Tumor deposits should not be placed in the M category of TNM: A comparative survival analysis using SEER data.

Tumor deposits (TD) are tumor nodules in the lymphatic drainage area of colorectal cancer patients, and they are currently classified in the N category in the TNM classification. However, due to the associated poor prognosis, some small cohort studies suggest that TD belong in the M category. A retrospective study using The Surveillance, Epidemiology, and End Results program (SEER) data was performed in Stages III and IV colon carcinoma (CC) patients to evaluate the prognostic impact of TD. In multivariate analysis, TD have significantly negative effect on survival in both stages (Stage III HR = 1.4 [95% CI 1.4-1.5] and Stage IV HR = 1.3 [95% CI 1.2-1.3]). In Stage III, 5-year overall survival (OS) for patients with TD 49%, whereas it was 64% for patients without TD (p < .001). Additionally, in Stage IV patients without TD, the 5-year OS rates are superior at 21% compared to patients with TD, who show 5-year OS rate of 10% (p < .001). Stage III patients with TD (5-year OS 49%) have a significantly better prognosis compared to Stage IV patients (5-year OS 17%, p < .001). Therefore, despite the previous suggestions, this large scale study (n = 52,332) on outcomes in CC does not support the classification of TD in Stage IV.

Rapid evolutionary change in trait correlations of single proteins.

Many organismal traits are genetically determined and covary in evolving populations. The resulting trait correlations can either help or hinder evolvability - the ability to bring forth new and adaptive phenotypes. The evolution of evolvability requires that trait correlations themselves must be able to evolve, but we know little about this ability. To learn more about it, we here study two evolvable systems, a yellow fluorescent protein and the antibiotic resistance protein VIM-2 metallo beta-lactamase. We consider two traits in the fluorescent protein, namely the ability to emit yellow and green light, and three traits in our enzyme, namely the resistance against ampicillin, cefotaxime, and meropenem. We show that correlations between these traits can evolve rapidly through both mutation and selection on short evolutionary time scales. In addition, we show that these correlations are driven by a protein's ability to fold, because single mutations that alter foldability can dramatically change trait correlations. Since foldability is important for most proteins and their traits, mutations affecting protein folding may alter trait correlations mediated by many other proteins. Thus, mutations that affect protein foldability may also help shape the correlations of complex traits that are affected by hundreds of proteins.

Lymph node metastases and recurrence in pT1 colorectal cancer: Prediction with the International Budding Consortium Score-A retrospective, multi-centric study.

BACKGROUND: The International Collaboration on Cancer Reporting proposes histological tumour type, lymphovascular invasion, tumour grade, perineural invasion, extent, and dimensions of invasion as risk factors for lymph node metastases and tumour progression in completely endoscopically resected pT1 colorectal cancer (CRC). OBJECTIVE: The aim of the study was to propose a predictive and reliable score to optimise the clinical management of endoscopically resected pT1 CRC patients. METHODS: This multi-centric, retrospective International Budding Consortium (IBC) study included an international pT1 CRC cohort of 565 patients. All cases were reviewed by eight expert gastrointestinal pathologists. All risk factors were reported according to international guidelines. Tumour budding and immune response (CD8+ T-cells) were assessed with automated models using artificial intelligence. We used the information on risk factors and least absolute shrinkage and selection operator logistic regression to develop a prediction model and generate a score to predict the occurrence of lymph node metastasis or cancer recurrence. RESULTS: The IBC prediction score included the following parameters: lymphovascular invasion, tumour buds, infiltration depth and tumour grade. The score has an acceptable discrimination power (area under the curve of 0.68 [95% confidence intervals (CI) 0.61-0.75]; 0.64 [95% CI 0.57-0.71] after internal validation). At a cut-off of 6.8 points to discriminate high-and low-risk patients, the score had a sensitivity and specificity of 0.9 [95% CI 0.8-0.95] and 0.26 [95% 0.22, 0.3], respectively. CONCLUSION: The IBC score is based on well-established risk factors and is a promising tool with clinical utility to support the management of pT1 CRC patients.

Fully Automated Tumor Bud Assessment in Hematoxylin and Eosin-Stained Whole Slide Images of Colorectal Cancer.

