Comprehensive genome-wide evaluation of lapatinib-induced liver injury yields a single genetic signal centered on known risk allele HLA-DRB1*07:01.

Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.

Case report: overnight hospital stay for minimally invasive bilateral total hip arthroplasty.

Bilateral total hip arthroplasty was performed on a 58-year-old man. He was successfully discharged home from hospital the following morning, 23 hours post surgery. A direct anterior, minimally invasive approach was used which avoided detachment of hip musculature. Preoperative assessment was carried out, with early multidisciplinary team input. Modified anaesthetic techniques with an ambulatory pain pump were employed. Follow-up in the community was carried out by an outreach team. All these factors were important in a successful early supported discharge. We believe this to be the first such case reported.

Pulmonary volume recruitment manoeuvre restores pulmonary compliance and resistance after apnoea in anaesthetized lambs.

BACKGROUND: We studied the effects of an episode of induced apnoea on the dynamic compliance (Crs) and resistance (Rrs) of the respiratory system in anaesthetized lambs and investigated the mechanisms underlying the effectiveness of a timed reexpansion inspiratory manoeuvre (TRIM). METHODS: Following 2 min of apnoea, three manoeuvres were randomly performed: (i) control: reventilated without TRIM using initial settings and gas composition of 30% oxygen in 70% nitrous oxide; (b) T1: TRIM with 30% oxygen in 70% nitrous oxide, followed by reventilation with the initial settings; and (c) T2: preoxygenate with 100% oxygen, apnoea, then TRIM with 100% oxygen, then reventilation with 100% oxygen at the initial settings. The percentage change in Crs and Rrs was calculated at first breath, second breath, 10, 20, 40, 60, 90, 120 and 180 s postapnoea. RESULTS: Mean control decreased 15% and did not return to baseline during the study period. TRIM increased mean Crs in T1 and T2 by 8% and 9%, respectively, at first breath and returned to baseline and did not deteriorate for the remainder of the study period. Mean Rrs in the control group increased 20% and did not return to baseline during the study period. Mean Rrs in T1 and T2 initially increased 17% and 27%, respectively, at first breath and returned to baseline within 40 s. CONCLUSIONS: These results demonstrate that significant deterioration occurs in Crs and Rrs following 2 min of apnoea in anaesthetized lambs, which is not corrected with normal ventilation but is rapidly and completely reversed with a TRIM. This supports our hypothesis that volume recruitment of alveoli is an effective manoeuvre in restoring lung function. The practice of preoxygenation is also reinforced as the lambs maintained maximal oxygen saturation if they were ventilated with 100% oxygen prior to the 2 min of apnoea.

Antenatal betamethasone and favourable outcomes in fetuses with 'poor prognosis' diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a common abnormality affecting 1 in 2,000 gestations. The mortality exceeds 50% despite recent advances in postnatal treatment. The widespread antenatal use of glucocorticoids to induce lung maturation in fetuses at risk of premature delivery suggests a potential for a therapeutic effect in other fetuses with impaired lung development. The parents of three fetuses referred with CDH and features suggesting a poor postnatal prognosis (early diagnosis, liver herniation, and lung area-to-head circumference ratio <1.0, or associated abnormalities) elected to receive maternal betamethasone starting at 24 to 26 weeks' gestation rather than undergo a fetal tracheal plug. All three infants survived and were extubated within 10 days. The long-term use of antenatal steroids in the treatment of CDH may thus be of benefit and warrants further study.

Role of leukocytes in cerebral autoregulation and hyperemia in bacterial meningitis in rabbits.

The effect of leukocytes on regional cerebral blood flow (rCBF) and cerebrovascular autoregulation in experimental meningitis was determined in rabbits. Four groups of animals were studied. Cerebrospinal fluid (CSF) leukocyte migration was prevented in two groups by pretreatment with 1.5 mg/kg of IB4, a monoclonal antibody directed against CD11/18 leukocyte adhesion receptors. Intracisternal inoculation was performed with saline (control and control-IB4 groups) or Haemophilus influenzae type b (Hib and Hib-IB4 groups). Eighteen hours later, rCBF was determined with radiolabeled microspheres. Autoregulation was assessed by graded hemorrhagic hypotension. Compared with untreated meningitis (Hib group), IB4-pretreated meningitis (Hib-IB4 group) was associated with a reduced CSF leukocyte count (1,980 +/- 880 vs. 200 +/- 110 cells/microliter; P < 0.05) and an elevated CSF colony count (2.87 +/- 0.08 vs. 5.63 +/- 0.72 log10colony-forming units/ml; P < 0.05). Compared with control, baseline CBF was elevated in both untreated and IB4-pretreated meningitis (51 +/- 2, 54 +/- 2, 66 +/- 5, and 102 +/- 17 ml.100 g-1.min-1 in control, control-IB4, Hib, and Hib-IB4 groups, respectively). The degree of hyperemia in meningitis was related to the CSF colony count, with a high CBF occurring in animals with high colony counts. During hypotension, CBF remained at or above baseline in the Hib group and both control groups, indicating preservation of cerebrovascular autoregulation in untreated Hib meningitis. In the Hib-IB4 group, the elevated baseline CBF was not maintained during hypotension, falling to 51% of baseline at a cerebral perfusion pressure of 30 mmHg and indicating impairment of cerebrovascular autoregulation. These results suggest that CSF leukocytes are not primarily responsible for the hyperemic response in Hib meningitis. Cerebral hyperemia may be induced either directly by bacterial components or indirectly by components of the inflammatory cascade that precede CSF leukocyte migration.

