Sodium taurocholate co-transporting polypeptide deficiency.

INTRODUCTION: Little is known about bile acid transporter defects on the basolateral side of hepatocytes. In 2015 Vaz et al. published a first case of SLC10A1 mutation causing Na-taurocholate Co-transporting Polypeptide deficiency with hypercholanemia and normal bilirubin and Autotaxin levels. The index patient presented with failure to thrive, but without pruritus or jaundice. Several new cases have been published since, but the full spectrum of clinical presentation of mutations in SLC10A is not known. The primary aim of this review is to report a patient with a novel homozygous mutation and discuss the findings in the light of all other reported cases to date. MATERIAL AND METHODS: We describe the findings of a patient with a previously unreported homozygous mutation and review all published cases to date in English on PubMed. RESULTS: Our female patient born in 2002 presented with a feeding disorder and failure to thrive akin to the first description by Vaz. Workup suggested underlying liver disease although she did not complain of pruritus. Serum levels of aminotransferases, alkaline phosphatase, gamma-glutamyl transferase and bilirubin were normal. Plasma bile acids were chronically elevated, up to 150-fold. A first liver biopsy performed at 2 years of age showed unspecific findings with focal steatosis. Ursodeoxycholic acid treatment was introduced and the liver panel monitored regularly. At age 14, a second biopsy was performed, and histology was within normal limits. At this time, serum Autotaxin levels were found to be in normal range. Finally, genetic analysis revealed a homozygous 5 bp deletion in the gene SLC10A1 resulting in a premature stop codon predicted to lead to a complete NTCP loss of function. Most other reported cases to date carry the c.800C>T (p.Ser267Phe) mutation and are asymptomatic. DISCUSSION: NTCP deficiency appears to have a benign course as most patients are asymptomatic. Many patients seem to present with transient neonatal jaundice. Large variations in total plasma bile acid levels are observed between patients; they may be linked to the underlying genetic mutation or to yet uncharacterized compensatory mechanisms. Longer follow-up is needed to evaluate the long-term consequences of this newly identified inherited disease of bile acid transport.

[Unexpected deposits in the upper gastrointestinal tract : When medical history matters]. / Unerwartete Ablagerungen im oberen Gastrointestinaltrakt : Wenn es ohne klinische Angaben nicht weitergeht.

In order to regulate their phosphate uptake, patients with end-stage renal disease rely on phosphate binders such as lanthanum carbonate (LC). The earliest histopathological reports of this rare entity in the gastrointestinal mucosa were described and published in 2015.We present a case of an 80-year-old patient with LC gastro-enteropathy. Histopathologically it can mimic other drug-induced depositions and even infectious or neoplastic entities. Evaluation of the patient's medical and especially drug history is essential to obtain the appropriate diagnosis. We present an overview of the clinical presentation and histological differential diagnosis of LC.

Coronary Heart Disease and an Incidental Parathyroid Carcinoma.

A 71-year-old woman was admitted with angina pectoris. During hospitalization she developed a myocardial infarction (NSTEMI). Laboratory results revealed a mild elevated troponin and an elevated calcium level (3.35 mmol/l). Subsequently, there was a decreased phosphate (0.36 mmol/l [normal 0.81-1.62 mmol/l]) as well as 16-fold elevated serum level of parathyroid hormone (PTH, 1156 ng/l [normal 10-73 ng/l]), indicating a primary hyperparathyroidism. Sonographically a thyroidal node was detected, not clearly demarcated (TIRADS 5). FNA showed a monomorphic, partial follicular cell population with an immunohistochemical positivity for PTH. Magnetic resonance imaging (MRI) showed a 5 cm large tumor at the right caudal pole of the thyroid with compression of the dorsolateral trachea without infiltration. Surgical removal with en bloc resection of the right hemithyroid with parathyroidectomy was performed. Postoperatively the PTH level dropped to 12.1 ng/l. Pathological examination revealed a 5 cm tumor with infiltration of the thyroid and a perineural invasion. The diagnosis of a presymptomatic parathyroid carcinoma could be established. The affirmative histopathological diagnosis of a parathyroid carcinoma can be challenging and is limited to tumors with evidence of invasive growth in adjacent structures such as the thyroid and/or soft tissue, perineural spaces, angioinvasion of capsular and/or extracapsular vessels, and/or documented metastases.

