Letrozole may be a valuable maintenance treatment in high-grade serous ovarian cancer patients.

OBJECTIVES: Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). METHODS: We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1. ESR1 expression data on all cancers (n=8901) and HGSOC (n=527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n=4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n=80). Finally, newly diagnosed ER+ HGSOC patients were offered a maintenance therapy with Letrozole. RESULTS: ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24months 60% when taking Letrozole versus 38.5% in the control group; p=0.035; RFS: IC50 reached by one subject versus 13.2months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12months compared to 87.5% when taking Letrozole in addition to Bevacizumab (p=0.026). CONCLUSIONS: Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.

[Necrotizing fasciitis of the hand and forearm : Acute surgical treatment and defect reconstruction with MatriDerm® and split-thickness skin graft]. / Nekrotisierende Fasziitis an Hand und Unterarm : Chirurgische Akutversorgung und Defektrekonstruktion mit Spalthaut und MatriDerm®.

This case report describes a 55-year-old male patient with type II necrotizing fasciitis (NF) of the hand and forearm. The rapid progression of the tissue infection could be successfully stopped with radical surgical débridement and antibiotic therapy. For the reconstruction of the extensive loss of soft tissue a combination of split-thickness skin graft (STSG) and the synthetic dermal substitute MatriDerm® was used. In cases of NF, MatriDerm® and STSG provide a rapidly available and simple alternative to other reconstruction techniques.

The epidemiology of knee injuries in children and adolescents.

BACKGROUND: Injuries in childhood and adolescence are frequent and the knee is one of the most common sites of injuries. This study aimed to analyze the epidemiology, gender distribution, age, and circumstances of knee injuries in childhood at a Level I Trauma Center in Austria. METHODS: All pediatric and adolescent trauma patients who presented in a 2-year period were recorded. Children managed with knee injuries were selected prospectively. Patients were divided into five age groups: infants (younger than 1 year); pre-school aged children (1-6 years); pre-pubertal school-aged children (7-10 years); early adolescent patients (11-14 years); and late adolescent patients (15-18 years). Five diagnosis-related groups were formed: extraarticular soft tissue injuries, intraarticular soft tissue injuries, patella disorders, fractures, and overload injuries. RESULTS: The study included 23,832 patients up to the age of 18 years, who presented with 1,199 knee injuries. There was a male predominance (m:f = 58,6%:41.4%). Boys had a lower mean age at presentation (11.9 years) as girls (12.3 years). The most common accident sites were outdoors (34.8%) and sports facilities (32.8%). Leading injury mechanisms were falls on level surfaces (58.1%) and traffic accidents (13.4%). The number of knee injuries and its severity increased with age. Knee injuries did not occur in infants. In general, extraarticular soft-tissue injuries were most common and fractures were rare. CONCLUSION: Knee injuries in children and adolescents are rare and extraarticular soft-tissue injury is the most frequent type of knee trauma. The number of knee injuries and its severity increases with age with a male predominance. Sports facilities and traffic injuries are important scenes of knee trauma. Mechanisms and patterns evaluated in this study can serve as the basis for knee-injury prevention efforts in children and adolescents and may be used for necessary precautions. LEVEL OF EVIDENCE: IV.

[Traumatic posterior dislocation of the sternoclavicular joint. A case report of joint stabilization with gracilis tendon graft]. / Die traumatische posteriore Luxation im Sternoklavikulargelenk. Fallpräsentation einer Stabilisierung mit Grazilissehnenplastik.

Dislocation of the sternoclavicular joint is an uncommon injury. Especially posterior dislocations with potentially life-threatening complications present a challenging situation for the treating surgeon regarding diagnosis and therapy. Reduction and fixation of the joint is the treatment of choice. We present the case of such an injury in an adolescent judoka who was treated by open reduction and reconstructive surgery using the gracilis tendon graft technique.

Prognostic and predictive value of TOPK stratified by KRAS and BRAF gene alterations in sporadic, hereditary and metastatic colorectal cancer patients.

BACKGROUND: Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. METHODS: Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. RESULTS: In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01). CONCLUSIONS: TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30-40% of CRC patients, may represent a new avenue of investigation for targeted therapy.

Neurohumoral interaction in the rat amygdala after central chemical stimulation.

The interactions of chemically induced thirst and hunger with deprivation-induced hunger and thirst, respectively, were studied in the amygdala. The results suggest direct neurohumoral blocking at this locus, rather than mediation through activated circuits.

