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Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m 2 , including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m 2 . Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a "cold tumour," a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8 + cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ischemic retinopathies are characterized by a progressive microvascular degeneration followed by a postischemic aberrant neovascularization. To reinstate vascular supply and metabolic equilibrium to the ischemic tissue during ischemic retinopathies, a dysregulated production of growth factors and metabolic intermediates occurs, promoting retinal angiogenesis. Glycolysis-derived lactate, highly produced during ischemic conditions, has been associated with tumor angiogenesis and wound healing. Lactate exerts its biological effects via G-protein-coupled receptor 81 (GPR81) in several tissues; however, its physiological functions and mechanisms of action in the retina remain poorly understood. Herein, we show that GPR81, localized predominantly in Müller cells, governs deep vascular complex formation during development and in ischemic retinopathy. Lactate-stimulated GPR81 Müller cells produce numerous angiogenic factors, including Wnt ligands and particularly Norrin, which contributes significantly in triggering inner retinal blood vessel formation. Conversely, GPR81-null mice retina shows reduced inner vascular network formation associated with low levels of Norrin (and Wnt ligands). Lactate accumulation during ischemic retinopathy selectively activates GPR81-extracellular signal-regulated kinase 1/2-Norrin signaling to accelerate inner retinal vascularization in wild-type animals, but not in the retina of GPR81-null mice. Altogether, we reveal that lactate via GPR81-Norrin participates in inner vascular network development and in restoration of the vasculature in response to injury. These findings suggest a new potential therapeutic target to alleviate ischemic diseases., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Habit cough is a chronic, persistent dry cough which occurs in children only when awake. It is considered functional (non-organic) and can have a significant impact on the quality of life of the child and their family. One possible treatment option for habit cough is hypnotherapy. At our centre we offered hypnotherapy sessions to patients diagnosed with habit cough, and conducted telephone interviews with patients' parents to determine the acceptability of this therapy. Nine patients' parents were interviewed, and despite being unsure of what to expect with hypnotherapy, all nine found it an acceptable treatment option. Parents reported that hypnotherapy appeared to result in cough reduction or cessation in 6 out of 9 cases., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Introduction: Patients with stage III non-small-cell lung cancer and poor performance status and/or weight loss do not seem to benefit from standard therapy. Based on the preclinical interaction between epidermal growth factor receptor inhibitors and radiation, we designed a trial of induction chemotherapy followed by thoracic radiotherapy and concurrent erlotinib., Methods: Patients with poor-risk unresectable stage III non-small-cell lung cancer received two cycles of carboplatin at an AUC of 5 and nab-paclitaxel at 100 mg/m on days 1 and 8 every 21 days, followed by erlotinib administered concurrently with thoracic radiotherapy. Maintenance was not permitted. Molecular analysis was performed in available specimens. Seventy-two eligible patients were required to test whether the 1-year survival rate was less than 50% or greater than or equal to 65% with approximately 90% power at a significance level of 0.10., Results: From March 2008 to October 2011, 78 patients were enrolled, three of whom were ineligible. The median age was 68 (range, 39-88) and 32% were aged greater than or equal to 75 years. Patients were evenly distributed between stages IIIA and IIIB and the majority had performance status 2. The overall response rate was 67% and the disease control rate was 93%. Treatment was well tolerated. The median PFS and OS were 11 and 17 months, respectively. The overall 12-month OS was 57%, which narrowly missed the prespecified target for significance., Conclusions: Patients with poor-risk stage III non-small-cell lung cancer had better than expected outcomes with a regimen of induction carboplatin/nab-paclitaxel followed by thoracic radiotherapy and erlotinib. However, as per the statistical design, the 12-month OS was not sufficiently high to warrant further studies.