Advanced breast cancer: a randomized study of doxorubicin or mitoxantrone in combination with cyclophosphamide and vincristine.

BACKGROUND: Drug selection for the treatment of advanced breast cancer is based on both efficacy and toxicity. Combination chemotherapy produces higher response rates than single agents, of which doxorubicin is the most active. This study compares efficacy and toxicity of the drugs doxorubicin and mitoxantrone when used as part of a 3 drug combination. Doxorubicin is the most active agent, but also one of the most toxic, and in this study was compared, in a 3-drug combination, with mitoxantrone with the aim of achieving comparable efficancy with reduced toxicity. PATIENTS AND METHODS: 110 patients with advanced breast cancer previously untreated by chemotherapy were randomized to receive cyclophosphamide and vincristine, together with either doxorubicin 50 mg/m2 i.v. (VAC) or mitoxantrone 10 mg/m2 (VNC) for up to 6 cycles. RESULTS: Of 53 eligible patients randomized to VAC, the overall response rate was 55% (CR rate 17%), while of 55 patients randomized to VNC the overall response rate was 42% (CR rate 7%). The difference is not statistically significant (p = 0.07), but there was a trend towards a higher response rate to VAC in patients aged less than 60, those with nodal and soft tissue disease, and those with 2 or more sites of disease. The principal difference in toxicity was reduced alopecia in favour of VNC. However there was also an increased number of deaths within the first cycle in patients randomized to VAC. There were no differences in survival, relapse free interval, or freedom from progression between the two arms. CONCLUSIONS: Both VAC and VNC are effective regimens in advanced breast cancer. While the confidence limits in this study mean the response rate advantages of VAC could have arisen by chance, younger patients with adverse prognostic factors may warrant consideration of the VAC regimen.

Congenital diaphragmatic hernia: lung compliance after antenatal tracheal obstruction or surgical correction of the defect.

Fetal lambs with diaphragmatic herniae (CDH) created surgically at 73 days' gestation were subjected to three different forms of intrauterine correction: silastic patch correction of the diaphragmatic defect plus an abdominal patch at 101 days gestation; an intrathoracic "silo" at 101 days; and a tracheal "plug" obstruction at 101 or 129 days. At 143 days' gestation (term 145-149 days), the lambs were delivered by caesarean section and ventilated for 30 min before undergoing respiratory compliance measurements. These results were compared to those of normal lambs and animals with uncorrected herniae. The total respiratory system compliance values in those groups undergoing corrections were remarkably similar: those with any form of correction had a significant improvement (P < 0.05) compared to those with herniae and no correction (patch = 1.57 = ± 0.182 ml/cm H2O; silo = 1.53 ± 0.179; plug at 101 days = 1.66 ± 0.311; plug at 129 days = 2.00 ± 0,175; without correction = 0.62 ± 0.073). None, however, reached the values of those with normal lungs: 2.72 ± 0.223 (P < 0.05). This improvement in compliance in all corrected groups suggests that fetal tracheal obstruction is as effective as the two more invasive forms of open fetal surgery carried out in this study and, as this procedure lends itself to surgery through a small uterine incision or "minimally invasive" surgery, it may be the procedure of choice to reduce the incidence of preterm labour for those human fetuses undergoing antenatal correction of a CDH.bb.

Cerebrovascular responsiveness to CO2 in Haemophilus influenzae type b meningitis in rabbits.

