Low urine pH is associated with reduced indinavir crystalluria in indinavir-treated HIV-infected individuals.

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.

Germline truncating mutations in both MSH2 and BRCA2 in a single kindred.

There has been interest in the literature in the possible existence of a gene that predisposes to both breast cancer (BC) and colorectal cancer (CRC). We describe the detailed characterisation of one kindred, MON1080, with 10 cases of BC or CRC invasive cancer among 26 first-, second- or third-degree relatives. Linkage analysis suggested that a mutation was present in BRCA2. DNA sequencing from III: 22 (diagnosed with lobular BC) identified a BRCA2 exon 3 542G>T (L105X) mutation. Her sister (III: 25) had BC and endometrial cancer and carries the same mutation. Following immunohistochemical and microsatellite instability studies, mutation analysis by protein truncation test, cDNA sequencing and quantitative real-time PCR revealed a deletion of MSH2 exon 8 in III: 25, confirming her as a double heterozygote for truncating mutations in both BRCA2 and MSH2. The exon 8 deletion was identified as a 14.9 kb deletion occurring between two Alu sequences. The breakpoint lies within a sequence of 45 bp that is identical in both Alu sequences. In this large BC/CRC kindred, MON1080, disease-causing truncating mutations are present in both MSH2 and BRCA2. There appeared to be no increased susceptibility to the development of colorectal tumours in BRCA2 mutation carriers or to the development of breast tumours in MSH2 mutation carriers. Additionally, two double heterozygotes did not appear to have a different phenotype than would be expected from the presence of a mutation in each gene alone.

Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir.

Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.

The natural history of leukocyturia associated with indinavir treatment in HIV+ individuals.

Urinary complications observed during indinavir treatment of HIV disease are often attributed to indinavir crystalluria. In a prospective study of urinalysis during the first year of indinavir therapy, 5 of 54 asymptomatic HIV+ individuals presented severe leukocyturia (> or =100 cells/HPF) usually accompanying indinavir crystalluria. The clinical course of these 5 individuals, successfully treated for HIV and monitored for an second follow-up year, suggests that recurrence of severe leukocyturia may be an indicator of renal damage, likely tubulointerstitial disease caused by indinavir crystalluria. This is in contrast to the remaining 49 subjects, including those presenting mild leukocyturia, who did not demonstrate any evidence of renal disease. Regular urinalysis is therefore recommended in the clinical management of indinavir-treated individuals to detect early renal damage secondary to indinavir crystalluria and to prevent further renal impairment.

Small-bowel resection for metastatic melanoma.

OBJECTIVE: To determine whether complete resection of small-bowel metastases from melanoma improves patient survival. DESIGN: A computer-aided chart review. SETTING: Hospitals associated with McGill University. PATIENTS: Twenty patients (17 men, 3 women), identified from 1524 patients with melanoma, who underwent surgery to the small bowel for metastases. Patient age and clinical presentation, tumour site and stage were recorded. INTERVENTION: Exploratory laparotomy with complete or partial resection of involved small bowel. MAIN OUTCOME MEASURES: Operative morbidity, mortality and length of survival related to the extent of small-bowel resection. RESULTS: Eleven patients had complete resection, 8 patients had partial resection and 1 patient had a palliative bypass only. Long-term survival (ranging from 2 to 10 years) was 36% in those who had complete resection and 0% in those who had partial resection; operative morbidity and mortality were 20% and 15% respectively. CONCLUSION: Complete resection of small-bowel metastases in patients with metastatic melanoma can result in long-term survival.

Clinicopathological relevance of the association between gastrointestinal and sebaceous neoplasms: the Muir-Torre syndrome.

The association between sebaceous neoplasms of the skin and visceral cancers, known as Muir-Torre syndrome, is described in three patients, including one with an extensive history of cancer in his family. The first patient, a 54-year-old man, developed multiple sebaceous adenomas, epitheliomas, and carcinomas in association with a colonic carcinoma 6 years after cardiac transplantation. Family history in this patient disclosed colon cancer in 17 relatives. The second patient was a 51-year-old man who had recurrent adenocarcinoma of the sigmoid colon, adenocarcinoma arising in Barrett's esophagus, and sebaceous epithelioma during a period of 15 years. The third patient was a 90-year-old man with a sebaceous adenoma followed 5 months later by adenocarcinoma of the sigmoid colon with liver metastases. Muir-Torre syndrome in 129 other patients published in the literature is reviewed. Although it is a rare disease, Muir-Torre syndrome requires recognition because skin lesions may be the first sign of the syndrome and this may lead to early diagnosis of associated visceral cancers. Moreover, because this syndrome appears to be inherited, family members should be screened for visceral cancer, especially colorectal adenocarcinoma.

