Genomic profiling of late-onset basal cell carcinomas from two brothers with nevoid basal cell carcinoma syndrome.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases, NBCCS presents with a late onset of BCC development. OBJECTIVE: To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40 years. Two other siblings did not show signs of NBCCS. RESULTS: We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763-6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss-of-function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations. CONCLUSIONS: Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS.

[Bronchoalveolar lavage in hairy cell leukemia with pulmonary infiltration]. / Bronchoalveoläre Lavage bei Haarzellleukämie mit Lungeninfiltration.

We report a 78-year-old male patient suffering from hairy cell leukemia, presenting clinically mainly with dyspnea. Radiology exhibited bilateral ground-glass shadows. In order to prevent pneumonia as a possible side effect due to conventional chemotherapy, it was decided to first treat the patient with rituximab; however, dyspnea persisted. Therefore, bronchoscopy was performed and specimens were sampled for both histological examination and bronchoalveolar lavage (BAL) analysis. BAL showed lymphocytosis (28.7%), and by means of immunocytochemistry a few CD79a+ B­lymphocytes as well as lymphoid cells positive for the hairy cell marker DBA44 were observed. In addition, molecular study revealed the BRAF V600E mutation. Thus, the findings of BAL were interpreted as lung infiltration by hairy cell leukemia. This result was confirmed by histology. Following a therapy switch to cladribine, a significant improvement was reached. Pulmonary infiltrates by hairy cell leukemia were rarely described. This case represents the first report of hairy cell leukemia diagnosed by means of BAL. It may be difficult to clearly separate between lymphoma infiltration of the lung and medicamentous pneumonitis, but this differential diagnosis can be supported by morphological methods.

[Thoracolumbar spinal fractures in the elderly : Classification and treatment]. / Thorakolumbale Wirbelsäulenfrakturen beim alten Menschen : Klassifikation und Therapie.

Thoracolumbar fractures in the elderly are frequently associated with osteoporosis. Osteoporosis can cause fractures or be a significant comorbidity in traumatic fractures. The OF classification is based on conventional X­ray, computed tomography (CT) scan and magnetic resonance imaging (MRI). It is easy to use and provides a clinically relevant classification of the fractures. Therapeutic decisions are made based on the clinical and radiological situation by using the OF score. The score takes the current clinical situation including patient-specific comorbidities into consideration. The treatment recommendations are based on an expert consensus opinion and include conservative and operative options. If surgery is indicated, vertebral body augmentation, percutaneous stabilization and even open surgery can be used.

Nd:YAG and pulsed dye laser therapy in infantile haemangiomas: a retrospective analysis of 271 treated haemangiomas in 149 children.

BACKGROUND: Infantile haemangiomas (IH) are common benign tumours in infancy. Most IH resolve spontaneously, but some require treatment due to ulceration, functional impairment or cosmetic disfiguration. While systemic propranolol is effective in many cases, laser therapy may be a safe topical alternative. OBJECTIVE: To assess the efficacy of combined Nd:YAG/pulsed dye laser (PDL) or PDL alone for therapy of IH. PATIENTS AND METHODS: A total of 271 IH in 149 infants were treated with combined Nd:YAG/PDL or PDL alone. Based on photographs before and 4-6 weeks after the last treatment, the results were evaluated independently by three physicians. Remissions were categorized as 0-25% (I), 26-50% (II), 51-75% (III) and 76-100% (IV). RESULTS: In total, 472 laser treatments were performed. In 137 of 149 infants (91.9%) laser therapy was performed during a short sevoflurane mask anaesthesia, while 12 of 149 infants (8.1%) received topical anaesthetic gel. Combined Nd:YAG/PDL was applied in 187 of 271 IH (69.0%), while PDL alone in 84 of 271 IH (31.0%). On average, 1.74 treatments per IH were necessary (Nd:YAG/PDL: 1.95, PDL: 1.26). Moderate or strong (III/IV) improvement was observed in 92.4% of all IH treated. No serious adverse effects were observed. CONCLUSION: Combined Nd:YAG/PDL therapy is an effective and well-tolerated local treatment option for IH of any classification, in any phase of development and at any age. With regard to the systemic use of propranolol, combined Nd:YAG/PDL therapy seems a safe and promising alternative in many cases.

Vedolizumab provides clinical benefit over 1 year in patients with active inflammatory bowel disease - a prospective multicenter observational study.