The effect of experimental meningitis on regional cerebral blood flow (rCBF), cerebral metabolic rate for oxygen (CMRO2), and cerebrovascular responsiveness to CO2 was determined in pentobarbital-anesthetized rabbits. The animals were inoculated intracisternally with saline (control) or log-phase Haemophilus influenzae type b (Hib). Eighteen hours later rCBF was determined with radiolabeled microspheres at normocapnia, hypocapnia, and hypercapnia. Cerebrovascular responses to hypocapnia and hypercapnia were assessed by calculating the change in cerebrovascular resistance per millimeter mercury change in PaCO2. At all CO2 levels, meningitis (M) was associated with elevated CBF compared with control (C: 47.5 +/- 3.0, M: 60.9 +/- 4.5 ml.100 g-1.min-1 at normocapnia, P < 0.01). Regional differences were present. In forebrain, the hyperemia in meningitis was confined to the superficial cortical grey matter. When compared with control, meningitis was not associated with altered vasoreactivity during hypocapnia (C: -0.026 +/- 0.006, M: -0.026 +/- 0.008 mmHg.ml-1 x 100 g-1.min-1.mmHg PaCO2(-1)) or hypercapnia (C: -0.037 +/- 0.004, M: -0.026 +/- 0.008 mmHg.ml-1 x 100 g.min.mmHg PaCO2(-1)). CMRO2 in meningitis was not significantly different from control (C: 3.53 +/- 0.29, M: 3.51 +/- 0.22 ml O2.100 g-1.min-1). These findings indicate that cerebrovascular responsiveness to CO2 is preserved in experimental Hib meningitis. Furthermore, enhanced CBF together with unchanged CMRO2 indicates that "luxury" cerebral perfusion is present in this model of bacterial meningitis.

A study of cis-platinum and ifosfamide in alkylating agent-resistant ovarian cancer.

Twenty patients with advanced epithelial ovarian carcinoma who had failed alkylating agent treatment were given cisplatin 60 mg/m2 together with ifosfamide 4 g/m2 and mesna 6 g/m2 every 4 weeks for 4-6 cycles. The overall response rate was 45% and the complete response rate 20%. The median time to disease progression was 9 months and 4 of the 9 responding patients are alive at more than 2 years. WHO Grade 3 or 4 myelosuppression was seen in 7 patients, nephrotoxicity in 4, and encephalopathy in 1 patient. Nausea and vomiting of moderate severity (WHO Grade 3) was seen in the majority of patients. While a dose escalation of 25% of both drugs was possible in 4 patients, myelosuppression became limiting at the higher dose. The combination of cisplatin and ifosfamide is effective in relapsed ovarian cancer even in this group of patients with heavy pretreatment.

Antibiotic resistance in the tropics. 3. Medical responsibilities of the pharmaceutical industry with respect to use of antibiotics in the tropics.

The pharmaceutical industry has three major medical responsibilities: the efficacy and safety of its products, the accuracy of the statements it makes about them, and the provision to governments and health workers of full and proper information concerning these products. The development of new antibiotics is very costly, and their provision to Third World countries alone can never be financially rewarding; furthermore, only about 20% of world-wide pharmaceutical sales are to Third World countries. The industry's interest in developing drugs for exclusive or major use in such countries is declining. However, support from industry for the World Health Organization's action programme on essential drugs is growing, and this should help to provide drugs more cheaply to the poorer countries of the world.

Sequential cisplatin/cyclophosphamide chemotherapy and abdominopelvic radiotherapy in the management of advanced ovarian cancer.

Forty-six previously untreated patients with advanced ovarian cancer were treated with combination chemotherapy comprising cisplatin 80 mg m-2 i.v. and cyclophosphamide 1 gm-2 i.v. every 28 days for 5 cycles. Eighty-five percent of patients received more than 75% of the calculated doses, and of 43 evaluable patients, a complete response was achieved in 31 (72%), a partial response in 4 (9.3%) and 8 patients had static or progressive disease. The actuarial survival of the whole group is 60% at a median follow-up of 2 years. Twenty-four patients in complete clinical or pathological remission were then treated with whole abdominal radiotherapy 2,500 cGy followed by a pelvic boost of 2,000 cGy. The pelvic boost was omitted in 3 patients, and the overall radiotherapy treatment time extended in a further 4 patients on account of myelosuppression. The actuarial survival of the 24 patients receiving both treatments at a median of 30 months follow-up is 75%. In the 10 patients with negative second-look procedures completing both treatments there have been no tumour related deaths at a median follow-up of 33 months.

Haemodynamic changes and left ventricular performance during high-dose oestrogen administration to male transsexuals.

Serial haemodynamic and systolic time interval measurements in 17 male transsexuals during high-dose oestrogen administration were compared with control values obtained after oestrogen withdrawal. During oestrogen treatment, cardiac output, stroke volume, plasma volume and total blood volume increased while total peripheral resistance, diastolic blood pressure and red cell mass decreased significantly. Changes in heart rate and systolic blood pressure were not significant. Despite a much higher dose of oestrogen, the haemodynamic changes observed in this study are similar in magnitude to those occurring in women taking oral contraceptives. Significant changes in systolic time intervals during oestrogen treatment were a shortened pre-ejection period (PEP) index, a prolonged left ventricular ejection time (LVET) index and a decreased PEP/LVET ratio indicating that left ventricular performance was augmented.

