Treatments and clinical outcomes in stage II colon cancer patients with 12-gene Oncotype DX Colon Recurrence Score® assay-guided therapy: real-world data.

BACKGROUND: The 12-gene Oncotype DX Colon Recurrence Score® result quantifies the recurrence risk in stage II/III colon cancer (CC). This real-world study investigated stage II CC patients whose treatment decisions incorporated the Recurrence Score® (RS) result. MATERIALS AND METHODS: This retrospective analysis of a prospectively designed cohort included all stage II, mismatch repair-proficient CC patients who underwent 12-gene testing through Clalit between January 2011 and December 2016 and had available data with a minimum 3-year follow-up. RESULTS: The analysis included 938 patients {median age 68 [interquartile range (IQR) 60-76] years; 96% T3 tumors}. The median RS was 26 (IQR 19-33) and the three RS categories (0-29, 30-40, 41-100) included 65%, 24%, and 11% of patients, respectively. Chemotherapy (CT) use differed significantly between the three RS categories (14%, 36%, and 60%, respectively; P < 0.001). The CT and observation-only groups were imbalanced with worse clinicopathologic characteristics in the former. Among observation-only patients, Kaplan-Meier (KM) estimates for recurrence-free interval (RFI) and CC-specific survival (CCSS) differed significantly between the three RS categories (P < 0.001). Clinical outcomes by treatment (CT versus observation) within each RS category revealed no differences in RFI and CCSS in the RS 0-29 and 30-40 categories. In contrast, in the RS 41-100 category, the difference in RFI trended toward significance (P = 0.066), and for CCSS, a statistically significant difference was observed, with better outcomes among CT-treated patients (P = 0.035). CONCLUSIONS: RS results are prognostic in stage II CC. Among RS 41-100 patients, outcomes were better in CT-treated versus observation-only patients despite worse clinicopathologic characteristics, suggesting that CT confers clinical benefit in high-risk patients.

A transporter that allows phosphate ions to control the polymorph of exoskeletal calcium carbonate biomineralization.

The SLC20A2 transporter supplies phosphate ions (Pi) for diverse biological functions in vertebrates, yet has not been studied in crustaceans. Unlike vertebrates, whose skeletons are mineralized mainly by calcium phosphate, only minute amounts of Pi are found in the CaCO3-mineralized exoskeletons of invertebrates. In this study, a crustacean SLC20A2 transporter was discovered and Pi transport to exoskeletal elements was studied with respect to the role of Pi in invertebrate exoskeleton biomineralization, revealing an evolutionarily conserved mechanism for Pi transport in both vertebrates and invertebrates. Freshwater crayfish, including the study animal Cherax quadricarinatus, require repeated molt cycles for their growth. During the molt cycle, crayfish form transient exoskeletal mineral storage organs named gastroliths, which mostly contain amorphous calcium carbonate (ACC), an unstable polymorph long-thought to be stabilized by Pi. RNA interference experiments via CqSLC20A2 dsRNA injections reduced Pi content in C. quadricarinatus gastroliths, resulting in increased calcium carbonate (CaCO3) crystallinity and grain size. The discovery of a SLC20A2 transporter in crustaceans and the demonstration that knocking down its mRNA reduced Pi content in exoskeletal elements offers the first direct proof of a long-hypothesized mechanism by which Pi affects CaCO3 biomineralization in the crustacean exoskeleton. This research thus demonstrated the distinct role of Pi as an amorphous mineral polymorph stabilizer in vivo, suggesting further avenues for amorphous biomaterial studies. STATEMENT OF SIGNIFICANCE: • Crustaceans exoskeletons are hardened mainly by CaCO3, with Pi in minute amounts • Pi was hypothesized to stabilize exoskeletal amorphous mineral forms in vivo • For the first time, transport protein for Pi was discovered in crayfish • Transport knock-down resulted in exoskeletal CaCO3 crystallization and reduced Pi.

Static Output-Feedback H∞ Control Design Procedures for Continuous-Time Systems With Different Levels of Model Knowledge.

This article suggests a collection of model-based and model-free output-feedback optimal solutions to a general H∞ control design criterion of a continuous-time linear system. The goal is to obtain a static output-feedback controller while the design criterion is formulated with an exponential term, divergent or convergent, depending on the designer's choice. Two offline policy-iteration algorithms are presented first, which form the foundations for a family of online off-policy designs. These algorithms cover all different cases of partial or complete model knowledge and provide the designer with a collection of design alternatives. It is shown that such a design for partial model knowledge can reduce the number of unknown matrices to be solved online. In particular, if the disturbance input matrix of the model is given, off-policy learning can be done with no disturbance excitation. This alternative is useful in situations where a measurable disturbance is not available in the learning phase. The utility of these design procedures is demonstrated for the case of an optimal lane tracking controller of an automated car.