BACKGROUND: Vedolizumab, a monoclonal antibody targeting the α4ß7-integrin, is effective in inducing and maintaining clinical remission in Crohn's disease and ulcerative colitis according to randomised clinical trials. AIM: To determine the long-term effectiveness of vedolizumab in a real-world clinical setting. METHODS: This observational registry assessed the clinical outcome in patients treated with vedolizumab for clinically active Crohn's disease (n = 67) or ulcerative colitis (n = 60). Primary endpoint was clinical remission (HBI ≤ 4/pMayo ≤ 1) at week 54. Secondary endpoints included clinical response rates (HBI/pMayo score drop ≥3) and steroid-free clinical remission at weeks 30 and 54. RESULTS: Vedolizumab was stopped in 69/127 (56%) patients after a median time of 18 weeks (range 2-49) predominantly owing to lack or loss of response. Using nonresponder imputation analysis, clinical remission and steroid-free remission rates were 21% and 15% in Crohn's disease and 25% and 22% in ulcerative colitis, respectively. Lack of clinical remission was associated with prior treatment with anti-TNF or with steroids for more than 3 months in the last 6 months in ulcerative colitis. At week 14, the absence of remission in Crohn's disease or nonresponse in ulcerative colitis indicated a low likelihood of clinical remission at week 54 [2/31 (7%) in Crohn's disease, 4/41 (10%) in ulcerative colitis]. Accordingly, declining C-reactive protein in inflammatory bowel disease and/or lower faecal calprotectin in ulcerative colitis at week 14 predicted remission at week 54. CONCLUSION: Among patients who started vedolizumab for active inflammatory bowel disease, clinical remission rates are 21-25% after 54 weeks.

[Structured rehabilitation after lumbar spine surgery : subacute treatment phase]. / Strukturierte Rehabilitation nach lumbaler Wirbelsäulenoperation : Subakute Behandlungsphase.

BACKGROUND: There are currently no uniform standards regarding rehabilitation of patients after lumbar spine surgery. Due to significant improvements in surgical methods in recent years, an increase in postoperative training intensity is now possible. Conservative rehabilitation has yet to adapt to this reality. Earlier initiation of structured rehabilitation after the acute phase is often regarded with skepticism. OBJECTIVE: To evaluate the effect of structured rehabilitation after lumbar spine surgery in the early phase of treatment (2 weeks after surgery), a group of seven spinal surgery clinics, two inpatient and three outpatient rehabilitation centers in the Rhine-Main area in Germany was formed. MATERIALS AND METHODS: In this prospective study, 124 patients were divided into groups (A/B/C) by their surgeon, regardless of diagnosis and surgical procedure. For each group of participants, the content of therapy was preplanned. RESULTS: The statistical analysis using the visual analog scale (VAS), Oswestry Disability Index (ODI), and short form-12 health survey (SF-12) to evaluate changes in impairment caused by back pain and in health-related quality of life was evaluated. In all three groups, significant improvements in VAS, ODI, and SF-12 were shown. Re-operation was unnecessary due to the absence of postoperative complications. CONCLUSION: A structured postoperative rehabilitation program results in significant improvements in the parameters of pain and quality of life, and does not increase the risk of postoperative complications.

Short- and long-term cure rates of short-duration trimethoprim-sulfamethoxazole treatment in female dogs with uncomplicated bacterial cystitis.

BACKGROUND: Long-duration beta-lactam antibiotics are used for empirical treatment in female dogs with uncomplicated bacterial cystitis. However, women with bacterial cystitis are treated with short-duration potentiated sulfonamides because longer courses of beta-lactams result in lower cure and higher recurrence rates. HYPOTHESIS/OBJECTIVES: Short-duration potentiated sulfonamide treatment is more efficacious than long-duration beta-lactam treatment in achieving clinical and microbiological cures in female dogs with uncomplicated bacterial cystitis. ANIMALS: Thirty-eight client-owned female dogs. METHODS: Randomized, double-blinded, placebo-controlled clinical trial. Dogs were treated with TMP-SMX (15 mg/kg PO q12h for 3 days followed by a placebo capsule PO q12h for 7 days; Group SDS; n = 20) or cephalexin (20 mg/kg PO q12h for 10 days; Group LDBL; n = 18). Dogs were monitored for clinical and microbiological cure during treatment and at short- and long-term follow-up. RESULTS: No statistically significant differences were found between treatment groups in clinical cure rates after 3 days of treatment (89% SDS, 94% LDBL; P = 1.00) and 4 days (85% SDS, 72% LDBL; P = .44) or >30 days (50% SDS, 65% LDBL; P = .50) after conclusion of treatment or in microbiological cure rates 4 days (59% SDS, 36% LDBL; P = .44) or >30 days (44% SDS, 20% LDBL; P = .40) after conclusion of treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: We did not identify a difference in cure rates between short-duration sulfonamide and long-duration beta-lactam treatments in female dogs with uncomplicated cystitis. Long-term cure rates in both treatment groups were low. In some female dogs, "uncomplicated" bacterial cystitis may be more complicated than previously recognized.

