Identification of clinically useful predictive genetic variants in pachyonychia congenita.

BACKGROUND: Pachyonychia congenita (PC) refers to a group of autosomal dominant disorders caused by mutations in five keratin genes (KRT16,KRT6A,KRT17,KRT6B or KRT6C). Current disease classification is based on the gene harbouring disease-causing variants. AIMS: We harnessed the International Pachyonychia Congenita Research Registry (IPCRR) containing both clinical and molecular data on patients with PC worldwide, to identify genetic variants predicting disease severity. METHODS: We ascertained 815 individuals harbouring keratin mutations registered in the IPCRR. We looked for statistically significant associations between genetic variants and clinical manifestations in a subgroup of patients carrying mutations found in at least 10% of the cohort. Data were analysed using χ2 and Kruskal-Wallis tests. RESULTS: We identified five mutations occurring in at least 10% of the patients registered in the IPCRR. The KRT16 p.L132P mutation was significantly associated with younger age of onset, presence of palmar keratoderma oral leucokeratosis and a higher number of involved nails. By contrast, the KRT16 p.N125S and p.R127C mutations resulted in a milder phenotype featuring a decreased number of involved nails and older age of onset. Patients carrying the p.N125S mutation were less likely to develop palmar keratoderma while p.R127C was associated with an older age of palmoplantar keratoderma onset. Moreover, the KRT17 p.L99P mutation resulted in an increased number of involved fingernails and patients demonstrating 20-nail dystrophy, while the opposite findings were observed with KRT17 p.N92S mutation. CONCLUSIONS: We have identified novel and clinically useful genetic predictive variants in the largest cohort of patients with PC described to date.

ST18 affects cell-cell adhesion in pemphigus vulgaris in a tumour necrosis factor-α-dependent fashion.

BACKGROUND: Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes. OBJECTIVES: To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion. METHODS: We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay. RESULTS: The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype. CONCLUSIONS: Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.

Palmoplantar keratoderma caused by a missense variant in CTSB encoding cathepsin B.

BACKGROUND: Palmoplantar keratoderma (PPK) refers to a large group of disorders characterized by extensive genetic and phenotypic heterogeneity. PPK diagnosis therefore increasingly relies upon genetic analysis. AIM: To delineate the genetic defect underlying a case of diffuse erythematous PPK associated with peeling of the skin. METHODS: Whole exome and direct sequencing, real-time quantitative PCR, protein modelling and a cathepsin B enzymatic assay were used. RESULTS: The patient studied had severe diffuse erythematous PPK transgrediens. Pedigree analysis suggested an autosomal dominant mode of inheritance. Whole exome sequencing revealed a heterozygous missense mutation in the CTSB gene, encoding the cysteine protease cathepsin B. Genomic duplications in a noncoding region, which regulates the expression of CTSB, were recently found to cause erythrokeratolysis hiemalis, a rare autosomal dominant disorder of cornification. This mutation affects a highly conserved residue, and is predicted to be pathogenic. Protein modelling indicated that the mutation is likely to lead to increased endopeptidase cathepsin B activity. Accordingly, the CTSB variant was found to result in increased cathepsin B proteolytic activity. CONCLUSION: In summary, we report the identification of the first gain-of-function missense mutation in CTSB, which was found to be associated in one individual with a dominant form of diffuse PPK.

Molecular epidemiology of pachyonychia congenita in the Israeli population.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant disorder featuring palmoplantar keratoderma, nail dystrophy, oral leucokeratosis, pilosebaceous cysts and natal teeth. PC results from dominant mutations in one of five genes (KRT6A, KRT6B, KRT6C, KRT16, KRT17) encoding keratin proteins. AIM: To delineate the clinical and genetic features of PC in a series of Israeli patients. METHODS: We used direct sequencing of genomic DNA, and also used cDNA sequencing where applicable. RESULTS: We collected clinical information and molecular data in a cohort of Israeli families diagnosed with PC (n = 16). Most of the patients were Ashkenazi Jews and had a family history of PC. The most common clinical findings were painful focal plantar keratoderma (94%) accompanied by nail dystrophy (81%), pilosebaceous cysts (31%) and prenatal/natal teeth (13%). In contrast to the high prevalence of KRT6A mutations in other populations, we found that KRT16 mutations were the most common type among Israeli patients with PC (56%). Most (77%) of the Israeli patients with PC with KRT16 mutation carried the same variant (c.380G>A; p.R127H) and shared the same haplotype around the KRT16 locus, suggestive of a founder effect. CONCLUSION: The data gleaned from this study emphasizes the importance of population-specific tailored diagnostic strategies.

Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma.

We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1-45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159-0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454-0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3-4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.