From sporadic single genes to a broader transcriptomic approach: Insights into the formation of the biomineralized exoskeleton in decapod crustaceans.

One fundamental character common to pancrustaceans (Crustacea and Hexapoda) is a mineralized rigid exoskeleton whose principal organic components are chitin and proteins. In contrast to traditional research in the field that has been devoted to the structural and physicochemical aspects of biomineralization, the present study explores transcriptomic aspects of biomineralization as a first step towards adding a complementary molecular layer to this field. The rigidity of the exoskeleton in pancrustaceans dictates essential molt cycles enabling morphological changes and growth. Thus, formation and mineralization of the exoskeleton are concomitant to the timeline of the molt cycle. Skeletal proteinaceous toolkit elements have been discovered in previous studies using innovative molt-related binary gene expression patterns derived from transcriptomic libraries representing the major stages comprising the molt cycle of the decapod crustacean Cherax quadricarinatus. Here, we revisited some prominent exoskeleton-related structural proteins encoding and, using the above molt-related binary pattern methodology, enlarged the transcriptomic database of C. quadricarinatus. The latter was done by establishing a new transcriptomic library of the cuticle forming epithelium and molar tooth at four different molt stages (i.e., inter-molt, early pre-molt, late pre-molt and post-molt) and incorporating it to a previous transcriptome derived from the gastroliths and mandible. The wider multigenic approach facilitated by the newly expanded transcriptomic database not only revisited single genes of the molecular toolkit, but also provided both scattered and specific information that broaden the overview of proteins and gene clusters which are involved in the construction and biomineralization of the exoskeleton in decapod crustaceans.

[Application of immunohistochemical study for the verification of diffuse axonal injury and determination of cause-and-effect relationships]. / Primenenie immunogistokhimicheskogo issledovaniia dlia verifikatsii diffuznogo aksonal'nogo povrezhdeniia i ustanovleniia prichinno-sledstvennykh sviazei.

Aim of this study is to establish a possibility of finding morphologic signs of diffuse axonal injury early after the injury. Use of immunohistochemical examination of the brain to detect protein ß-APP made it possible not only to diagnose this condition correctly, but also to reasonably and categorically answer the question of a causal relationship between causing damage and the onset of death.

[Certain modern methods for the diagnostics of gunshot injuries]. / Nekotorye sovremennye metody diagnostiki ognestrel'nykh povrezhdenii.

The objective of the present work was the analysis of the literature publications concerned with the modern approaches to the diagnostics of gunshot injuries with special reference to the most promising applications of the immunohistochemical methods. The use of certain antibodies for determining of intravitality and prescription of gunshot injuries is illustrated by concrete examples. It is concluded that further studies on the possibilities for the application of the immunohistochemical methods are needed.

[The role of the immunohistochemical investigations in the documentation of intravitality and severity of the gunshot injuries to the soft tissues]. / Rol' immunogistokhimicheskogo issledovaniia v ustanovlenii prizhiznennosti i vyrazhennosti ognestrel'nykh povrezhdenii miagkikh tkanei.

The objective of the present study was to determine intravitality and severity of a gunshot-inflicted trauma making use of the immunohistochemical (IGH) methods for the evaluation of the injury to the soft tissues of the wound canal. The immunohistochemical methods were employed to estimate the expression of fibrinogen and vimentin. The positive immunohistochemical reaction was obtained in the fibrinogen assay whereas the reaction in the zone of necrosis was negative. These findings give evidence of the thermal impact produced by the firearm projectile on the soft tissues. Deformation of the cytoskeleton registered in the IGH test for vimentin suggests its disintegration and therefore the severity of the injury. It is concluded that the investigations with the use of the immunohistochemical methods, make it possible to identify the affected parts of the wound canal.

[On the possibilities for the identification of the signs of the thermal impact of a gunshot associated with the formation of the resulting wound]. / O vozmozhnostiakh vyiavleniia priznakov termicheskogo vozdeistviia faktorov vystrela pri formirovanii ognestrel'nykh ran.

The present review of the literature publications is focused on the methods designed for the identification of the signs of the thermal impact of a gunshot associated with the formation of the resulting wound inflicted by various firearm projectiles. The historical and contemporary aspects of this topic are discussed with special reference to the immunodiagnostics as a new method extending the possibilities of forensic medical histology for the evaluation of the injuries to the soft tissues under the influence of thermal factors of the gunshot producing the firearm trauma.

[The detection of the biomolecular markers of the axonal damage resulting from the craniocerebral injury by the immunohistological methods]. / Immunogistokhimicheskaia detektsiia biomolekuliarnykh markerov aksonal'nogo povrezhdeniia pri cherepno-mozgovoi travme.