[Primary Hodgkin's lymphoma of the colon]. / Primäres Hodgkin-Lymphom des Kolons.

Primary Hodgkin's lymphoma of the colon is exceedingly rare. We report on the case of a 74-year-old female patient presenting with weight loss and hematochezia. Proctocolonoscopy revealed a bleeding tumor localized in the right colonic flexure. Histological examination of initial mucosal biopsies could not verify malignancy; however, explorative surgery was decided in an interdisciplinary conference setting and right-sided hemicolectomy was performed. Macroscopically, a tumor measuring 5.5 cm in maximum diameter was found. By means of histology and immunohistochemistry the diagnosis of classic Hodgkin's lymphoma was made. Mesenteric lymph nodes were not affected and postoperative staging revealed no systemic spread. Therefore, the tumor fulfilled the criteria of a primary colonic Hodgkin's lymphoma. Diagnosis of primary colonic lymphoma can be difficult as clinical symptoms are typically unspecific and, as shown in this case, even primary biopsy histology can be falsely negative.

[Rational and efficient diagnosis in different stages of Crohn's disease]. / Rationale und rationelle Diagnostik in unterschiedlichen Krankheitsphasen des Morbus Crohn.

The treatment of patients with inflammatory bowel disease has become more complex in recent years through the introduction of various immunosuppressive agents as well as the approval of monoclonal antibodies. Patients receiving such treatment must be carefully monitored. National and international guidelines define a diagnostic and therapeutic context for the practitioner, but can only partially respond to specific questions on the procedure for individual patients. Within the framework of a project initiated by Abbott entitled "IBD ahead" 34 German IBD experts have elaborated concrete proposals for the utility of clinical symptom assessment, endoscopy and the use of laboratory parameters including foecal markers of inflammation. Furthermore, we discuss the significance of conventional X-rays, computed tomography, ultrasound and magnetic resonance tomography. These recommendations are illustrated by case studies from everyday practice in the participating centres.

Biomechanical comparison of an interspinous device and a rigid stabilization on lumbar adjacent segment range of motion.

PURPOSE OF THE STUDY: Decompression surgery with or without fusion is the gold standard treatment of lumbar spinal stenosis, but adjacent segment degeneration has been reported as a long-term complication after fusion. This led to the development of dynamic implants like the interspinous devices. They are supposed to limit extension and expand the spinal canal at the symptomatic level, but with reduced effect on the range of motion of the adjacent segments. The aim of the present study is the evaluation of the biomechanical effects on the range of motion (ROM) of adjacent lumbar segments after decompression and instrumentation with an interspinous device compared to a rigid posterior stabilization device. MATERIALS AND METHODS: Eight fresh frozen human cadaver lumbar spines (L2-L5) were tested in a spinal testing device with a moment of 7.5 Nm in flexion/extension, lateral bending and rotation with and without a preload. The preload was applied as a follower load of 400N along the curvature of the spine. The range of motion (ROM) of the adjacent segments L2/L3 and L4/L5 was measured with the intact segment L3/L4, after decompression, consisting of resection of the interspinous ligament, flavectomy and bilateral medial facetecomy, and insertion of the Coflex® (Paradigm Spine, Wurmlingen) and after instrumentation with Click X® (Synthes, Umkirch) as well. RESULTS: The interspinous and the rigid device caused a significant increase of ROM at both adjacent segments during all directions of motion and under follower load, without significant difference between these devices. The ROM of L2/L3 tends to increase more than the ROM of L4/L5 after instrumentation without statistical significance. DISCUSSION: The "dynamic" Coflex device caused a significant increase of ROM at both adjacent lumbar segments comparable to the increase of ROM after instrumentation with the rigid Click X device. Other in vitro studies observed comparable biomechanical effects on the adjacent segments after fusion, but biomechanical spacer studies concentrated on the "noncompressible" X-Stop® and could not demonstrate a significant adjacent segment effect of this device. CONCLUSIONS: The hypothesis, that an interspinous device would reduce the stress on adjacent segments compared to a rigid posterior stabilization device, could not be demonstrated with this biomechanical in vitro study. Therefore, the protection of adjacent segments after instrumentation with dynamic devices is still not completely achieved.