Prognostic factors in systemic necrotizing vasculitis of the polyarteritis nodosa group--a review of 45 cases.

OBJECTIVE: To evaluate the prognostic importance for mortality of age, fever, hypertension, and involvement of renal, cardiac, neural, pulmonary, gastrointestinal and cutaneous systems as well as elevated transaminases, thrombocytosis, leukocytosis, anemia, smoking status, comorbid diseases and disease severity, in 45 patients with systemic necrotizing vasculitis (SNV) identified by histological, radiological, and clinical criteria. METHODS: Kaplan-Meier nonparametric survival functions and Cox proportional hazards regression models were used. RESULTS: Twenty-four deaths were observed during the 5 year mean followup period. Five year survival was 58%. Comorbidity and severity of involvement were not predictive of mortality. Multivariable survival analysis showed that cardiac or renal involvement was associated with a relative risk of dying of 2.91 (95% CI: 1.25, 6.77). Elevated serum transaminase demonstrated a trend to having a protective effect [relative risk of 0.14 (95% CI: 0.02, 1.07)]. No other variable was an independent predictor of fatality. No cohort effect could be documented following the introduction of cytotoxic drugs in the treatment of SNV. CONCLUSION: SNV remains associated with a high mortality due largely to renal or cardiac involvement.

Histopathology in erythroderma: review of a series of cases by multiple observers.

This study examines the utility of objective histopathological studies in the evaluation of adult patients with erythroderma. A series of 56 skin biopsies, from 40 erythrodermic patients, was reviewed sequentially by 4 Canadian dermatopathologists who were unaware of clinical details of the cases. The final diagnosis (gold standard), in each instance, had already been determined by others, based on clinicopathologic data and response to therapy. Direct comparison revealed that the mean accuracy of the histopathological diagnoses was 53% (range: 48-66%), a favorable result in view of the difficulty of the task at hand. Additional points of information which evolved from the study are as follows: (i) identification, by microscopy alone, of spongiotic dermatitis, cutaneous T-cell lymphoma and psoriasis, as underlying causes of erythroderma was more successful than that of drug eruptions and pityriasis rubra pilaris; (ii) the epidermotropism which characterizes cutaneous T-cell lymphoma may be mistaken for inflammatory interface changes seen in drug eruptions and vice versa, thus constituting a pitfall in diagnosis; (iii) finally, it appears that submission of multiple simultaneous biopsies, rather than a single specimen, from patients with erythroderma would be likely to enhance the accuracy of histopathological diagnosis.

Costello syndrome.

In 1971, Costello described a new syndrome in 2 patients. The major clinical findings comprise short stature; redundant skin of the neck, palms, soles, and fingers; curly hair; relative macrocephaly; depressed nasal bridge; papillomata around the mouth and nares; distinct facial gestalt; hyperextensible joints; and mental retardation. We present a third patient and review the manifestations of this condition.

Halo balloon cell nevus.

We report an unusual case occurring in a 25-year-old male of a balloon cell nevus which also showed clinical and pathological features of a halo nevus.

Vasculitis as a presenting manifestation of primary biliary cirrhosis: a case report.

The association of vasculitis and asymptomatic primary biliary cirrhosis (PBC) was documented in a 39 year old female. Cyclophosphamide was used with good results. The Raji cell assay for circulating immune complexes (CIC) was positive initially with further values changing in parallel with disease activity. The C1q binding assay failed to reveal significant levels of CIC at any time. Lymphocytotoxic antibodies were not detected in the serum. Sucrose density ultra-centrifugation experiments revealed 9-17S material in sera that were positive for CIC by the Raji cell assay. We conclude that intermediate size CIC may be important in the pathogenesis of the vasculitis associated with PBC.