The objective of the present study was to define and evaluate the parameters of validity of the diagnostic signs of the diffuse axonal damage resulting from the craniocerebral injury with the use of the immunohistological reaction for the presence of amyloid precursor protein (beta-APP) in the brain tissue associated with the craniocerebral injury. Both histological and immunological methods were used. The positive beta-APP reaction was documented in 2 of the six cases. It is concluded that the positive results of the immunohistological reaction for the presence of beta-APP protein provide an additional information about the mechanism behind the damage and confirm the diagnosis of the craniocerebral injury in the cases when its macroscopic signs are either absent or unapparent.

[The importance of marker proteins of the nervous tissue for morphological diagnostics of the craniocerebral injury]. / Znachenie belkov-markerov nervnoi tkani dlia morfologicheskoi diagnostiki cherepno-mozgovoi travmy.

The present review of the literature involves 50 publications concerning various substrates of importance as the biological markers of axonal damages with special reference to the secondary molecular and cellular mechanisms on which to base in vitro and in vivo modeling of the craniocerebral injury. The results of the investigations with the application of mass-spectrometry for the identification of the proteins specifically synthesized in response to the injury are presented; their biological functions are described. The use of the sequential microscopic imaging technique and the immunohistochemical methods made it possible to determine that the majority of the marker proteins are involved in the specific intracellular processes that are triggered in response to the traumatic impact including apoptosis, proliferation, formation of lamellipodia, axon regeneration, actin remodeling, cell migration and inflammation. In addition, a rise in the amount of intracellular actin-associated proteins has been observed. It is concluded that the investigations into the properties and the physiological role of beta-amyloid precursor protein (beta-APP) are of special value for the characteristic of nervous tissue damages and morphological diagnostics of the craniocerebral injury.

[The interstitial disease of the lungs revealed by a histological study]. / Interstitsial'noe zabolevanie legkikh, ustanovlennoe gistologicheskim issledovaniem.

The authors report a case of the interstitial disease of the lungs revealed by a histological study that demonstrated intravital diagnostic faults in the patient in question. Moreover, a postmortem diagnostic error occurred; namely, the macroscopic study of the thoracic organs had shown the 0.5 cm long linear rupture of the adhesion in the right lung root region that was considered to be the cause of hemothorax and anemia of the internal organs which supposedly resulted in the patient's death. The definitive diagnosis of interstitial disease of the lungs was established based on the results of the histological study. The histological picture of the process is illustrated.

The natural history of pericardial tamponade secondary to recurrent ovarian carcinoma - A case report and review of the literature.

•We report a case of malignant cardiac tamponade secondary to ovarian carcinoma•We emphasize the quick and fatal outcome of such a complication•It seems that aggressive treatment offers the longest overall survival.

Conservative management for an entero-adnexal fistula at initial presentation of advanced ovarian carcinoma.

Gastrointestinal fistulae can occur in ovarian cancer patients, usually in the setting of advanced relapsed disease. Treatment typically involves immediate surgery.Here, we describe a case of an abscess resulting from an intestinal fistula as the first manifestation of advanced epithelial ovarian cancer, and we review the current literature on this subject. The patient was successfully treated with a combination of chemotherapy, antibiotics, and delayed surgery. Optimal debulking was achieved without a need for bowel resection.This report is the first of conservative management of a fistula in an ovarian cancer patient in the chemotherapy-naïve setting.

Chest wall shrapnel-induced beryllium-sensitization and associated pulmonary disease.

Chronic beryllium disease (CBD) is an exposure-related granulomatous disease mimicking sarcoidosis. Beryllium exposure-associated disease occurs mainly via inhalation, but skin may also be a source of sensitization. A 65-year-old male with a history of war-related shrapnel wounds was initially diagnosed with pulmonary sarcoidosis. Twenty years later, the possibility of a metal-related etiology for the lung disease was raised. A beryllium lymphocyte proliferation test, elemental analysis of removed shrapnel, and genetic studies were consistent with a diagnosis of CBD. This case demonstrates that retained beryllium-containing foreign bodies can be linked to a pathophysiologic response in the lung consistent with CBD.

HPV E6 degradation of p53 and PDZ containing substrates in an E6AP null background.

Human papillomavirus (HPV) type 16 and 18 E6 proteins target many of their cellular substrates for proteasome-mediated degradation. In the case of p53, this is mediated by the E6AP ubiquitin ligase. However it is still unclear whether other E6 substrates, in particular those containing PDZ domains, are also degraded in a similar manner. To investigate this, we established an epithelial cell line from E6AP-null mice and used these cells as a background to perform E6-mediated in vivo degradation assays. We show that the PDZ domain-containing substrates of E6, including Scribble, MAGI-1 and MAGI-3, are all subject to E6-mediated degradation in these cells. Strikingly, we also found that p53 could be degraded by E6 within these cells in a proteasome-dependent manner. These results demonstrate that HPV-16 and -18 E6 can target substrates for degradation in a manner independent of the E6AP ubiquitin ligase.