[IBD ahead 2010--Answering important questions in Crohn's disease treatment]. / IBD ahead 2010--Antworten auf zehn zentrale Fragen in der aktuellen Therapie des Morbus Crohn.

The treatment of patients with inflammatory bowel disease has become more complex in recent years through the introduction of various immunosuppressive agents as well as the approval of monoclonal antibodies against TNF-α and patients receiving such treatment must be carefully monitored. National and international guidelines define a diagnostic and therapeutic context for the practitioner, but can only partially respond to specific questions on the procedure for individual patients. Within the framework of a project initiated by Abbott entitled "IBD ahead" 38 German IBD experts have elaborated concrete proposals for dealing with corticosteroids, immunosuppressants and TNF-α antibodies on the basis of the published literature and their own personal experience in order to close the gap between these guidelines and daily clinical practice. Statements were developed on the choice of correct timing of initiation, dose and duration of the individual substances and on how to proceed with patients exhibiting treatment failure. Moreover, recommendations are also made on drug combination strategies, safety monitoring and the risks regarding the development of infectious complications and malignancies. These recommendations are illustrated by case studies from everyday practice in participating centres.

Female patients suffering from inflammatory bowel diseases are treated less frequently with immunosuppressive medication and have a higher disease activity: a subgroup analysis of a large multi-centre, prospective, internet-based study.

BACKGROUND: The introduction of immunosuppressants and biologic agents has led to active debate and research about optimal therapeutic strategies considering risk factors and predictors of clinical outcome in inflammatory bowel disease (IBD). Data about gender-specific treatment differences and risk factors is lacking for IBD. The aim of the present study was to evaluate gender-related differences in the treatment of a distinct IBD patient population treated in the Rhein-Main region, Germany. METHODS: Data about past medical history, disease status and medical treatment of 986 outpatients treated in ten gastroenterological practices and three hospitals were collected from November 1st 2005-July 31st 2007 and analyzed with regard to gender-related differences in therapy and disease management. RESULTS: With the exception of an extended disease duration in women, no significant gender-related differences in demographic and clinical characteristics were observed. Men showed a significantly higher remission rate than women (p=0.025), while women received significantly less immunosuppressive medication compared to men (p=0.011). In addition, treatment with immunosuppressants was not different in women with child-bearing potential compared to menopausal women. CONCLUSION: Our investigation demonstrates for the first time gender-specific differences in the therapeutic management in a large cohort of IBD patients.

Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia.

BACKGROUND: To study the effects of deferring pegfilgrastim until day 4 on the reduction of chemotherapy-induced leukocytopenia. PATIENTS AND METHODS: Patients of age 61-80 years with aggressive lymphoma were randomly assigned to receive 6 mg pegfilgrastim on day 2 or 4 of a 2-week chemotherapy regimen (R-CHOP-14). RESULTS: Two hundred and ninety-two and 313 chemotherapy cycles were evaluable in 103 patients. Post-nadir pegfilgrastim serum levels were higher after day 4 than after day 2 application. This was associated with an attenuated leukocyte nadir after day 4 pegfilgrastim and there were fewer days with leukocytes <2 × 10(3)/mm(3) compared with day 2 pegfilgrastim. Grade 3 and 4 leukocytopenias (70% versus 43.3%; P < 0.001) and grade 4-only leukocytopenias (47% versus 20.5%; P < 0.001) were more frequent after day 2 pegfilgrastim. There were more chemotherapy cycles with grade 3 and 4 infections after day 2 than day 4 pegfilgrastim (9.4% versus 6.0%; P = 0.118). Interventional antibiotics were given more often after day 2 than after day 4 pegfilgrastim (30.7% versus 21.9% of cycles; P = 0.008). There were five deaths during leukocytopenia after day 2 and none after day 4 pegfilgrastim (P = 0.027). CONCLUSIONS: Administration of pegfilgrastim on day 4 was more effective in reducing severe leukocytopenias and resulted in fewer deaths during leukocytopenia. Pegfilgrastim should be given on day 4 to better exploit its myeloprotective potential.

Misinterpretation of NSAID-induced Colopathy as Crohn's disease.