[Digital pathology : The time has come!] / Digitale Pathologie : Die Zeit ist reif!

BACKGROUND: Digital pathology (DP) and whole-slide imaging (WSI) technology have matured substantially over the last few years. Meanwhile, commercial systems are available that can be used in routine practice. AIMS: Illustration of DP experiences in a routine diagnostic setting. RESULTS AND CONCLUSIONS: A DP system offers several advantages: 1) glass slides are no longer unique; 2) access to cases is possible from any location; 3) digital image analysis can be applied; and 4) archived WSI can be easily accessed. From this point, several secondary advantages arise: a) the slide compilation of the case and the case assignment is fast and safe; b) carrying cases to the pathologist is obsolete and paperless work is possible; c) WSI can be used for a second opinion and be accessible in remote locations; d) WSI of referred cases are still accessible after returning the slides; e) histological images can easily be provided in tumor boards; f) the office desk is clean; and g) a "home office" is possible. To introduce a DP system, a comprehensive workflow analysis is needed that clarifies the needs and wishes of the respective institute. In order to optimally meet the requirements, open DP platforms are of particular advantage, because they enable the integration of scanners from various manufacturers. Further developments in image analysis, such as virtual tissue reconstruction, could enrich the diagnostic process in the future and improve treatment quality.

Reproducibility of histopathologic tumor grading in penile cancer--results of a European project.

Since reliable molecular prognostic parameters for inguinal lymph metastases in penile cancer are not available, tumor grading is often used as a surrogate prognostic tool for the indication of inguinal lymphadenctomy and has been integrated into the current TNM classification for penile cancer. The reliability of tumor grading is under discussion. We examined interobserver grading variability in 90 primary penile carcinomas, assessed by 12 different uropathologists from five European countries. Tumor grading, following the CAP scheme, was compared, and interobserver variability was calculated using kappa statistics. The interobserver variability was high as reflected by an overall low kappa coefficient (mean k = 0.34) and reached a moderate level only in 26.4 % of the cases (range 0.02-0.67). The percentage of G1 tumors assigned ranged from 8.6 to 52.5 %, G2 tumors from 27.1 to 72.6 % and G3 tumors from 11.7 to 48.7 %. Only some observers assigned G4 with a range of 0.6-21.9 %. Subdivision into low and high grade according to UICC and EAU classifications differed significantly (P < 0.001). Low reproducibility of grading in penile carcinomas with the favored method does not allow a reliable prognostication of tumor aggressiveness. Inclusion of histological grading into the TNM classification currently seems not to be a benefit.

Perianal abscess caused by Actinomyces: report of a case.

Most anal abscesses are caused by anal fistula and invasion of the surrounding tissues by a mixed colonic flora. The treatment comprises excision of the abscess and. if appropriate, fistulectomy. Primary anorectal actinomycosis and perianal actinomycosis are very rare and are caused by Actinomyces, which is a ubiquitous microaerophilic bacterium. Here we report a case of perianal actinomycosis. The patient had a short history of painless perineal induration without fever or leucocytosis with normal routine blood tests. After excision sulphur granules drained from the cavity and the pathological investigations were indicative of perianal actinomycosis. Appropriate surgery and antibiotic treatment healed the perianal infection. After elimination of other diagnoses, e.g. Crohn's disease, tuberculosis and malignant growths, this rare case of perianal actinomycosis should be kept in mind in the differential diagnosis of a painless perianal mass.

[Development of a three-dimensional primary prostate cancer cell culture model]. / Entwicklung eines dreidimensionalen Prostatakarzinomzellkulturmodells.