HPV16 E6 confers p53-dependent and p53-independent phenotypes in the epidermis of mice deficient for E6AP.

High-risk human papillomaviruses are the causative agents of cervical and other anogenital cancers. In these cancers, two viral oncogenes, E6 and E7, are expressed. E6 is best known for its ability to inactivate the tumor suppressor p53, which is thought to arise through ubiquitin-mediated degradation of p53 and involve a ternary complex between E6, p53 and the E3 ligase, E6AP. In mice transgenic for wild-type HPV16 E6, its expression leads to epithelial hyperplasia and an abrogation of normal cellular responses to DNA damage. Whereas only the latter phenotype is dependent upon E6's inactivation of p53, both are reduced in transgenic mice expressing an E6 mutant severely reduced in its binding to E6AP and other cellular proteins that bind E6 through a shared alpha-helix motif. Here, we investigated whether E6AP is required for the induction of the above phenotypes through the use of both E6AP-mutant and E6AP-null mice. E6, in the absence of E6AP retains an ability to induce epithelial hyperplasia, abrogate DNA damage responses and inhibit the induction of p53 protein following exposure to ionizing radiation. We conclude that E6 is able to induce both p53-dependent and p53-independent phenotypes through E6AP-independent pathways in the mouse.

An independent comparison of terbinafine and itraconazole in the treatment of toenail onychomycosis.

BACKGROUND: Previously, sponsored publications have shown that either terbinafine or itraconazole (pulse regimen) are effective for patients with toenail onychomycosis. However, independent comparative studies are lacking. OBJECTIVES: To objectively compare treatment with terbinafine and itraconazole in patients with toenail onychomycosis. METHODS: The effectiveness of terbinafine (250 mg/day 3 months) versus itraconazole pulse regimen (400 mg/day for the first week of each month, for three cycles) was retrospectively evaluated in patients with toenail onychomycosis using mycological tests and subjective outcome measures. Statistical analyses were performed using one-way analyses of variance (ANOVA) for continuous variables and Fisher exact tests for categorical variables. RESULTS: Included in the study were 117 patients (74 patients treated by terbinafine and 43 patients treated with itraconazole). Patients were examined at an average period of 20 months after the end of therapy. Mycological cure was observed in 70.6% and 62.8% of the patients who were treated by terbinafine or itraconazole, respectively (not statistically significant). Mean visual analogue scale assessment of treatment outcome was 79.9 mm (SD 24.7 mm) and 65.2 mm (SD 34.6 mm) for patients treated by terbinafine or itraconazole, respectively (p=0.008). When the results were stratified according to age and gender, it was observed that the advantage of terbinafine versus itraconazole retained statistical significance only for patients who were 55 years old and above, or females. CONCLUSIONS: Mycological cure proportions were not statistically significant between patients treated by terbinafine or itraconazole for toenail onychomycosis. However, better subjective outcome measures indicated an advantage for terbinafine over itraconazole, noticeable in females and patients 55 years old and above.

Tungiasis.

A 24-year-old man developed slow-growing lesions on subungual and plantar areas that appeared a few weeks after returning from a trip to South America. The diagnosis of tungiasis was established by microscopic examination of a lesion. Tungiasis is rarely seen in non-endemic areas.

Transition between solar keratosis and basal cell carcinoma.

Transition from solar keratosis (SK) to squamous cell carcinoma (SCC) is well known and vastly documented. The possible relation between SK and basal cell carcinoma (BCC) is rarely mentioned in the dermatopathological literature. In order to identify the characteristics of the relation between SK and BCC, 40 slides of the head and neck regions in which both SK and BCC had been diagnosed, were retrieved from a collection in the Institute of Pathology of Beilinson Medical Center, seen between 1984 and 1994. Gradual and continuous transition between SK and BCC was found in 15 (37.5%) of these 40 slides. In order to estimate the prevalence of this phenomenon, 73 additional slides, which had been diagnosed as BCC of the head and neck, were re-examined. Atypia of the spinous layer, as an initial marker for the development of SK, was sought in each slide. Revision revealed spinous layer atypia in 26 (35.6%) slides, in addition to the previously diagnosed BCC. In seven (9.6%) the transition between atypical spinous cells and BCC was gradual and continuous. A gradual and continuous transition between SK and BCC can be explained by the presence of pluripotent stem cells in the epidermis. Stem cells, following malignant transformation, may differentiate in different directions, resulting in both SK and BCC.