Introduction: To evaluate the efficacy and safety of myeloid growth factors in patients with locally advanced non-small cell lung cancer treated with combined modality therapy (CMT)., Methods: Patients with stage IIIA/B non-small cell lung cancer, performance status 0 to 1, and forced expiratory volume in 1 second > or =1.5, received cisplatin 75 mg/m(2) on day 1 + etoposide 80 mg/m(2) on days 1 to 3 every 3 weeks for 2 cycles concurrent with thoracic radiotherapy to 61 Gy. filgrastim 5 mcg/kg/d was administered for 10 days beginning on day 4 of each chemotherapy cycle. Patients without progression received docetaxel 75 mg/m(2) every 21 days for 3 cycles with peg-filgrastim 6 mg on day 2. The primary end point was a 50% reduction in the incidence of grade (3/4) neutropenia compared with historical controls., Results: A total of 26 eligible patients were enrolled. Median age was 67, 76% were men, and 58% had stage IIIA. Gr3/4 neutropenia during CMT was 19.2% and 3.8%, respectively. There were no episodes of febrile neutropenia. Gr4 thrombocytopenia was 15.4% with 2 patients requiring transfusions. Gr3 esophagitis was noted in 7.7% and Gr (3/4) pneumonitis in 21.6% of patients. No patients died of treatment-related toxicities. Dose reductions/delays occurred in 3.8% of patients during CMT. Median progression-free survival and median survival were 10.7 and 27.6 months, respectively. The 1- and 2-year survival rates were 61.5% and 46.2%, respectively., Conclusions: Our data suggest that the addition of filgrastim to CMT is safe and effective. The rate of grade (3/4) toxicities, including febrile neutropenia, compares favorably to previous trials using a similar regimen. Dose intensity is maintained. This strategy merits further evaluation.

We ascertained two families in Eastern Canada segregating a form of ataxia consistent with a recessive mode of inheritance. We performed a whole genome scan using dense SNP genotyping, and despite an absence of shared homozygosity in the families we defined linkage to a small region on chromosome 13. Direct DNA resequencing was employed to screen biologically relevant candidate genes in the interval, and two presumptive pathogenic mutations were found in the gene encoding sacsin. One variant is an obligate truncating mutation, the second is a missense variant in a highly conserved residue. Unexpectedly, one family was homozygous for the missense mutation, the other compound heterozygous for the two mutations. Our results expand the genotype phenotype correlation of mutations in the sacsin gene, and highlight the challenge of diagnosing genetically heterogeneous disorders on primarily clinical grounds. We demonstrate that whole genome genotyping on a modest scale can be productive in research, and potentially in a clinical context.

Objectives: Cocaine abuse is often associated with reproductive cycle dysfunction including altered menstrual cyclicity and decreased ovulation rates. Cocaine might also alter prolactin (PRL) secretion, presumably through the effects of this drug on hypothalamic dopamine, the primary factor regulating pituitary PRL secretion. We assessed basal and pulsatile PRL levels to determine whether hyperprolactinemia is associated with cocaine-induced disruption of menstrual cyclicity in rhesus monkeys., Methods: Normally cycling, drug-naïve monkeys were studied. Cocaine-treated animals were pair-fed with controls to minimize cocaine-related differences in caloric intake. Twenty-eight monkeys were randomized to receive daily intravenous (iv) infusion of saline or cocaine (1, 2, or 4 mg/kg) on cycle days 2-14. Daily blood samples were obtained through indwelling catheters for measurement of ovarian steroids, gonadotropins, and PRL. Laparoscopy was performed 2 days after the midcycle estradiol surge to document ovulation. Sixteen other monkeys were randomized to receive daily iv infusion of saline or cocaine (4 mg/kg). Blood samples were obtained every 15 minutes for 8 hours in the early (cycle day 1-5), mid- (cycle day 6-10), and late (cycle day 11-15) follicular phase. Plasma was assayed for PRL, and pulses were identified by cluster analysis., Results: All seven control monkeys had laparoscopically confirmed ovulation compared to two of seven monkeys receiving 1 mg/kg, three of seven monkeys receiving 2 mg/kg, and one of seven receiving 4 mg/kg of cocaine hydrochloride. Cycle length was normal in six of seven controls, and in one of seven, two of seven, and two of seven monkeys receiving the 1, 2, and 4 mg/kg of cocaine, respectively. Estradiol levels were significantly higher in controls versus cocaine-treated monkeys, but there was no difference in basal gonadotropin levels during treatment. Mean PRL levels during treatment were significantly lower (P <.05) in controls (4.6 +/- 0.2 ng/mL) as compared to monkeys receiving 1 (6.5 +/- 0.6 ng/mL), 2 (6.1 +/- 0.4 ng/mL), and 4 mg/kg (7.2 +/- 0.6 ng/mL) of cocaine. There was no significant difference in PRL pulse amplitude or frequency between controls and cocaine-treated monkeys during each cycle phase., Conclusions: Circulating PRL levels were slightly higher in monkeys receiving cocaine during the follicular phase. Although this increase was statistically significant, PRL levels remained well within the euprolactinemic range in cocaine-treated monkeys.