Metastatic involvement of the urinary tract in patients with advanced ovarian carcinoma: lessons from the autopsy for an interdisciplinary treatment approach.

PURPOSE OF INVESTIGATION: Frequency and extent of metastases in urologic organs found at autopsy of ovarian carcinoma patients were evaluated. METHODS: Autopsy reports from 170 patients who died of advanced ovarian carcinoma between 1975 and 2005 were studied. The distribution of abdominal metastatic sites with particular attention to the involvement of the urologic organs, and hydronephrosis was analyzed. RESULTS: The distribution of metastatic sites was as follows: kidney (n = 6, 3.5%), urinary bladder (n = 38, 22.4%), and ureter (n = 20, 11.8%). In 36 patients, hydronephrosis was observed (21.2%); of these patients, 20 (55.6%) also had ureteral involvement. All patients with ureteral involvement had hydronephrosis. CONCLUSION: Hydronephrosis in late stages of ovarian carcinoma, usually attributed to extrinsic compression of the ureter by an abdominal tumor, may also be explained by ureteral metastases. This fact must be considered in the clinical management of these patients, particularly in the restoration of luminal patency through an endoscopically placed internal ureteral stent.

Comprehensive biodiversity analysis via ultra-deep patterned flow cell technology: a case study of eDNA metabarcoding seawater.

The characterization of biodiversity is a crucial element of ecological investigations as well as environmental assessment and monitoring activities. Increasingly, amplicon-based environmental DNA metabarcoding (alternatively, marker gene metagenomics) is used for such studies given its ability to provide biodiversity data from various groups of organisms simply from analysis of bulk environmental samples such as water, soil or sediments. The Illumina MiSeq is currently the most popular tool for carrying out this work, but we set out to determine whether typical studies were reading enough DNA to detect rare organisms (i.e., those that may be of greatest interest such as endangered or invasive species) present in the environment. We collected sea water samples along two transects in Conception Bay, Newfoundland and analyzed them on the MiSeq with a sequencing depth of 100,000 reads per sample (exceeding the 60,000 per sample that is typical of similar studies). We then analyzed these same samples on Illumina's newest high-capacity platform, the NovaSeq, at a depth of 7 million reads per sample. Not surprisingly, the NovaSeq detected many more taxa than the MiSeq thanks to its much greater sequencing depth. However, contrary to our expectations this pattern was true even in depth-for-depth comparisons. In other words, the NovaSeq can detect more DNA sequence diversity within samples than the MiSeq, even at the exact same sequencing depth. Even when samples were reanalyzed on the MiSeq with a sequencing depth of 1 million reads each, the MiSeq's ability to detect new sequences plateaued while the NovaSeq continued to detect new sequence variants. These results have important biological implications. The NovaSeq found 40% more metazoan families in this environment than the MiSeq, including some of interest such as marine mammals and bony fish so the real-world implications of these findings are significant. These results are most likely associated to the advances incorporated in the NovaSeq, especially a patterned flow cell, which prevents similar sequences that are neighbours on the flow cell (common in metabarcoding studies) from being erroneously merged into single spots by the sequencing instrument. This study sets the stage for incorporating eDNA metabarcoding in comprehensive analysis of oceanic samples in a wide range of ecological and environmental investigations.

The local microbiome after pediatric bladder augmentation: intestinal segments and the native urinary bladder host similar mucosal microbiota.

INTRODUCTION: Next-generation sequencing (NGS) techniques have provided novel insights into the microbiome of the urinary bladder (UB). In children after bladder augmentation using either ileum (ileocystoplasty, ICP) or colon (colocystoplasty, CCP), the fate of the mucosal microbiome introduced into the urinary tract remains unknown. OBJECTIVE: The aim was to compare the mucosal microbiome of the native UB vs the augmented intestinal segment (IS) using NGS. STUDY DESIGN: Twelve children after bladder augmentation (ICP n = 6, CCP n = 6) were included. Biopsies were taken during routine postoperative cystoscopy from the native UB and the IS. Specimens underwent whole-genome DNA extraction, 16S rRNA gene amplification, NGS, and Quantitative Insights Into Microbial Ecology (QIIME) data analysis. Downstream statistical data analyses were performed in Calypso. RESULTS: Patients' median age at the time of surgery was 11 years (6-17 years), and the median interval between augmentation and sampling was 7 years (4-13 years). α-Diversity (Shannon diversity index) was not significantly different between IS vs UB, ICP vs CCP, and male vs female. No general differences in the overall bacterial pattern (ß-diversity) were found between IS, UB, ICP, and CCP groups. The groups overlapped in principal coordinate analysis (PCoA) and non-metric multidimensional scaling (NMDS) analysis (Figure). Age at sampling had a statistically significant influence on ß-diversity at the genus level. Corynebacterium, Pseudoxanthomonas, Lactobacillus, Flavobacterium, and Micrococcus were the most dominating taxa detected over all samples. There was an obvious dominance of the genus Corynebacterium in the samples taken from the UB and IS in both ICP and CCP patients. Limitations of this study include the relatively small number of patients. CONCLUSION: After bladder augmentation, the native UB and augmented ISs (ICP and CCP) host similar microbiota despite their distinct differences of originating mucosal anatomy.