Alopecia in calves associated with milk substitute feeding.

Outbreaks of alopecia with unusually high morbidity occurred among calves reared on milk substitutes on two unrelated farms in Suffolk. On one farm alopecia occurred for three consecutive years; during the winter of 1981-82 there were also clinical signs of muscular dystrophy among the same calves. On the second farm calves with alopecia also showed signs of muscular dystrophy. The apparent relationship between alopecia and milk substitute feeding is discussed together with the possible involvement of vitamin E.

Human lymphoblastoid interferon in the treatment of small cell lung cancer.

Ten patients with small cell lung cancer were treated with high dose human lymphoblastoid interferon (50-100 megaunits m-2) for 5 days, followed by low dose interferon (3 megaunits m-2) for 3 weeks. At the end of treatment, and one month later, there was no evidence of either complete or partial response. The treatment produced fever, anorexia and weight loss, with transient leucopenia and thrombocytopenia; there was evidence of a non-cholestatic elevation of serum alanine aminotransferase, with clinical deterioration in the condition of three patients presenting with hyponatraemia. A transient hypocalcaemia during high dose therapy was also noted. It seems that lymphoblastoid interferon as a single agent is unlikely to have a role in the treatment of small cell lung cancer, and that its administration as employed in this study is associated with considerable toxicity.

The investigation and treatment of germ cell tumours of the testis.

Fifty-five per cent of patients presenting with testicular tumours in 1973--78 had teratomata. A history of undescended testis was only found in patients with seminoma. The right testis was the more frequent site of the primary. Radiation doses of 3400 cGy (rad) in 20 fractions for seminoma and 4500 cGy in 25 fractions for teratoma were well tolerated and sterilised microscopic disease in the majority of patients. Forty-two of 44 seminoma patients are alive and free from disease at a median follow-up of three years. Only 15 of 22 Stage I teratoma patients remain disease free, however. A combination of vinblastine and bleomycin produced 12 complete remissions in 30 patients with metastatic teratoma. Survival was significantly longer for patients achieving complete remission. Although six of the complete responders remain alive, only three are in their initial complete remission. Alpha-foeto-protein and/or beta-subunit human chorionic gonadotrophin levels were elevated in almost all cases of advanced teratoma. The biological half-life of alpha-foeto-protein in the serum is less than six days. The value of these markers in predicting relapse was limited in this series. The doubling of complete response rate in metastatic teratomata that can be achieved by adding cis-platinum to the vinblastine/bleomycin combination, together with the propensity for extranodal metastasis shown by testicular teratomata, suggest that adjuvant chemotherapy should be explored in early disease.

The immunotherapy of acute myelogenous leukaemia using intravenous BCG.

In a 2-year period, 37 of 81 adults with acute myelogenous leukaemia achieved complete remission after repeated courses of Daunorubicin (DNR) and Cytosine Arabinoside (ARAC). They were randomized to maintenance treatment with monthly DNR/ARAC, or to identical chemotherapy plus intravenous BCG. Eighteen BCG treated patients had significantly longer survival times than 19 patients treated with chemotherapy only although no statistically significant difference can be seen in the remission duration of the two groups. Eleven patients in the BCG treated group who have relapsed, have received DNR/ARAC reinduction and five second and two third remissions have been obtained. Twelve control group patients have relapsed and 10 have received further reinduction treatment with DNR/ARAC but only one patient has entered a complete remission. Seven patients in the BCG treated group who survived for 75 weeks or more (76, 76, 96, 124, 125, 138 and 145 weeks) were either PPD positive before treatment or converted to PPD positivity after BCG treatment. Using a battery of skin tests it may be possible to define a good prognostic group of patients and design future treatment accordingly. The BCG group had a total of 198 intravenous treatments. All patients had pyrexia 6-12 h after injection lasting 12-72 h and occasionally headaches and muscle pains. Two patients had non-fatal anaphylactic reactions which did not recur when BCG was subsequently re-administered. Other complications of BCG therapy were not a problem and we have not needed to withdraw treatment for any patient.

Granuloma formation in patients receiving BCG immunotherapy.

Eleven patients with acute myeloblastic leukaemia have received repeated intravenous injections of BCG containing 4-9 X 10(6) live organisms per millilitre. Non-caseating epithelioid granulomas, sometimes with giant-cell formation, have been demonstrated in eight bone marrow aspirates. Seven patients had granulomas in the liver, three in the lung, one in the spleen, one in lymph nodes, and one in a skin biopsy. One patient had a raised serum alkaline phosphatase, but none of the patients had any illness which could be related to the presence of granulomas. Granuloma formation appeared more extensive in four patients who were probably anergic before BCG treatment. Until the significance of this finding becomes clear great care should be taken when giving BCG by the intratumour of intravenous routes to potentially immunoincompetent patients.