Presented here is a stable isotope dilution technique for determining cortisol production rate (CPR). The method involves extraction and derivatization of cortisol isoforms from serum (0.5 ml), separation of derivatives by gas chromatography, and detection by using negative ion chemical ionization mass spectrometry. This method provides 50-100-fold greater sensitivity than positive ion mass spectrometry and allows for estimations of cortisol production rate with the use of small amounts of pooled serum, even in the presence of high concentrations of lipophilic contaminants. The area under the curve for the total selected ion chromatogram of fluoroacyl derivatives of cortisol (d0, m/z 782) and deuterated cortisol (d3, m/z 785) were used to determine the isotopic dilution ratio in three types of samples: 1) standards: d0/d3 ratios ranging from 1 to 8%; 2) controls: d3-cortisol added to serum with known cortisol concentration; 3) subjects: 24-h pooled serum samples (q 30 min over 24 h) from healthy children (male 10-13 years; female 7-11 years) receiving continuous infusions of d3-cortisol at 2-4% of their estimated CPR. Recovery after the solid phase extraction and derivatization process was >90%, as determined by thin-layer chromatography. Expected versus measured ratios for d3/d0 in standards and serum controls were highly correlated (r2(standard) = 0.99; r2(control) = 0.99) over a wide range of d3-cortisol enrichment (1.0-10.0%). Mean 24-h CPRs were 4.8 +/- 0.6 mg/m2/24 h (mean +/- SEM, n = 7) in male children and 4.4 +/- 0.5 mg/m2/24 h in female children (n = 4). These CPR values are lower than those derived by radio tracer methods, but are in agreement with previous isotopic dilution studies. This technique is an important tool for assessing CPRs in a wide range of disease states affecting cortisol production.

Objective: To assess cocaine's effect on follicular phase pulsatile gonadotropin secretion in normally cycling rhesus monkeys., Methods: Sixteen monkeys were paired by body weight and randomized to receive intravenous saline (n = 8) or cocaine (4 mg/kg, n = 8) daily on cycle days 2 to 14. Monkeys were chronically cannulated to allow frequent blood collections without anesthesia. Blood samples were obtained every 15 minutes for 8 hours in early (EFP; cycle days 1 to 5), mid-(MFP; cycle days 6 to 10), and late (LFP; cycle days 11 to 15) follicular phase. Plasma concentrations of LH, FSH, and estradiol-17 beta (E2) were determined by radioimmunoassay. Pulses were identified by cluster analysis. Statistical differences were determined by analysis of variance (ANOVA) and Sidak's multiple comparison test., Results: Seven out of eight monkeys in the control group demonstrated timely ovulation. Only one monkey in the cocaine-treated group ovulated. Similar gonadotropin pulse intervals (70 to 90 minutes) were observed throughout the follicular phase in both the controls and cocaine-treated monkeys. LH and FSH pulse amplitudes increased significantly from the EFP/MFP to the LFP in controls. In cocaine-treated monkeys, gonadotropin pulse amplitudes remained at EFP/MFP levels throughout the study period. The mean gonadotropin pulse amplitude and the mean E2 levels in the LFP were significantly greater in controls as compared with cocaine-treated monkeys (P < .001)., Conclusion: These findings demonstrate that cocaine suppresses the normal increase in LH and FSH pulse amplitude seen in the LFP. Further studies are in progress to determine the mechanism of cocaine's disruption of the hypothalamic-pituitary-ovarian axis.