Apoptosis, Fas and systemic autoimmunity: the MRL-lpr/lpr model.

Proteins encoded by the fas and fas ligand (fasL) genes are involved in apoptotic cell death in lymphocytes. In this article we review the recent elucidation of the role of the Fas-FasL interactions in the maintenance of tolerance to self antigens and in the homeostatic regulation of lymphocyte clonal expansion, and discuss the mechanisms of autoimmunity in Fas- and FasL-deficient mutant mouse strains.

Breast cancer sagittal/horizontal plane location influences axillary lymph node involvement.

AIM: To assess the influence of tumour location on axillary lymph node involvement (ALNI) and prognosis in breast cancer by evaluating the significance of the sagittal/horizontal alignment. METHODS: We compared 57 patients with superficially located breast carcinomas up to 3.0 cm with patients having lesions in posterior planes of the breast. Both groups were matched according to age, time of diagnosis, tumour size, grade, hormonal receptor status and tumour site within the frontal plane. Histologic evidence of skin involvement, excluding tumours fulfilling the criteria for pT4b, was defined as inclusion criteria and reference plane for superficial tumour location. RESULTS: Tumours situated in the superficial region of the breast, compared to those located in deeper planes, have an increased risk of ALNI (p=0.023), whereas no difference was observed with reference to disease-specific survival (p=0.203). CONCLUSION: This study shows that ALNI is dependent on sagittal/horizontal as well as frontal tumour location. Clinicians should be aware that tumours lying posteriorly may be at increased risk of occult spread outside axillary lymph nodes.

Carcinogenicity of N'-nitrosonornicotine in Sprague-Dawley rats.

N'-Nitrosonornicotine was added to the drinking water of outbred Sprague-Dawley rats. Adenocarcinomas of the olfactory epithelium occurred in all 15 rats, squamous papillomas o- the esophagus in 1, squamous papillomas of the nonglandular stomach in 1, and a hepatacellular tumor in 1. The possible ingestion and subsequent in vivo nitrosation of nicotine and/or nornicotine could create a serious carcinogenic hazard to cigarette smokers.

Carcinogenesis in F344 rats by N-nitrosomethyl-n-propylamine derivatives.

The carcinogenicity of N-nitrosomethyl-n-propylamine and five of its derivatives, including N-nitrosomethyl-n-butylamine, was compared by oral administration of the compounds to inbred F344 rats. N-Nitromethyl-n-propylamine and N-nitrosomethyl-n-butylamine given in drinking water induced tumors of the upper gastrointestinal tract, mainly carcinomas of the esophagus, and appeared to be of comparable potency. N-Nitrosomethyl(2-hydroxypropyl)amine also mainly induced esophageal carcinomas (100% incidence) and lung tumors, whereas N-nitrosomethyl(2,3-dihydroxypropyl)amine mainly induced nasal cavity tumors and gave rise to a high incidence of esophageal tumors; however, it appeared to be less potent than the monohydroxy compound. N-Nitrosomethyl(2-oxopropyl)amine, the ketone corresponding to N-nitrosomethyl(2-hydroxypropyl)amine, was a more potent carcinogen than the latter at comparable doses in drinking water and gave rise to a high incidence of esophageal tumors and tumors of the trachea; female rats had a high incidence (15/20) of angiosarcomas of the liver, but only 2 male rats died with this tumor. When N-nitrosomethyl(2-oxopropyl)amine was administered at a lower dose in drinking water or at the same dose given by gavage, the incidence of esophageal tumors was lower and there were fewer carcinomas. After administration of large doses in drinking water to male and female rats, N-nitrosomethyl(3-carboxypropyl)amine, a urinary metabolite of several N-nitrosomethyl-n-alkylamines that induce tumors of the urinary bladder in rats, gave rise to a high incidence of transitional cell carcinomas of the bladder. The time to death of animals with these tumors was long, and there were few other tumors.

