Laboratory tumor lysis syndrome complicating LBH589 therapy in a patient with acute myeloid leukaemia.

LBH589 is a novel cinnamic hydroxamic acid analog (HAA) pan-histone deacetylase inhibitor (HDACi) currently in early phase clinical development.

Insect renal tubules constitute a cell-autonomous immune system that protects the organism against bacterial infection.

Innate immunity is a widespread and important defence against microbial attack, which in insects is thought to originate mainly in the fat body. Here we demonstrate that the fluid-transporting Malpighian (renal) tubule of Drosophila melanogaster constitutes an autonomous immune-sensing tissue utilising the nitric oxide (NO) signalling pathway. Reverse transcriptase PCR (RT-PCR) shows that tubules express those genes encoding components of the Imd pathway. Furthermore, isolated tubules bind and respond to lipopolysaccharide (LPS), by upregulating anti-microbial peptide (diptericin) gene expression and increased bacterial killing. Excised, LPS-challenged tubules, as well as tubules from LPS-infected flies, display increased NO synthase (NOS) activity upon immune challenge. Targetted expression of a Drosophila NOS (dNOS) transgene to only principal cells of the tubule main segment using the GAL4/UAS system increases diptericin expression. In live flies, such targetted over-expression of dNOS to tubule principal cells confers increased survival of the whole animal upon E. coli challenge. Thus, we describe a novel role of Malpighian tubules in immune sensing and insect survival.

Ephrin-as cooperate with EphA4 to promote trunk neural crest migration.

Trunk neural crest cells delaminate from the dorsal neural tube and migrate on two distinct pathways: a dorsolateral route, between the ectoderm and somites,and a ventromedial route, through the somitic mesoderm. Neural crest cells that migrate ventromedially travel in a segmental manner through rostral half-somites, avoiding caudal halves. Recent studies demonstrate that various molecular cues guide the migration of neural crest cells, primarily by serving as inhibitors to premature pathway entry orby preventing neural crest from entering inappropriate territories. Trajectories of migrating trunk neural crest are well organized and generally linear in nature, suggesting that positive, migration-promoting factors may be responsible for this organized cell behavior. However, the identity of these factors and their function are not well understood. Here we examine the expression of members of the EphA subclass of receptor tyrosine kinases and ephrins using RT-PCR and immunocytochemistry. Neural crest cells express ephrins and EphA4 at distinct stages during their migration. In functional analyses, addition of ephrin-A2-, ephrin-A5-, and EphA4-Fc disrupted the segmental organization of trunk neural crest migration in explants: neural crest cells entered rostral and caudal halves of somites. Finally, to test the specific effects of these factors on cell behavior, neural crest cells were exposed in vitro to substrate-bound EphA and ephrin-As. Surprisingly, neural crest cells avoided ephrin-A2 or ephrin-A5 substrates; this avoidance was abolished by the addition of EphA4. Together, these data suggest that ephrin-As and EphA4 cooperate to positively promote the migration of neural crest cells through rostral half somites in vivo.

Spinal motor axons and neural crest cells use different molecular guides for segmental migration through the rostral half-somite.

The peripheral nervous system in vertebrates is composed of repeating metameric units of spinal nerves. During development, factors differentially expressed in a rostrocaudal pattern in the somites confine the movement of spinal motor axons and neural crest cells to the rostral half of the somitic sclerotome. The expression patterns of transmembrane ephrin-B ligands and interacting EphB receptors suggest that these proteins are likely candidates for coordinating the segmentation of spinal motor axons and neural crest cells. In vitro, ephrin-B1 has indeed been shown to repel axons extending from the rodent neural tube (Wang & Anderson, 1997). In avians, blocking interactions between EphB3 expressed by neural crest cells and ephrin-B1 localized to the caudal half of the somite in vivo resulted in loss of the rostrocaudal patterning of trunk neural crest migration (Krull et al., 1997). The role of ephrin-B1 in patterning spinal motor axon outgrowth in avian embryos was investigated. Ephrin-B1 protein was found to be expressed in the caudal half-sclerotome and in the dermomyotome at the appropriate time to interact with the EphB2 receptor expressed on spinal motor axons. Treatment of avian embryo explants with soluble ephrin-B1, however, did not perturb the segmental outgrowth of spinal motor axons through the rostral half-somite. In contrast, under the same treatment conditions with soluble ephrin-B1, neural crest cells migrated aberrantly through both rostral and caudal somite halves. These results indicate that the interaction between ephrin-B1 and EphB2 is not required for patterning spinal motor axon segmentation. Even though spinal motor axons traverse the same somitic pathway as neural crest cells, different molecular guidance mechanisms appear to influence their movement.