Narrow band UVB: is it effective and safe for paediatric psoriasis and atopic dermatitis?

BACKGROUND: Phototherapy has a time-honoured place in the treatment of variety of skin diseases in adults. The use of this modality in children is limited mainly due to concerns about long-term carcinogenic potential. Only a few clinical trials have been performed on the efficacy and safety of phototherapy in children. OBJECTIVES: To determine the efficacy and safety of NB-UVB phototherapy in children with atopic dermatitis (AD) and psoriasis. METHODS: This is a retrospective review of the treatment outcomes of 129 children with psoriasis and AD, who were treated with NB-UVB between 1998 and 2006 at our institute. RESULTS: Fifty per cent of the psoriatic patients and 25% of patients with AD achieved clearance by the end of the treatment. NB-UVB phototherapy was well-tolerated, with no serious adverse effects except one doubtful case of melanoma in situ. CONCLUSIONS: NB-UVB may be considered as a viable therapeutic option in children with psoriasis and AD. Children who are treated by phototherapy should remain under annual dermatologic observation. To determine true carcinogenic risk of UV therapy, longer follow-up is essential.

[Oncocytoma of the kidney--morphologic variation in 102 cases]. / Onkocytom ledviny--morfologická variabilita 102 prípadu.

From the collection of 2500 cases of renal epithelial tumors in our files, 102 renal oncocytomas were analyzed for size, multifocality and a morphologic spectrum of the growth pattern. The size of the tumors ranged from 1.5 to 13 cm in diameter, with a mean of 6.3 cm. Three cases were multifocal, four cases were combined with another primary renal tumor (1x angiomyolipoma, 1x conventional renal carcinoma, 2x papillary renal cell carcinoma). A central fibrosis or a scar was noted in 13 cases, and there was a gross area of hemorrhage in 11 cases. In 4 cases extensive necroses were recognized. Histologically, an alveolar pattern was noted in 70 cases. A tubular pattern was revealed in 31 cases and an unusual tubopapillar ("glomeruloid") pattern was noted in one case. Foci of atypical nuclei were identified in 58 cases. In 4 oncocytomas broad areas of clearance of the oncocytes were found. Psammoma bodies were recognized in 9 tumors and foci of ossification were present in 4 cases. Intracellular and extracellular hyaline globules were noted in two cases. Renal oncocytoma has a variable morphologic spectrum, and its diagnosis should be based on an analysis of structural and cytologic features. Differential diagnosis of renal oncocytomas with various tumors of the kidney which contain granular cytoplasm is discussed. These tumors with granular cytoplasm include conventional renal cell carcinomas, chromophobe cell carcinomas, and rare examples of papillary renal carcinomas.

Diagnosis of polycythemia vera in an anemic patient.

Criteria proposed by the Polycythemia Vera Study Group (PVSG) as well as several derived algorithms are currently used for the diagnosis of polycythemia vera. Although these guidelines have significantly enhanced diagnostic accuracy, they uniformly consider erythrocytosis as the requisite premise for instigating the subsequent workup. We describe the unusual presentation of a patient with microcytic anemia in whom the diagnosis of polycythemia vera was reached using the PVSG criteria and confirmed by in vitro culture assay of erythroid progenitor cells. This case highlights the usefulness of the PVSG criteria, including the red cell mass determination, for the diagnosis of polycythemia vera even in anemic patients. The roles of spleen red cell pooling and plasma volume expansion as major determinants of this unusual presentation are discussed.

Current management of pancreatic pseudocysts.

BACKGROUND/AIMS: Between 1980 and 1995, we treated 98 patients with pancreatic pseudocysts. The aim of this study was to determine the time and indices for both surgical and non-surgical management of pancreatic pseudocysts. METHODOLOGY: Evaluate the results of treatment of 98 patients with pancreatic pseudocysts. RESULTS: Resolution of the pseudocyst occurred in 20.4% of cases, after intensive therapy, with satisfactory clinical follow-up. Transcutaneous drainage was used in 38.8% of patients. In 93.3% of cases of immature pancreatic pseudocyst, transcutaneous drainage was effective. Patients who eventually underwent an operation tended to have larger pseudocysts than patients managed non-operatively. Fifty patients underwent primary operative therapy, with 36% undergoing emergency operations for pseudocyst-related complications. Eighty-three per cent of cases of external drainage resulted in postoperative complications. CONCLUSIONS: Small pseudocysts can be resolved with treatment in the early stages of development. Surgical treatment of patients with immature pseudocysts is necessary when complications develop. Internal drainage is the operation of choice for the treatment of mature pseudocysts without complications.

Dose depending effect of the complex action hemocorrector "Lactosorbal" on the motility of the distal colon in the paralitic ileus dogs.