Carcinogenesis by isomers of N-nitroso-3,5-dimethylpiperidine.

The cis- and trans-isomers of N-nitroso-3,5-dimethylpiperidine were administered separately in drinking water solution to groups of 20 female F344 rats for 50 weeks. The concentrations of the solutions were 0.72 m M for the cis-isomer and 0.14 mM for the trans-isomer. In both groups the animals died with tumors of the upper gastrointestinal (GI) tract, mainly carcinomas of the esophagus, at about the same time. A third group of animals was given a mixture of the two isomers in the ratio of 5 cis:1 trans, and these animals died more rapidly with the same upper GI tumors. The trans-isomer appeared to be a more potent carcinogen than the cis-isomer. The 3,5-dimethyl derivative is a less potent carcinogen than nitrosopiperidine.

Relationship of rat urinary metabolites of N-nitrosomethyl-N-alkylamine to bladder carcinogenesis.

Nitrosomethylalkylamines with chain lengths from C4 (n-butyl-) to C14 (n-tetradecyl-) were each administered in three rats at doses equimolar with 12 mg of the butyl compound. All of the compounds administered to rats at this dose, twice a week for 30 weeks, induced tumors in 100% of the animals. Some of the compounds with even-numbered alkyl chains induced bladder tumors, and a connection was sought with the metabolites of these excreted in urine. The pooled 24-hr urine was extracted with ethyl acetate before and after acidification to provide a neutral fraction and a fraction containing nitrosoamino acids. The fraction containing the acids was analyzed by capillary gas chromatography and by gas chromatography-mass spectrometry after esterification with diazomethane; the neutral fraction was analyzed similarly. The principal metabolite of the nitrosoamines with odd-numbered chains was found in the acidic fraction and was identified as nitrosomethyl-2-carboxy-ethylamine. There were several acids in the mixtures derived from the nitrosamines with even-numbered chains, nitrososarcosine and nitrosomethyl-3-carboxypropylamine being the major components. There was no trend in the yields of the nitrosamino acids that could be correlated with the differences in carcinogenic potency between the nitrosamines; the maximum yield of acids was more than 30% (from the tetradecyl compound). The principal component of the neutral fraction (less than or equal to 1% of the nitrosomethylalkylamine administered) was nitrosomethyl-2-oxopropylamine. The yield of this compound increased with length of the even-numbered chain nitrosamines.

Carcinogenesis by derivatives of 1-nitroso-3,5-dimethylpiperazine in rats.

Four mononitrosopiperazines were administered to groups of 20 female Fischer 344 rats to compare their effectiveness as carcinogens. The four, 1-nitroso-3,5-dimethylpiperazine, its 4-acetyl derivative, its 4-benzoyl derivative, and 1-nitroso-3,4,5-trimethylpiperazine, were given as 0.7 mM solutions in drinking water, 100 ml to each rat per week. The length of treatment varied from 26 weeks for nitrosotrimethylpiperazine to 50 weeks for 1-nitroso-3,5-dimethyl-4-benzoylpiperazine. Dimethyl- and trimethylnitrosopiperazine gave rise to virtually 100% incidence of undifferentiated lymphomas of the thymus and leukemias within 30 weeks (in contrast to the non-C-methylated analogs which are noncarcinogenic or only weakly so). Acetyldimethylnitrosopiperazine was also a potent carcinogen, all of the rats treated with it dying within 30 weeks with tumors of the esophagus. In contrast, benzoyldimethylnitrosopiperazine was weakly carcinogenic, inducing only a small number of tumors of the forestomach and reducing the normal life span of the rats very little.

[Pollicization of the Index Finger in Patients with Congenital Thumb Hypoplasia]. / Pollizisation des Zeigefingers bei kongenitaler Daumenhypolasie.

Congenital thumb hypoplasia is a radial deficiency occurring in the form of sole dysplasia or in combination with additional aberrations. Thumb hypoplasia can be categorised into 5 grades ranging from mild deformity to complete absence of the thumb. Thumb hypoplasia leads to a disturbance of grip function depending on its severity. The choice of treatment is based on the degree of thumb hypoplasia. For hypoplasia greater than grade 3B, restoration of the thumb using pollicization of the index finger is the treatment of choice. For this purpose the index finger is transformed into a thumb and is transposed to the position of the thumb with vessels and nerves being retained. The skeleton has to be shortened, rotated and abducted, followed by reconstruction of the muscles in line with the function of the new thumb. This procedure facilitates a restoration with maximal stability, sensitivity and mobility. In cases of isolated thumb hypoplasia, pollicization of the index finger yields good results persisting into adulthood. If associated aberrations are present, the outcome is less predictable because of the preexistent stiffness of the index finger. Nevertheless, associated aberrations do not represent a contraindication for index finger pollicization.