Postoperative adjuvant radiotherapy and 5-fluorouracil chemotherapy for rectal carcinoma.

Postoperative combined modality therapy with radiotherapy and 5-fluorouracil (5FU) chemotherapy is an effective adjuvant approach that reduces locoregional and distant metastatic disease in patients with high-risk rectal carcinoma. However, this approach results in a treatment regimen of at least 6 months' duration. The present prospective study investigates the integration of radiotherapy and 5FU chemotherapy in a protocol designed to minimize toxicity and reduce the overall treatment time. A total of 40 patients with TNM stage II or III disease received postoperative radiotherapy at four fractions per week with weekly 5FU bolus injections delivered on the fifth non-radiotherapy day. Patients also received systemic chemotherapy with leucovorin both before and after pelvic irradiation, with the total treatment duration extending for only 18 weeks. Patients were able to complete radiotherapy in 90% of cases, while the delivery of full-dose chemotherapy was achievable in the vast majority. The incidence of haematologic and gastrointestinal toxicities requiring the cessation of treatment was acceptable. With a median follow-up of 20.9 months among surviving patients, the estimated progression-free and overall survival at 2 years were 71% and 79%, respectively.

Clumping of lymphoma cells in peripheral blood induced by EDTA.

A peripheral blood smear from a patient with probable splenic lymphoma with villous lymphocytes (SLVL) showed clumping of lymphoma cells. The clumping was not seen in films made from unanticoagulated blood, and has not been previously described in lymphomas. The patient also had metastatic prostatic adenocarcinoma for 30 months before lymphoma was diagnosed and the clumped cells posed diagnostic problems.

Breast cancer and pregnancy.

Although breast cancer is a rare event in pregnancy, the consequences of a delay in its detection and of late-stage disease are tragic for the young woman who presents in her childbearing years. Therefore, all pregnant women with breast problems should undergo a careful assessment. Pregnancy is not a contraindication to orthodox investigations for breast cancer, provided that special care is taken to reduce the risk to the developing fetus. Management is also orthodox, and breast cancer in pregnant or lactating women is thought to behave no differently from breast cancer in non-pregnant women, when age, stage and histological type are similar. For women who have developed early breast cancer during pregnancy, termination of the pregnancy does not appear to have a beneficial influence on the disease. There is no convincing evidence that a subsequent pregnancy has any effect on the outcome of a breast cancer that has been managed successfully previously. The prevention of subsequent pregnancy is not an indication for a prophylactic oophorectomy. A decision for further pregnancies must be made by the patient and the family after sound advice is given as to the prognosis and consideration of the social, economic and spiritual factors. There is no evidence that the termination of a subsequent pregnancy will affect beneficially or adversely the prognosis of a patient with breast cancer.

The role of the social worker in provincial psychiatric hospitals: an Ontario study.

Confusion still exists about the roles and functions of social workers in the mental health care system. The authors discuss this role ambiguity and its effects. They then present and discuss the findings of a study that explored the current role of the social worker in Ontario psychiatric hospitals with the following objectives: to document social workers' major roles and activities; to assess role satisfaction; to assess involvement in decision making; and to identify major types of therapy used.

Response time and percentage correct as measures of hearing aid performance.

A paradigm yielding response time and percentage correct data was implemented to assess the relative efficacy in differentiating subjects' performance between two disparate hearing aids. These aids represented high-frequency response (HFR) and conventional-frequency response (CFR) categories. Ten men with flat, moderate, sensorineural hearing losses were employed as subjects. The results revealed that (a) percentage correct measures did not differentiate between the two experimental aids, (b) response time measures did discriminate between the aids, and (c) response time data revealed superior performance with the CFR compared to the HFR instrument. Implementation of this method is advocated to increase the discriminating power of word recognition testing.

Node-positive breast cancer: a comparison of clinical and pathological findings and assessment of axillary clearance.