Much prostate cancer research is based on cell culture results. Recent genomic studies found major differences between primary prostate cancer tissue and established prostate cancer cell lines, which calls into question the clinical relevance of study results based on cell cultures.Using primary cultures of prostate cancer cells from prostatectomy specimens seems to be a reasonable solution, but primary cell cultures are much more difficult to establish. In this study, a primary cell culture model was combined with an invasion assay. With this combination it was possible not only to select invasive cell clones from the primary culture but also to culture these cells in a three-dimensional model, forming spheroids. A further characterization of this cell population was done by comparative genomic hybridization, showing numerous genetic alterations. The presented cell culture model offers, for the first time, an opportunity to isolate invasive growing cells from primary prostate cancer tissue and cultivate these cells for further analyses.

Submucosal cushioning with water jet before endoscopic mucosal resection : Which fluids are effective?

BACKGROUND: Several new techniques have recently been described that allow the endoscopic mucosal resection even of broad-based flat lesions in the gastrointestinal tract. The technique recently described by us of using a water jet dissector (Helix HydroJet) for a selective deposition of liquid in the submucosal lamina has now been combined with different substances, and their effects have been compared. MATERIAL AND METHODS: Gastroscopies were carried out in 8 pigs under intubation anesthesia, and 2 submucosal cushions each were created in the stomach using one out of 4 test substances (gelatin, glucose 50, hydroxyethyl starch [HES] 10%, dextran 40), as well as one cushion of isotonic saline solution placed in each area via the Helix HydroJet). The height of the submucosal cushions was intermittently measured over a period of 40 or 20 min, respectively, by miniprobe endosonography. In 7 of the animals the stomach was subsequently subjected to mucosal resection. The specimens and the gastric wall were histologically assessed to evaluate the localization of the liquid cushion and the effect on adjacent layers of the gastric wall. RESULTS: All test substances produced strictly selective liquid cushions in the submucosa. With HES 10% and dextran the maximum height of the cushions initially increased and then decreased during the further course to an average of 90% of the initial height within 40 min. Isotonic saline solution showed the most rapid decrease in height (72% after 20 min). The histological assessment confirmed the selective nature of the liquid deposit in the submucosa. DISCUSSION: Plasma expanders produced cushions that initially increased in height but then remained constant for a longer period than cushions produced using glucose 50, gelatin, or isotonic saline solution. The combination of transmucosal jet application for elevation of the mucosa with plasma expanders is therefore an interesting approach to optimize endoscopic mucosal resections.

Sterilized mosquito net versus commercial mesh for hernia repair. an experimental study in goats in Mbarara/Uganda.

BACKGROUND: In industrialized countries alloplastic meshes are routinely used for hernia repair. However, in developing countries they are rarely available or affordable. This study compares textile properties and tissue response of commercial polypropylene mesh (PM) vs. sterilized nylon mosquito net (MN). METHODS: Textile properties were examined in vitro. In 12 goats one MN and one PM (5.5 x 8 cm) were implanted onto the posterior layer of the rectus sheath. Wound healing was clinically assessed. Histology was assessed after 4 or 16 weeks. RESULTS: MN was thinner and lighter, but weaker than PM. All wounds healed without complications. After 16 weeks foreign body granulomas in the MN group contained a higher proportion of inflammatory tissue (32.7 vs. 22.1%) and more giant cells (3.1 vs. 1.7/10 granulomas) with a significantly lower partial volume of foreign body (23.2 vs. 36.9%). Partial volume of fibrotic tissue was similar. MN was 1,000-fold cheaper than PM. CONCLUSIONS: PM was superior concerning strength and extent of inflammatory response. However, the findings indicate that MN might serve as a cheap substitute if an alloplastic mesh is needed but no commercial one is available or affordable. Further studies are justified which should include mosquito nets of different materials and long-term outcome.

[Optimized standards for prostate biopsy]. / Optimierte Standards der Prostatastanzbiopsie.