Quantitative analysis of glucose loss during acute therapy for hyperglycemic hyperosmolar syndrome.

Four patients with severe hyperglycemia and hyperosmolality were studied to quantitate the major mechanisms responsible for the fall in blood glucose concentration. Insulin was not administered to any of these patients during the first 15 h of therapy. In each case, there was a fall in glucose concentration due to dilution; this was quantitated by chloride space analysis and accounted for 24-34% of the fall in concentration. The size of the glucose pool decreased for two reasons. Glucosuria accounted for the majority of the reduction in the size of the glucose pool in the patients with the smallest decrease in extracellular fluid (ECF) volume [and hence the best preserved glomerular filtration rate (GFR)]. In contrast, glucosuria was a less important factor in causing glucose loss in the patients with very low GFR values. The size of the glucose pool also decreased due to glucose metabolism that did not require exogenous insulin. Thus the fall in glucose concentration in the initial therapy in patients with the hyperglycemic hyperosmolar syndrome is multifactorial and is not absolutely dependent on exogenous insulin. Furthermore, the patients grouped in this diagnostic category represent a heterogeneous population with the common features of severe hyperglycemia, hyperosmolality, and a negative or weakly reactive test for serum ketones.

Limited hepatitis B immunoglobulin with potent nucleos(t)ide analogue is a cost-effective prophylaxis against hepatitis B virus after liver transplantation.

BACKGROUND: Prophylaxis against hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) includes lifelong hepatitis B immunoglobulin (HBIG) and oral antiviral agent(s). In the presence of high-genetic-barrier nucleos(t)ide analogues, the need for lifelong HBIG is questioned. We evaluated the safety and cost-effectiveness of a limited HBIG course. METHODS: OLT from 2006 to 2013 were reviewed. Patients with pre-OLT hepatitis B virus surface antigen who received HBV prophylaxis with 2 HBIG doses (anhepatic and first post-operative day; 10,000 units/dose) and potent nucleos(t)ide analogues were included. The primary end point was HBV recurrence (HBV-DNA detection). RESULTS: Thirteen patients (primary transplants) were included, median Model for End-Stage Liver Disease score was 18, and there was no fulminant failure; HBV-DNA was detected in 4 patients at OLT. After OLT, 10 patients received entecavir and/or tenofovir. Median follow-up was 23 months. One recurrence occurred (7.7%) at month 13 (HBV-DNA: 14 IU/mL); the graft maintained excellent function. This minimal viremic expression is related to hepatocellular carcinoma recurrence with neoplastic replication carrying integrated HBV-DNA; thus, there is no defined HBV viral recurrence. No graft loss or patient death was related to HBV recurrence. The 1-year patient and graft survival rate was 84.6%. Cost-savings in the first year was $178,100 per patient when compared with Food and Drug Administration-approved HBIG dosing. CONCLUSIONS: In the era of potent oral nucleos(t)ide analogues, a limited HBIG course appears to be cost-effective in preventing HBV recurrence.

A reinterpretation of schedule-induced behaviors based on a systematic analysis of behavior.

Confusion exists regarding the criteria to be used in determining whether or not particular behaviors are schedule-induced. Four critical characteristics of schedule-induced behaviors are suggested and a comparison made of the complete range of behaviors exhibited by body weight-reduced rats drinking in response to one of three stimuli. These were (1) a fixed-time food reinforcement schedule, (2) a meal of dry food, and (3) 24 hour water deprivation. Drinking, locomotion, rearing and oral and perioral behaviors occurred in accordance with the defining characteristics of schedule-induced behaviors. Rats in the fixed-time reinforcement condition also deposited significantly greater numbers of fecal boli. Sniffing and food bowl related behaviors occurred as terminal responses for this group. It is concluded that animals which receive reinforcers intermittently maintain high levels of arousal for extended periods, and that the presence of the schedule may mimic conditions experienced by wild rats in non-laboratory settings. In such conditions ambulatory behaviors may be particularly adaptive. In contrast, reinforcing sensory feedback and a stress reducing role may be particularly important in the mediation of oral behaviors (such as drinking) which occur during intermittent reinforcement.