According to the proposed hypothesis-assessment model, the strength of inductive categorical arguments, such as {All Robins Have Substance X therefore All Birds Have Substance X}, is determined by the same factors that affect hypothesis plausibility in the everyday social milieu. The premises of such arguments are viewed as evidence and the conclusion is viewed as a hypothesis. Specifically, the proposed model predicts that the perceived strength of general-conclusion categorical arguments will be a function of (a) the number of premises that instantiate the conclusion; (b) the scope of the conclusion; and (c) the number of accessed alternatives to the conclusion. In Experiment 1, one group rated the strength of individual arguments and another constructed superordinate hypotheses in response to the premise information alone. Most of the variance in perceived argument strength was accounted for by the proposed predictors, R = .94. Experiment 2 employed a new set of arguments and included an additional forced-choice condition in which subjects had to choose the stronger of two arguments. Again, the correlation between predictors and argument strength was high, R = .91, and, all significant forced-choice preferences except one were correctly predicted by the model. The one unpredicted preference suggests the need to include conclusion accessibility as a fourth factor. Also, on a subset of the forced-choice pairs in which no significant preference was observed, two distinct patterns of responding were detected-one predicted and the other unanticipated. Some strengths and limitations of the proposed hypothesis-assessment model are discussed in light of these results.

This article examines Cushing's syndrome in four main categories as associated with nodular adrenal glands: adrenal adenoma, adrenal carcinoma, primary pigmented nodular adrenal dysplasia, and macronodular adrenal hyperplasia. A summary of clinical features of these four categories is presented.

The effect of the neck seal used in the application of negative extra-thoracic pressure ventilation was studied using near infrared spectroscopy. Changes in cerebral blood volume (CBV) were monitored during discontinuation of negative pressure and during removal of the neck seal. CBV increased by 0.17 ml 100 ml brain-1 (95% CI +0.0875 to +0.481) when negative pressure was discontinued. Removal of the neck seal had no significant effect on CBV. It is concluded that the neck seal does not cause significant jugular venous occlusion.

Central hypothyroidism is an uncommon condition characterized by insufficient thyroid gland stimulation by TSH, owing to hypothalamic and/or pituitary dysfunction. It is rarely isolated but more often occurs in conjunction with deficiencies of other pituitary hormones, as well as with neurologic symptoms and signs owing to hypothalamic/pituitary lesions. The diagnosis rests on documentation of clinical and biochemical hypothyroidism with an inappropriately low or nonelevated serum TSH level. Recent studies suggest that the temporal pattern of TSH secretion, as well as TSH structure, is altered in central hypothyroidism, providing a mechanism for the induction of the hypothyroid state in this condition.

Objective: Our objective was to determine whether cocaine alters gonadotropin secretion in oophorectomized monkeys., Study Design: Oophorectomized monkeys with elevated gonadotropin levels were chronically cannulated to allow blood sampling every 15 minutes. Monkeys received either saline solution or 2 or 4 mg/kg cocaine hydrochloride as an intravenous bolus. Other oophorectomized monkeys were pretreated with either saline solution or 4 mg/kg cocaine 2 hours before bolus gonadotropin-releasing hormone administration, and plasma luteinizing hormone and follicle-stimulating hormone levels were measured every 15 minutes for 3 hours. Monkeys were also given either saline solution or 4 mg/kg of cocaine with gonadotropin-releasing hormone simultaneously, and plasma gonadotropin levels were measured every 15 minutes for 3 hours. Serum luteinizing hormone and follicle-stimulating hormone levels were measured by radioimmunoassay., Results: Both doses of cocaine resulted in a significant decrease in luteinizing hormone levels compared with controls. Follicle-stimulating hormone levels were significantly decreased only with the 4 mg/kg dose of cocaine. There was no difference in luteinizing hormone and follicle-stimulating hormone responses to gonadotropin-releasing hormone in the cocaine-treated monkeys compared with saline solution-treated monkeys by using repeated-measures analysis of variance., Conclusion: These findings demonstrate that acute cocaine administration to oophorectomized primates inhibits basal luteinizing hormone-follicle-stimulating hormone secretion but not gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone release. In the absence of an effect on gonadotropin-releasing hormone-stimulated gonadotropin release, we conclude that the impaired luteinizing hormone-follicle-stimulating hormone secretion after cocaine administration is due in part to a direct effect of cocaine on gonadotropin-releasing hormone neurons or on hypothalamic neurotransmitter modulation of gonadotropin-releasing hormone release.