Tumor budding (TB), the presence of single cells or small clusters of up to 4 tumor cells at the invasive front of colorectal cancer (CRC), is a proven risk factor for adverse outcomes. International definitions are necessary to reduce interobserver variability. According to the current international guidelines, hotspots at the invasive front should be counted in hematoxylin and eosin (H&E)-stained slides. This is time-consuming and prone to interobserver variability; therefore, there is a need for computer-aided diagnosis solutions. In this study, we report an artificial intelligence-based method for detecting TB in H&E-stained whole slide images. We propose a fully automated pipeline to identify the tumor border, detect tumor buds, characterize them based on the number of tumor cells, and produce a TB density map to identify the TB hotspot. The method outputs the TB count in the hotspot as a computational biomarker. We show that the proposed automated TB detection workflow performs on par with a panel of 5 pathologists at detecting tumor buds and that the hotspot-based TB count is an independent prognosticator in both the univariate and the multivariate analysis, validated on a cohort of n = 981 patients with CRC. Computer-aided detection of tumor buds based on deep learning can perform on par with expert pathologists for the detection and quantification of tumor buds in H&E-stained CRC histopathology slides, strongly facilitating the introduction of budding as an independent prognosticator in clinical routine and clinical trials.

Response Inhibition and Interference Control in Adult Attention Deficit Hyperactivity Disorder.

Introduction: Among the executive functions affected in attention deficit hyperactivity disorder (ADHD), inhibitory control is one of the primary areas of impairment, characterized by components that include response inhibition and interference control. Determining the impaired inhibitory control components will be useful in the differential diagnosis and treatment of ADHD. The present study aimed to investigate response inhibition and interference control abilities of adults with ADHD. Methods: The study included 42 adults diagnosed with ADHD and 43 healthy controls. The stop-signal task (SST) and Stroop test were used for assessing the response inhibition and interference control, respectively. Multivariate analysis of covariance was used for comparing the ADHD and healthy control groups in terms of their SST and Stroop test scores, wherein the age and education level of the participants were taken as covariables. The relationship between SST and Stroop Test and Barratt Impulsiveness Scale-11 (BIS-11) was tested by Pearson correlation analysis. Mann-Whitney U test was used for comparing the test scores between those who were administered with psychostimulants among the adults with ADHD and those who were not. Results: Response inhibition was observed to be impaired in adults with ADHD compared with the healthy controls, whereas no difference regarding interference control was observed. As per the Barratt Impulsiveness Scale-11 (BIS-11), a weak and moderately negative relationship was found between the stop signal delay and the attentional, motor, non-planning scores, and total scores and a weak positive relationship was found between the stop-signal reaction time and the attentional, motor, non-planning scores, and total scores. A significant improvement was observed in the response inhibition skills of the adults with ADHD who had received methylphenidate treatment compared to those who had not, and the former also showed lower impulsivity levels as measured by the BIS-11. Conclusions: It should be noted that response inhibition and interference control, which are considered under the umbrella of inhibitory control, may exhibit different characteristics in adult individuals diagnosed with ADHD and this is important for differential diagnosis. An improvement was observed in the response inhibition of adults with ADHD caused by psychostimulant treatment, which was associated with positive outcomes that were also noticeable by the patients. Understanding the underlying neurophysiological mechanisms of the condition would further facilitate the development of appropriate treatments.

The Relationship Between Disease Activity and Platelet Indices in Pemphigus: An Observational Preliminary Study.

Tests which have proven their efficacy and reliability in the follow-up of pemphigus patients are used only on a limited scale or take time to complete due to a lack of technical facilities in several centers. Therefore, more accessible methods are being considered for monitoring disease activity. We aimed to investigate the relationship between platelet function and disease activity based on the change in proinflammatory cytokine profile in pemphigus pathogenesis. The size of platelets correlates positively with their activity. Platelet sizes can be evaluated by the platelet volume index consisting of mean platelet volume (MPV), platelet-crit (PCT), and platelet distribution width (PDW). These indicators can be easily measured in complete blood count (CBC) with automatic blood counting devices, which do not require additional costs and are readily available. Patients diagnosed with pemphigus between April 2010 and February 2016 (n=18) in our center were retrospectively included in the study. Demographic data, follow-up period, clinical variants of the patients, platelet parameters (MPV, PDW, PCT), and platelet count (PLT) in CBC analysis with concurrent clinical activity, as well as indirect immunofluorescence (IIF) findings (positive highest titer) at the 6th and 12th month were recorded for each patient. MPV changes were consistent with the course of the disease. A statistically significant decrease in PCT levels was observed at the 12th month compared with the baseline levels (P<0.05). According to the baseline measurement, a statistically significant positive correlation (58.9%) was found between the 12-month difference measurements of IIF and PCT. Our data demonstrated that PCT decrease is correlated with IIF values. The significant correlation between PCT and IIF values in our study is important in showing the possible role of platelet index in the measurement of disease activity.