As individual risk assessment mainly depends on the correct prediction of the tumor's biological behavior, primary diagnosis plays a key role in the clinical management of prostate cancer patients. Prostate core needle biopsy, as a primary diagnostic tool, should not only confirm clinical suspicion but also supply the urologist with information which is necessary for risk-adapted therapy. The experience and competence of both the urologist and the pathologist are crucial for the quality of prostate core needle biopsy diagnosis. Optimized handling and submission of prostate core needle biopsy specimens by the urologist to the pathologist are of outstanding importance for improving the number of cancer cases detected. Increasing availability of molecular markers leads to the necessity of developing new tissue sampling procedures which allow prostate core needle biopsy specimens to be simultaneously studied histologically and by molecular approaches.

A phase II study of capecitabine and irinotecan in combination with concurrent pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer.

We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan (50 mg m(-2) weekly) and capecitabine (500 mg m(-2) bid days 1-38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/-/-; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/-, nausea/vomiting 9/10/2/-, and increased activity of transaminases 3/3/1/-. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy.

[Scrotal lymphangioma--a rare cause of acute scrotal pain in childhood]. / Das skrotale Lymphangiom--eine seltene Ursache des akuten Skrotums im Kindesalter.

INTRODUCTION: Scrotal lymphangioma is a rare differential diagnosis in boys with acute scrotal pain. CASE REPORT: A 5-year-old boy presented with acute scrotal pain and swelling. Physical examination demonstrated an unusual cystic scrotal mass with a normal testis. Ultrasound and MRI showed a complex septated cystic mass. The tumor was excised completely via an inguinal and scrotal approach. 2-year follow-up examinations with physical examination and ultrasound have shown no evidence of recurrence. CONCLUSIONS: Scrotal lymphangiomas are commonly misdiagnosed preoperatively. When ymphangioma is suspected, ultrasound and MRI imaging of the adjacent inguinal, perineal and pelvic region should be performed. To prevent recurrence, complete surgical excision is mandatory.

Overexpression of a member of the pentraxin family (PTX3) in human soft tissue liposarcoma.

A unique feature of human soft tissue liposarcoma is a stable (12;16)(q13;p11) translocation observed mainly in myxoid and roundcell liposarcomas. This translocation results in FUS/CHOP fusion transcripts with a corresponding oncogenic protein. We hypothesised that genes downstream of FUS/CHOP might serve as attractive candidates for novel tumour associated antigens. Among a panel of analysed genes, only pentraxin related gene (PTX3) demonstrated high expression in liposarcomas as compared to normal tissues. The analysis of RNA and protein expression demonstrated concordant results. However, the level of RNA and protein overexpression did not correlate in all cases. Finally, PTX3 expression was not related to presence of a FUS/CHOP fusion transcript within the liposarcoma tissues. PTX3 has been associated with adipocyte differentiation and now, additionally, is characterised by a markedly increased expression in human soft tissue liposarcoma. This finding mandates further research efforts to clarify the exact role of PTX3 in liposarcoma oncogenesis.

[Malignant mesothelioma of the testes]. / Das maligne Mesotheliom des Hodens.

INTRODUCTION: Malignant mesothelioma of the tunica vaginalis is a very rare malignant tumour. The prevalence of mesothelioma is about 1 : 1 000 000: Only 1 % have their origin in the tunica vaginalis testis with a 5-year survival of less than 5 %. About 80 cases have been reported in the literature. In 41 % of these cases exposure to asbestos for many years was determines. CASE REPORT: We report on a 76-year-old patient who presented with an atypical hydrocele testis. Intraoperatively, thickened testicular walls and an crystalline lawn adjacent to the tunica vaginalis testis were found. CONCLUSIONS: Ultrasonography showing snow flurries together with cloudy hydrocele fluid and visible crystal particles and thickened testicular walls may help to identify a mesothelioma of the testicular walls. Intraoperative frozen section and a high inguinal orchiectomy is the operative method of choice.

Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted.