The pluripotent murine embryonal carcinoma cell line, P19, differentiates along at least three main pathways under the inductive influence of retinoic acid (RA). The events most critical to the establishment of a particular differentiation pathway must occur early since P19 cells are committed to differentiation pathways after 30 min of exposure to RA (M. W. McBurney, personal communication and our unpublished results). We have, therefore, looked for genes that are induced (or repressed) within 30 min of RA addition and find that Egr-1 is one of these genes. Egr-1 is a transcription factor of the zinc-finger class and is known to transactivate genes after binding to specific oligonucleotide sequences. We describe here the extremely rapid and transient increase of Egr-1 transcript and protein levels in P19 cells after RA addition. Stable induction of Egr-1 transcripts occurred in the presence of protein synthesis inhibitors. Simultaneous addition of RA and cycloheximide did not result in an additive effect. The mechanism of induction with either drug appears to involve relief of a block to transcriptional elongation. The response was more rapid at high RA concentrations and this suggests that the Egr-1 transcription factor could play a role in initiation of differentiation pathways of P19 EC cells.

The mutant F9 cell line F9att-5.51 synthesizes reduced amounts of uvomorulin (UM) protein and we hypothesized earlier (Adamson, Baribault, and Kemler, Dev. Biol. (1990), 138, 338) that this may account for its inability to compact into tightly aggregated balls of cells. Subsequently, when 5.51 cells are treated with retinoic acid to stimulate their differentiation, they are unable to form embryoid bodies as do wild-type cells which form an outer epithelial layer of visceral endoderm cells. We have now examined the possibility that the UM protein made in the mutant line is defective, but find that it is normal in structure and stability. The gene coding for UM appears to be normal as does the mRNA which is synthesized at a normal rate but is severely reduced in steady-state measurements of mutant cells. A rescue experiment was performed by increasing levels of UM in mutant cells by means of transfection with a UM expression vector. The resulting cells expressed abundant UM mRNA and protein but were still unable to form compacted aggregates and did not differentiate into embryoid bodies. Interestingly, the stability of endogenous UM mRNA was improved in the presence of exogenous UM; therefore, a positive feedback mechanism contributes to low mRNA levels in mutant cells. The accumulated data suggest that UM in 5.51 cells is unable to mount a compaction activity because a distal connecting link in the multicomponent process initiated by UM is missing or or aberrant. The missing component is likely to connect UM to actin and the cytoskeleton of the cell.

Day time video records of 14 girls with the Rett syndrome (RS) (6-17, mean 7 years) were analysed to correlate episodic abnormalities in respiration, movement and electroencephalograms (EEG). Records were compared with those of 12 healthy girls (6-18, median 14 years) who hyperventilated voluntarily. Three RS girls (6-7 years) had minimal respiratory dysrhythmia and showed no correlation between EEG respiration and movement. The other 11 RS girls (6-17 years) had severe awake respiratory dysrhythmia; 10 showing hyperventilation (with hypocapnia) which alternated with active expiratory apnoeic pauses and one with the latter only. All had periods of awake regular breathing with normal respiratory gases. In these girls EEG showed non-epileptic generalised slow activity some of which was paroxysmal. In the six youngest (6-10 years) of these 11 RS girls, non-epileptic paroxysms of EEG slow activity at 1 1/2-4 Hz occurred and were associated with periods of normal breathing and normal pCO2 levels whether girls were alert, drowsy or asleep, but were uncommon during episodes of hyperventilation (and hypocapnia). In four of these girls the EEG paroxysms occupied less than or equal to 1-3% of the time during periods of respiratory dysrhythmia (81 minutes) and 8-100% of the time during alert periods with normal breathing (29 minutes), p less than or equal to 0.001 for this difference. Short bursts of EEG slowing occasionally followed prolonged apnoeic pauses. In two cases brief partial complex seizures occurred. In five of these girls stereotypic movements exacerbated during episodes of respiratory dysrhythmia and reduced during normal breathing.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-nine patients with small cell lung cancer were treated with large dose intravenous cyclophosphamide combined with vincristine. Sequential split-course radiotherapy was added when the gross disease was limited to one hemithorax and draining scalene nodes. Fifteen of 16 patients in the limited disease category showed objective response, eight of which were complete. Fourteen of 23 patients in the extensive disease category yielded an objective response, six of which were complete. The median survival for complete responders was 48 weeks, 38 weeks for partial responders and 14 weeks for non-responders. The difference between responders and non-responders was statistically significant. The major toxicity was myelosuppression with a median leukocyte nadir of 500/mm-3 noted on treatment day no. 15. Prompt recovery was the rule. Toxicity appeared to be cumulative for patients receiving radiotherapy. These results are superior to those evolving from treatment with cyclophosphamide as a solitary agent.