Challenges of the treatment of pediatric hepatosplenic bartonellosis: case report and literature review.

The hepatosplenic (HS) form of cat scratch disease (CSD) is rarely seen; however, management of the treatment is challenging for clinicians. Monotherapy or combination regimens may be preferred based on severity of cases. Along with that, there are uncertainties as to the combination and duration of antibiotics effective against the microorganisms. In this report, a 12-year-old girl diagnosed with HS-CSD and unresponsive to primary treatment with macrolide group antibiotic was presented. The patient had liver findings compatible with CSD, confirmed radiologically and pathologically, and Bartonella henselae indirect immunofluorescence assay IgG was positive at 1/2048 titre. A combination therapy for six months with doxycycline and rifampicin was initiated, and the patient was successfully treated. The preference for monotherapy or combination regimen in HS-CSD is predominantly determined by the clinician according to the severity of the patient's clinical findings. The effectivity of antimicrobial regimen in HS-CSD requires further investigation.

A comprehensive overview of tumour deposits in colorectal cancer: Towards a next TNM classification.

The management of colorectal cancer (CRC) highly relies on the TNM staging system. Tumour deposits (TDs), important histoprognostic factors, are detected in approximately 20% of CRCs and associated with poor prognosis. Integration of TDs in the TNM staging remains a subject of lively debate and differs over the successive TNM classifications. Currently TDs, whatever their number, are considered in pathologic staging only in the absence of lymph node metastasis (LNM; subcategory pN1c). However, the medical community is divided over this way of integrating TDs in the TNM staging system. Considering the personalization of the type and duration of adjuvant chemotherapy in stage III colon cancer according to the number of LNM, this issue has become of growing importance. Thus, ignoring TDs in the presence of LNM represents a major prognostic underestimation and leads to wrong therapeutic decisions. Hence, considering the growing significance of prognostic role, the scientific complexity, and a potential therapeutic effect of TDs, we provide an overview of current knowledge about TDs. Based on the results from recent publications, we also provide plausible scenarios of integration of TDs into the next TNM classification system.

Cancer and constitutional Mismatch Repair Deficiency syndrome due to homozygous MSH 6 mutation in children with Café au Lait Spots and review of literature.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations of mismatch repair (MMR) genes. CMMRD syndrome is characterised by early onset malignancies in children. CASE: Here we present affected children of consanguinous parents diagnosed with CMMRD syndrome due to germline bi-allelic MSH 6 gene mutations with café au lait spots and multiple family cancers from Turkey and reported cases with CMMRD syndrome associated MSH 6 mutation in English literature. Hence, we reviewed English literature from 1990 to 2020 using Pub-Med database. Keywords used to search included constitutional mismatch repair deficiency syndrome, childhood cancer and MSH 6 gene mutation. CONCLUSIONS: We emphasize that the inclusion of CMMRD syndrome in the differential diagnosis of a patient who presents with cafe´ au lait spots and/or hypopigmented skin lesions and cancer especially when consanguinity and/or a history of cancer coexist in children.

Neurocognitive Functions in Bipolar Disorder in Relation to Comorbid ADHD.

INTRODUCTION: Bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) often co-occur in adult population. Both conditions present various neurocognitive and behavioral problems. We aimed to examine neurocognitive functions in adult patients with comorbid BD and ADHD (BD+ADHD) in comparison to patients with only BD, only ADHD and healthy controls (HCs). METHOD: An extensive cognitive battery which evaluates verbal learning and memory, visual memory, processing speed, attention, executive functions, working memory and verbal fluency, was used to assess neurocognitive functions respectively in adult (age 18-65 years) patients with BD (n=37), ADHD (n=43), BD+ADHD (n=20) in comparison to HCs (n=51). The Multivariate Analysis of Covariance models, where age, level of education and total BIS-11 scores were included as covariates, were used for comparing neurocognitive scores among groups. RESULTS: Both BD and BD+ADHD groups showed significantly poorer performance than HCs in processing speed, attention, executive functions, and verbal fluency domains. The BD group had additional significant deficits in executive functions, verbal learning and memory domains. There were no significant differences between BD and BD+ADHD groups with regards to verbal learning and memory, visual memory, processing speed, attention, executive functions, working memory and verbal fluency domains. Patients with only ADHD showed significantly poorer performance than HCs in verbal fluency domain. CONCLUSIONS: Our results show similarities in the neurocognitive functions of adults with BD and BD+ADHD across a wide range of cognitive domains. The findings point to the need for further exploration of diverging and converging neurodevelopmental trajectories of BD and ADHD.

