In conclusion, ondansetron therapy resulted in significantly improved control of nausea and vomiting, fewer side effects, and better quality of life than standard antiemetic therapy in the same patients receiving similar chemotherapy regimens.

Predictors of postoperative ventricular dysrhythmias: a multivariate study.

Postoperative ventricular dysrhythmias were studied to document their incidence after coronary bypass grafting and to identify risk factors for their development with the hope of finding a subgroup of patients who might benefit from postoperative, prophylactic drug therapy. One-hundred-nine patients who were undergoing urgent or elective coronary bypass grafting were studied, prospectively. Twenty-five of 109 patients (23%) developed significant postoperative ventricular dysrhythmias that required counter-shock or drug intervention. Seven of eight instances of sustained ventricular tachycardia, the most serious dysrhythmia, occurred within 36 hours of operation. There was no postoperative mortality related to these dysrhythmias. Serious postoperative complications, such as stroke, hemorrhage, or myocardial infarction, were decreased in patients with ventricular dysrhythmias versus those without (8% versus 16%, p = 0.053 for the Fisher's exact test statistic). Univariate statistical analysis was performed using 15 patient variables and revealed that advanced age (p = 0.008 for the unpaired t test), failure to use an internal mammary artery conduit (p = 0.03 for the two-tailed Fisher's exact test), and development of postoperative atrial dysrhythmias (p = 0.02 for the two-tailed Fisher's exact test) were significantly more common in patients with postoperative ventricular dysrhythmias. Variables such as previous myocardial infarction, ejection fraction less than 50%, prolonged operative time, perioperative myocardial infarction, or fewer number of vessels bypassed were not significantly increased in patients with dysrhythmias (the statistical power for these "negative" results was greater than 0.8).(ABSTRACT TRUNCATED AT 250 WORDS)

Pericardial substitutes: a survey.

Many thoracic surgeons have used pericardial substitutes to reduce the risk of reoperation, but there have been few reports of these procedures. Therefore, we used a questionnaire to gather information on experience with use of pericardial substitutes and to document the findings at reoperation. A six-question survey was sent to 2,344 members of The Society of Thoracic Surgeons, requesting surgeons to list their experience with pericardial substitutes and at reoperation in patients with these substitutes in place. Of the 634 surgeons who responded to the survey, 120 reported the insertion of 3,828 pericardial substitutes. Two hundred thirty-six reoperations were reported by 89 surgeons. None of the pericardial substitutes was reported to be completely successful in facilitating reoperation. The experience with polytetrafluoroethylene (PTFE) pericardial substitutes was reported to be significantly more satisfactory than that with all other substitutes (p = 0.0004 by chi-square analysis), but 14% of surgeons who used PTFE said they were dissatisfied at reoperation. Based on the results of this survey, we suggest caution, careful documentation, and long-term follow-up studies before widespread use of pericardial substitutes can be recommended.

Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting.

Thirty-four patients were entered into a non-blinded, randomized study to test the effect of preoperative aspirin ingestion on postoperative blood loss and transfusion requirements after coronary artery bypass grafting. Sixteen patients in the aspirin-treated group had significantly increased chest-tube blood loss 12 hours after operation (1,513 +/- 978 versus 916 +/- 482 ml; p = 0.038). In addition, aspirin users had significantly increased requirements for postoperative packed red blood cells (4.4 +/- 3.5 versus 1.8 +/- 1.3 units; p = 0.014), platelets (1.3 +/- 1.3 versus 0.2 +/- 0.4 six-donor units, p = 0.0049), and fresh-frozen plasma (3.6 +/- 5.0 versus 0.78 +/- 1.6 units; p = 0.042) transfusions. The only patients requiring reoperation for bleeding were in the aspirin-treated group (2 patients). Six patients were not entered into the randomized part of the study because of excessively prolonged post-aspirin bleeding times (greater than 10 minutes). This finding suggests that a subset of patients are particularly sensitive to aspirin and have significantly prolonged bleeding times after aspirin ingestion. We conclude that aspirin ingestion increases postoperative blood loss and transfusion requirements, and we recommend discontinuation of aspirin therapy before cardiac procedures.