For the model of paralytic ileus caused by the severe surgery it has been studied the influence of different doses of hemocorrector of "Lactosorbal" on distal colon motility. It has been established that stimulating effect of "Lactosorbal" on the motility of distal colon is of the dose-dependent nature. The results of the current survey are making the ground for multiple use of "Lactosorbal" to reach the most beneficial outcome of severe paralytic ileus resulting from major traumatic surgery in clinic.

Thrombotic thrombocytopenic purpura following coronary artery bypass graft surgery: prospective observations of an emerging syndrome.

Thrombotic thrombocytopenic purpura (TTP) is a rapidly progressive syndrome of thrombocytopenia, microangiopathic hemolysis, and organ dysfunction. While most TTP is idiopathic, we have observed four cases following coronary artery bypass graft (CABG) surgery in a 2-year period. We have studied these cases prospectively to define the natural history, and potentially unique characteristics, of a post-CABG TTP syndrome. On average, the onset occurred 4.75 days postoperatively (post-op), but the diagnosis was made 8.5 days post-op. All four patients exhibited microangiopathic hemolysis, thrombocytopenia, mental status changes, and severe renal failure. Three also had unexplained fever. All patients received therapeutic plasma exchange for 5, 6, 8, and 11 days, respectively, and all achieved complete hematological remission. Three patients required dialysis for 7, 15, and 16 days, respectively, but were restored to baseline renal function if they survived. One patient with severe pre-existing peripheral vascular disease died of Candida sepsis. None of the surviving patients have relapsed at a median follow-up of 19 months. These cases appear distinguished by a delay in diagnosis despite intensive medical supervision, a florid presentation with most, or all, of the components of the classic TTP pentad, an excellent and rapid response to plasma exchange, and a tendency not to relapse. As such, they may represent a subgroup characterized by a more rapid and severe onset, but also a rapid response to therapy and earlier recovery than the typical idiopathic form of TTP. An aggressive approach to management is warranted.

[Multiple lymphomatous polyposis of the gastrointestinal tract]. / Mnohotná lymfomatózní polypóza gastrointestinálního traktu.

We studied three patients in whom histology revealed multiple lymphomatous polyposis of the gastrointestinal tract. It is a distinctive type of primary gastrointestinal lymphoma characterized by polypoid accumulations of lymphoma tissue involving long segments of the gastrointestinal tract. This lymphoma consists of a diffuse proliferation of small round lymphocytes and small cleaved cells and tends to an extraintestinal dissemination. Clinical behavior of this entity is more aggressive than that of the same primary nodal lymphoma. We discuss the evolution of opinions of this entity.

[Ileopsoas muscle abscess]. / El absceso del músculo psoas iliáco.

The experience with 14 patients affected of abscess of the psoas iliac muscle, attended at a general hospital through 1983-1995 is analized. This is a disease difficult to diagnose; it is usually diagnosed after a long delay (average of 45 days); it affects mainly women (rate F/M 11: 3), with a mean age in our patients of 50.4 years (14-79). The most frequent sign was fever (86% of the patients). Pain involving the thigh was present in 57%, and the psoas' sign in 36%. Even when this sign was present it did not always orient to the correct diagnosis. In two cases, the abscess was considered primary and in twelve it was associated to osteomyelitis, urinary tract infection or tumor (cancer of colon, metastasis in small bowell, melanoma and cancer of cervix). Gram smears and cultures of the material obtained by puncture were useful for detecting the causal germ, but blood cultures were inferior in yielding it (1 positive in 8 cases). Gram positive germs were predominant (Staphylococci coag. + in 4, Staph. coag.--in one, beta hemolytic Streptococci, 1). Gram negative germs were associated with urinary tract infections and staghorn lithiasis. In one case the etiology was TBC. Abdominal TAC was diagnostic when correlated with clinical data in 100% of the cases; ecography was diagnostic in only 2 of 11 cases. Patients were treated with antibiotics and percutaneous drainage; the only deaths occurred in patients with cancer.

[Operations guided by echography]. / Les interventions guidées par l'échographie.

The considerable development, during the last few years, of the antenatal diagnosis of congenital abnormalities is due to progress in cytogenetics but also to rapid improvements in obstetrical ultrasonography. With high-resolution ultrasound scanners, various interventions performed increasingly early during pregnancy can be guided with an ever decreasing risk. Thus, genetic diseases can now be detected at a very early stage by chorion biopsy combined with genetic engineering, and direct foetal blood sampling with a needle guided by ultrasound increases our knowledge of foetal physiology and provides an access to antenatal pathology. In the forthcoming years a true antenatal medicine will no doubt develop, no longer to eliminate foetuses, but to treat and cure them.