Evolution of ß-lactamases and enzyme promiscuity.

ß-Lactamases represent one of the most prevalent resistance mechanisms against ß-lactam antibiotics. Beyond their clinical importance, they have also become key models in enzymology and evolutionary biochemistry. A global understanding of their evolution and sequence and functional diversity can therefore aid a wide set of different disciplines. Interestingly, ß-lactamases have evolved multiple times from distinct evolutionary origins, with ancestries that reach back billions of years. It is therefore no surprise that these enzymes exhibit diverse structural features and enzymatic mechanisms. In this review, we provide a bird's eye view on the evolution of ß-lactamases within the two enzyme superfamilies-i.e. the penicillin-binding protein-like and metallo-ß-lactamase superfamily-through phylogenetics. We further discuss potential evolutionary origins of each ß-lactamase class by highlighting signs of evolutionary connections in protein functions between ß-lactamases and other enzymes, especially cases of enzyme promiscuity.

Spinopelvic alignment does not change after bilateral total hip arthroplasty in patients with bilateral Crowe type-IV developmental dysplasia of the hip.

OBJECTIVE: This prospective study aimed to evaluate the changes in the sagittal alignment after total hip arthroplasty (THA) in patients with hip osteoarthritis (OA) secondary to Crowe type-IV developmental dysplasia of the hip (DDH) and whether THA would contribute to the relief of low-back pain (LBP). METHODS: A total of 27 patients (2 men and 25 women) with bilateral hip OA secondary to Crowe type-IV DDH were enrolled in this study. Their mean age at the time of surgery was 40,36±12,35. All patients underwent simultaneous, bilateral THA between January 2015 and December 2016. Clinical assessment included Oswestry disability index (ODI) score and Harris hip score (HHS), and pelvic incidence (PI), sacral slope (SS), lumbar lordosis (LL), and pelvic tilt (PT) were measured from radiographs. RESULTS: Preoperatively, all the patients had hip and low-back pain. Preoperative and final follow-up ODI scores were 48.3 and 3.9 (p=0.000), respectively. HHS changed from 43.54 to 92.68 (p=0.000). PT and PI significantly changed from -20.4°±20.4° to 3.2°±16.7° (p=0.001) and from 26.6°±35.1° to 47.4°±17.9° (p=0.001), respectively. There were no significant differences regarding the SS and LL measurements. Age or limb-length discrepancy was not significantly associated with the spinopelvic alignment measurements. CONCLUSION: Restoring the function of the hip with THA is shown to improve hip-associated LBP, but the accompanying hyperlordosis does not change. THA in patients with bilateral Crowe type-IV hips relieves hip pain as well as associated LBP. Hyperlordosis of the lumbar vertebra does not change after surgery, but PI and PT changes are observed; this improvement might have a role in the relief of LBP. LEVEL OF EVIDENCE: Level IV, Therapeutic study.

Bone Marrow Necrosis in a Patient Following Blinatumomab Therapy.

Bone marrow necrosis (BMN) is an extremely rare condition characterized by necrosis of the myeloid tissue and medullary stroma leaving an amorphous eosinophilic background and ill-defined necrotic cells in the hematopoietic bone marrow. Several conditions are associated with BMN, including sickle cell disease, metastatic carcinoma, and hematologic malignancies. It is also associated with the use of antineoplastic drugs, such as fludarabine, interferon alpha, and imatinib. Blinatumomab is a CD19/CD3 bispecific T-cell engager antibody which redirects autologous CD3-positive T cells to CD19-positive lymphoblasts creating a cytolytic synapse leading to blastic cells. Cytokine release syndrome, cerebral nervous system toxicities, and febrile neutropenia are the most frequent adverse effects of blinatumomab. Here, we report an adolescent boy with relapse/resistant acute lymphoblastic leukemia developing BMN following blinatumomab therapy. To our knowledge, this is the first case report on BMN following blinatumomab treatment.

A synchronous occurrence of bifocal intracranial germinoma and bilateral testicular epidermoid cyst in an adolescent patient with Klinefelter`s syndrome.