Although NSAID-induced colonopathy characterised by erosions, ulcers, strictures and diaphragms has been known for quite some time, it is not infrequently misinterpreted endoscopically and histologically as Crohn's disease. This is exemplified by the present case history of a 39-year-old man with bloody diarrhoea and a stenosis in the transverse colon that was histologically interpreted as "consistent with Crohn's disease". Treatment with glucocorticoids, however, merely gave rise to adverse reactions. After surgical treatment of the stenosis, the episodes of bloody diarrhoea persisted, and endoscopy continued to reveal erosions and ulcers in the transverse colon. Changing treatment to azathioprine also failed to produce any positive response, merely causing side effects. Subsequent evaluation of the histological specimens by a consultant pathologist turned up the tentative diagnosis of NSAID-induced colonopathy. An analysis of the patient's medical history revealed that he was suffering from Bechterew's disease, for which he had long been taking diclofenac. This case history is a good example of the fact that NSAID-induced enterocolopathy is still too poorly recognised among internists, gastroenterologists and pathologists, and, on the basis of the discontinuous endoscopic and histological findings, is often misinterpreted as Crohn's disease.

[Pathophysiological-based diagnosis and therapy of iron-deficient anaemia in inflammatory bowel disease]. / Pathophysiologisch-orientierte Diagnostik und Therapie der Eisenmangelanämie bei chronisch entzündlichen Darmerkrankungen.

Anaemia is the most frequent extraenteric complication of inflammatory bowel disease (IBD, Crohn's disease and ulcerative colitis). A disabling complication of IBD, anaemia worsens the patient's general condition and quality of life, and increases hospitalization rates. The main types of anemia in IBD are iron deficiency anemia and anemia of chronic disease. The combination of the serum transferrin receptor with ferritin concentrations and inflammatory markers allows a reliable assessment of the iron status. Iron deficiency is usually treated with oral iron supplements. However, it is less effective in IBD and may lead to an increased inflammatory activity through the generation of reactive oxygen species. A systematic review of anemia in IBD, its pathogenetic features, epidemiology, diagnosis and therapy based on the evidence from recent studies will be the focus of this article.

Disruption of the FA/BRCA pathway in bladder cancer.

Bladder carcinomas frequently show extensive deletions of chromosomes 9p and/or 9q, potentially including the loci of the Fanconi anemia (FA) genes FANCC and FANCG. FA is a rare recessive disease due to defects in anyone of 13 FANC genes manifesting with genetic instability and increased risk of neoplasia. FA cells are hypersensitive towards DNA crosslinking agents such as mitomycin C and cisplatin that are commonly employed in the chemotherapy of bladder cancers. These observations suggest the possibility of disruption of the FA/BRCA DNA repair pathway in bladder tumors. However, mutations in FANCC or FANCG could not be detected in any of 23 bladder carcinoma cell lines and ten surgical tumor specimens by LOH analysis or by FANCD2 immunoblotting assessing proficiency of the pathway. Only a single cell line, BFTC909, proved defective for FANCD2 monoubiquitination and was highly sensitive towards mitomycin C. This increased sensitivity was restored specifically by transfer of the FANCF gene. Sequencing of FANCF in BFTC909 failed to identify mutations, but methylation of cytosine residues in the FANCF promoter region was demonstrated by methylation-specific PCR, HpaII restriction and bisulfite DNA sequencing. Methylation-specific PCR uncovered only a single instance of FANCF promoter hypermethylation in surgical specimens of further 41 bladder carcinomas. These low proportions suggest that in contrast to other types of tumors silencing of FANCF is a rare event in bladder cancer and that an intact FA/BRCA pathway might be advantageous for tumor progression.

[Future of chemotherapy]. / Zukunft der Chemotherapie.

The future development of chemotherapy is derived based upon recent advances. With regard to adjuvant therapy a trend towards standardized prediction of recurrence risk using all available prognostic markers (e.g., nomograms) is observed. Furthermore, in some tumors major progress has been made regarding the development of "molecular classifiers" defining tumor biology (predicting clinical outcome) by analysis of molecular changes. In adjuvant therapy considerable advances may be achieved by use of new chemotherapeutic agents as well as sequential, dose-dense and dose-intensified regimens. However, in metastatic disease no breakthrough can be expected at least with regard to survival suggesting that quality of life needs to be addressed with more emphasis. Using targeted drugs alone or in combination with chemotherapy advances concerning adjuvant therapy as well as metastatic disease are observed. Further targeted drugs have entered clinical development. However, clarification of the relation between detection of the target(s) and drug activity will fundamentally change current treatment concepts.