Tumours ferment glucose to lactate even in the presence of oxygen (aerobic glycolysis; Warburg effect). The pentose phosphate pathway (PPP) allows glucose conversion to ribose for nucleic acid synthesis and glucose degradation to lactate. The nonoxidative part of the PPP is controlled by transketolase enzyme reactions. We have detected upregulation of a mutated transketolase transcript (TKTL1) in human malignancies, whereas transketolase (TKT) and transketolase-like-2 (TKTL2) transcripts were not upregulated. Strong TKTL1 protein expression was correlated to invasive colon and urothelial tumours and to poor patients outcome. TKTL1 encodes a transketolase with unusual enzymatic properties, which are likely to be caused by the internal deletion of conserved residues. We propose that TKTL1 upregulation in tumours leads to enhanced, oxygen-independent glucose usage and a lactate-based matrix degradation. As inhibition of transketolase enzyme reactions suppresses tumour growth and metastasis, TKTL1 could be the relevant target for novel anti-transketolase cancer therapies. We suggest an individualised cancer therapy based on the determination of metabolic changes in tumours that might enable the targeted inhibition of invasion and metastasis.

A new technique of endoscopic full-thickness resection using a flexible stapler.

There is a significant need for a safe and easy technique for endoluminal endoscopic resection of gastrointestinal lesions, but such procedures are usually restricted to resection of the mucosal layer in order to preserve the integrity of the wall of the gastrointestinal tract. We present two patients, one with early cancer and one with a carcinoid tumor, who were treated by endoscopic full-thickness resection. We used a stapling device, consisting of a flexible shaft, which was positioned intraluminally, and a remote control. After pilot investigations in pigs and in human anatomical preparations, we performed a full-thickness resection of the gastric wall in these patients, using the flexible stapling device under gastroscopic control. Gastric wall specimens up to 4 cm x 4 cm in size were resected with the use of two to three stapler magazines. Both procedures followed an uneventful course and the patients made an uncomplicated recovery. Further studies are necessary to test the applicability of the technique in the management of other gastric neoplastic lesions.

[Regressive changes after short-term neoadjuvant antihormonal therapy in prostatic carcinoma: the value of Gleason grading]. / Regressive Veränderungen nach kurzzeitiger neoadjuvanter antiandrogener Therapie beim Prostatakarzinom Wann ist das Grading nach Gleason noch sinnvoll?

Although neoadjuvant, antihormonal therapy does not lead to an improvement in the outcome of prostatic carcinoma it is still used in the short-term in a subset of patients. Here we report the regressive changes due to this short-term treatment and analyse the impact on Gleason grading. The most frequent regressive changes in 82 tumors treated short-term were determined and quantified. The results were compared to a matched control group and also to the preoperative needle biopsies.A steep increase in regressive changes was observed within the first 4 weeks. After this point, changes increased only mildly. Within the first 2 weeks of treatment no significant changes compared to control tissue were present. Compared to the preoperative needle biopsies, pretreated tumors showed a significant upgrading. After 2 weeks of neoadjuvant antihormonal therapy, regressive changes are so great, that Gleason grading can no longer be recommended.

[Relevance of the neuroendocrine differentiation in prostatic carcinoma]. / Bedeutung der neuroendokrinen Differenzierung im Prostatakarzinom.

BACKGROUND: NE tumor cells are present in virtually all prostatic adenocarcinomas. As they express no androgen receptor they are hormone independent. During anti-androgenic therapy their number increases. Their prognostic value is controversial. MATERIAL AND METHODS: In 233 patients with prostatic carcinoma the NE differentiation was determined in a hot spot (7.9 mm(2)) with maximum CgA positive cell density. A high NE differentiation (HNE) was defined by a least 30 NE tumor cells, while less means a low NE differentiation (LNE). In addition the occurrence of NE tumor cells was defined as solitary or clustered (> or =5 NE tumor cells in close proximity). RESULTS: In advanced and high grade tumors more and clustered NE tumor cells could be found than in low grade and organ confined tumors. Moreover HNE tumors and occurrence of NE clusters resulted in a significant shorter progression-free interval. CONCLUSIONS: Besides the quantity of NE differentiation the quality of the growth pattern of NE tumor cells is of relevance in prostatic carcinoma.