Transmission of hepatitis B virus by artificial insemination.

Although the capacity for transmission of hepatitis B infection by semen is well recognized, the potential for transmission by artificial insemination remains theoretical. Currently, screening of semen donors for hepatitis B virus infection is not standard practice. We saw a case of acute viral hepatitis B in a woman following artificial insemination with semen from a donor subsequently found to be positive for hepatitis B surface antigen (HBsAg). Both the donor serum and semen contained HBsAg and hepatitis B e antigen, and the HBsAg subtype was identical to that of the patient. Documentation of hepatitis B virus transmission by artificial insemination indicates that HBsAg screening of semen donors should be routine practice.

Value of cyclophosphamide or melphalan as combined chemotherapy in hormonally unresponsive prostatic carcinoma.

This prospective randomized study in nonhormonally responsive adenocarcinoma of the prostate shows that response rates to melphalan vs cyclophosphamide groups were virtually identical.

Transseptal control of the difficult aortic annulus.

Successful control of the aortic root in extensive erosive endocarditis, with or without mycotic ventricular septal defect, frequently depends on secure prosthetic fixation to the interventricular septum. We describe transseptal suture fixation of aortic root prostheses through a pulmonary infundibular approach and recommend its early use to avoid difficult, often injurious, attempts at septal suture from within the left ventricular outflow tract.

Taurolithocholate increases heme catabolism and alters the clearance of antipyrine in the rat.

Taurolithocholate has been implicated in human cholestatic syndromes. Its action is believed to be due to an alteration in liver plasma membrane composition. To investigate whether other membranes are similarly affected, we studied the effect of taurolithocholate on hepatic heme turnover by means of a new 14CO breath test. Between 2 and 7 h after taurolithocholate administration, 14CO production was significantly increased, suggesting increased heme catabolism. This was substantiated by the finding of a 47% reduction of microsomal cytochrome P450 content 3 h after taurolithocholate administration. There was a reciprocal increase of 50% in heme oxygenase activity, the key enzyme in heme catabolism. To probe the biological significance of these findings, we measured plasma disappearance of propranolol and antipyrine. Clearance of neither propranolol nor antipyrine was altered by acute taurolithocholate administration. Prolonged administration of taurolithocholate, by contrast, decreased metabolic clearance rate of antipyrine by 48%. This was accompanied by a 25% decrease in microsomal cytochrome P450 content. Our findings suggest that taurolithocholate affects composition and function of the smooth endoplasmic reticulum, and that its action is not limited to the liver plasma membrane.

Urea synthesis after protein feeding reflects hepatic mass in rats.

Urea synthesis is an exclusive biosynthetic function of the liver. Since the exact relationship between urea synthesis in vivo and functional liver mass remains unclear, we established an animal model using oral protein loading and measurement of resultant urea synthesis in rats. We studied rats subjected to sham operation, 40% hepatectomy, 66% hepatectomy, portacaval shunt and CCl4-induced cirrhosis. Urea synthesis was calculated as the sum of urinary urea excretion and accumulation of urea in body water during the 6-hr period after oral administration of a casein protein load equivalent to 20 gm per kg body weight. Peak urea synthesis rate in the sham-operated group of rats was 142 +/- 11 mumoles per hr per gm wet liver weight (mean +/- 1 S.D.), 473 +/- 34 mumoles per hr per gm liver protein and 80 +/- 5 mumoles per hr per mg liver DNA. This rate closely matched those of the other groups for each type of liver mass measurement. Marked reduction (p less than 0.01) of urea synthesis on a DNA basis was noted only in the CCl4-cirrhotic livers, related to the significantly higher (p less than 0.01) DNA content of the cirrhotic livers. Similarly, increased (p less than 0.05) liver protein content of the sham-operated rats when compared with the other groups was reflected in slightly lower urea synthesis rates expressed on the basis of liver protein (p less than 0.05) when compared to that of all other groups.(ABSTRACT TRUNCATED AT 250 WORDS)