The Breast Adjuvant Chemotherapy Study of the Anti-Cancer Council of Victoria was set up to encourage the cooperation of clinicians from many centres who are involved in the management of early node-positive breast cancer in Victoria. Data sheets were completed by participants, and an analysis was made of the first 100 registered patients to determine the reliability of clinical assessment related to pathological findings and to study the extent of axillary node clearance. Although all subjects were histologically node positive, 47 had no palpable axillary lymph nodes, and in only 38 were nodes considered to be clinically involved. Correlation between clinical and pathological measurements of breast tumour size was significantly better (86%) with tumours over 5 cm in extent than with tumours of 5 cm or less (70%). Total mastectomy with total axillary clearance was the most common operative procedure performed. The pectoralis major was preserved in 97 and the pectoralis minor was divided or removed in 71 cases as part of the axillary clearance. In a subgroup (33) the location of involved nodes in the axilla was studied, and of these seven (21%) were found to have involved upper axillary nodes in the absence of lower axillary nodal involvement, emphasizing the inadequacy of axillary sampling in determining nodal status.

Effect of cigarette smoking on tympanic membrane admittance characteristics.

The effect of cigarette smoking on the admittance characteristics at the plane of the tympanic membrane was investigated using 40 young adults evenly divided into two groups, smokers and nonsmokers. Otoadmittance measurements, which included conductance, susceptance, admittance and phase angle, were administered for all subjects. Otoadmittance values, expressed in mmhos, were computed for both 220 and 660 Hz probe tone frequencies. Statistical analysis revealed no significant difference and no significant interaction between smokers and nonsmokers for measures of susceptance, conductance admittance, or phase angle. These findings indicate that the condition of smoking has no significant effect on the admittance characteristics at the plane of the tympanic membrane. As expected, a significant frequency difference was found between 220 and 660 Hz probe tones in measurements of conductance, admittance, and phase angle.

The management of febrile episodes in-neutropenic cancer.

The management of 33 febrile episodes in neutropenic patients suffering from acute leukaemia and other cancers is described. In 32 out of 33 episodes, the fever subsided. One patient died of cerebral haemorrhage while infected. The most common clinical sites of infection were, in order of frequency, the chest, the throat and the skin. Positive cultures were obtained in about half the episodes, the most common site being the throat followed by blood and sputum. The most common organisms isolated were Gram negative. Eighty-four per cent of febrile episodes occurred with neutrophil counts of less than 500/mm3, and in the majority of these, less than 100 neutrophils per cubic millmetre. All patients were reverse barrier nursed and on becoming febrile were given 48 hours of parenteral antibiotic therapy. The most common antibiotic combination used was gentamicin and cephalothin. At 48 hours, granulocyte transfusion and a third antibiotic were added to the regimen of patients not responding. The percentage response to antibiotics alone, in this series, at 58% was similar to that of other series, but the mortality experienced was lower.

Filtration leukopheresis granulocyte support for infected neutropenic patients.

A pilot study of granulocyte support for neutropenic infected patients by means of white cells collected from the Aminco Celltrifuge at the Peter MacCallum Clinic showed acceptable side effects in donor and recipients, and an encouraging recovery occurred in two out of four patients treated. White cell filtration leukopheresis was introduced at the Alfred Hospital Haematology and Medical Oncology Unit in November, 1975, for supportive therapy of all patients with white cell counts below 500/mm3 who had sustained febrile episodes (temperatures greater than 38 degrees C for more than 48 hours) while receiving appropriate or empiric parenteral antibiotic therapy. A minimum of four or more daily transfusions was given from group and cross-matched compatible donors until fever lysis, recovery of the neutrophil count to over 500/mm3 or death. Of 13 patients given white cell support, 12 survived and were discharged from hospital. One patient died having received only one transfusion when he was moribund. We believe that white cell filtration leukopheresis cell support is useful when used with parenteral antibiotic therapy for infected neutropenic patients, and it has resulted in a high rate of recovery from life-threatening infection in patients at risk.

Patient-controlled delivery of monosyllabic words in a test of auditory discrimination.

Normal- and sensorineural-hearing subjects repeated monosyllabic words under a conventional and subject-controlled method of presentation at 0, 8, 16, and 44 dB SL. Results of the study revealed little difference between discrimination scores obtained with the two methods of presentation. Discussion of clinical relevance was concerned with (1) saving of time, (2) standardization of test, and (3) favorable subjective reports of the new procedure.