Sixty patients with initial stage III germinal tumors treated with conventional vinblastine, bleomycin and cisplatin chemotherapy (VB + P) were surgically explored. Twenty-two patients not treated with an initial retroperitoneal node dissection were surgically explored to pathologically confirm a complete remission following chemotherapy. Thirty-eight patients had a persistent mass in the absence of elevated serum markers. Seventeen (28%) patients had viable carcinoma at surgery. Eight (47%) of the 17 patients with viable carcinoma at surgery died of recurrent tumor. All but three patients with persistent viable carcinoma at surgery were treated with surgery followed by chemotherapy. Fourteen patients were found to have mature teratoma and one (7%) developed recurrent carcinomatosis. Two (8%) of the 25 patients found to have scar died. One patient died of recurrent carcinomatosis and one of postoperative complications. Ten additional patients with a suboptimal response to chemotherapy were surgically explored for attempted salvage. All ten died of recurrent tumor, with a median postoperative survival of 7 months. We believe optimal individualized chemotherapy is required for the management of stage III testis cancer. Therapeutic benefit for surgery can be demonstrated only in unusual circumstances. Attempted surgical excision of a clinically active germinal tumor is futile; hence patients with elevated serum biomarkers should not be explored. Patients with non-seminomatous germinal tumors and a residual postchemotherapy mass must be explored. The excision of mature teratoma is mandatory, as is documentation of the absence of viable carcinoma prior to cessation of therapy.

We examined the clinical and pathological features of 26 patients who presented with a diagnosis of CNS toxoplasmosis. Patient data was analyzed with respect to demographics, clinical presentation, treatment course and pathology. Patients presented with a wide variety of signs and symptoms. All patients had positive serum antitoxoplasma IgG; ring enhancing lesion(s) were present on all but one brain CT scans. A series of guidelines in the management of CNS toxoplasmosis in AIDS patients are presented. Prior to biopsy, patients with positive serology and characteristic CT scans should receive two weeks of treatment. Biopsy is indicated in those cases with negative serology, atypical presentation, progressive clinical deterioration, or differential response of lesions to empiric therapy.

Primary endodermal sinus tumor (EST) of the mediastinum has been regarded as a rare and rapidly fatal germ cell neoplasm. We describe two cases of extensive EST treated with a new high-dose sequential combination chemotherapy regimen (CISCA-VB) followed by radical surgical excision. They are alive at 11 and 20 months, respectively, postoperatively. These cases stand in marked contrast to previously reported series. A new approach to the management of this tumor is proposed.

Criteria are discussed for using analysis of covariance (ANCOVA) and t-tests in analysis of clinical trials. Revisions are suggested in the guidelines given recently by Egger et al. (Controlled Clin Trials 6:12-24, 1985). Specifically, if one assumes that treatment groups have been successfully balanced by randomization, then ANCOVA is more powerful than the t-test under a broad range of conditions; this is true even in the model assumed by the t-test, and regardless of the presence of measurement error. If the balance cannot be assumed, then under certain conditions the t-test should be preferred over ANCOVA on grounds of validity.