Özyörük D, Kocayozgat A, Yaman-Bajin I, Çetindag F, Oguz- Erdogan AS, Günes A. A synchronous occurrence of bifocal intracranial germinoma and bilateral testicular epidermoid cyst in an adolescent patient with Klinefelter`s syndrome. Turk J Pediatr 2019; 61: 456-459. Klinefelter syndrome (KS) is characterized by an additional X chromosome in males leading to a karyotype of 47,XXY. It is associated with an increased risk of certain malignancies, including leukemia, breast cancer and extragonadal germ cell tumor such as mediastinal germ cell tumors and rarely intracranial germ cell tumors. It is possible that the increased risk of developing certain cancers can be attributed to a direct effect of the chromosomal abnormality or the combined action of the abnormal chromosomes and hormonal imbalances. Here we describe a synchronous occurrence of bifocal intracranial germinoma and bilateral testicular epidermoid cyst in an adolescent patient with Klinefelter`s syndrome. The synchronous occurrence of the dual tumors in this patient with Klinefelter`s syndrome might be resulted from the migration defect during embriyogenesis due to underlying genetic disease or it is a coincidental condition, yet there has been no case reported in the literature, so far.

Cetuximab and epirubicin HCl-combined application as a possibility to treat both parental and epirubicin HCl-resistant liver cancer cells.

BACKGROUND AND AIMS: Targeted chemotherapeutics such as cetuximab can cause many side effects such as skin toxicity when used in high concentrations. In addition, cancer cells can develop resistance to some of the anticancer agents during treatment. The lack of the desired success in chemotherapy and the development of resistance to chemotherapeutics, such as epirubicin HCl, suggest that there is a need for combined therapies. The combination of targeted chemotherapeutics and conventional chemotherapy drugs may lead to the emergence of new strategies in the treatment of cancer. In this study, cytotoxic, antiproliferative, cell cycle inhibitive, oxidative stress generation, and apoptotic effects and effect mechanisms of cetuximab alone and together with epirubicin HCl on parental liver cancer cells (P-Hep G2) and epirubicin HCl-resistant liver cancer cells (R-Hep G2) were investigated. MATERIALS: Cytotoxic effects of cetuximab alone and with epirubicin-HCl on cells were determined by Cell Titer-Blue® Cell Viability and Lactate Dehydrogenase Activity tests. Cell cycle distributions and apoptosis were detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Cetuximab with epirubicin HCl treatment increased the cytotoxic effect on both cells. Caspase-3/7 activity increased 3 and 1.5 times in comparison with control group in P-Hep G2 and R-Hep G2 cells, respectively, after treating with cetuximab alone, whereas the increase was found to be approximately 4.7 and 2.5 times when cetuximab was treated with epirubicin HCl in P-Hep G2 and R-Hep G2 cells, respectively. Both cetuximab alone and together with epirubicin HCl treatments caused increases in Bax/Bcl-2 ratio in both cells. DISCUSSION: Treatment of cetuximab with epirubicin HCl to P-Hep G2 and R-Hep G2 cells was found to be more effective in cytotoxic effect and inducing apoptosis comparison to cetuximab alone treatment. In addition, combination treatment showed different effects on pro-apoptotic/anti-apoptotic genes expression according to cells drug resistance properties.

High-Riding Congenital Hip Dislocation: THA With Unilateral vs Bilateral Transverse Femoral Shortening Osteotomy.

BACKGROUND: We argue that 1-stage bilaterally total hip arthroplasty (THA) could be acceptable in bilateral coxarthrosis because of high-riding developmental dysplasia of the hip (DDH). METHODS: Sixty-nine cases (51 patients) of high-riding DDH in patients who underwent THA from 2010 to 2013 were reviewed. Patients were divided into 2 groups: unilateral (group 1) and 1-stage bilateral surgery (group 2). The clinical measurements were the visual analog scale and Harris Hip Score. RESULTS: The average follow-up was 37.3 months for group 1 and 38.8 months for group 2. The hospital stay time was 5.2 days in group 1 and 6.2 days in group 2 (P = .334). The mean Harris Hip Score and visual analog scale score were improved significantly after surgery for both groups, and there was no statistically significant difference (P = .988). There was no difference between groups 1 and 2 in terms of complications (P = .137). CONCLUSION: Our data confirm that 1-stage bilateral transverse osteotomy with THA is an effective method as unilateral and it does not increase the length of patients' hospital stays and features a low risk of postoperative complications in the treatment of patients with high-riding DDH.

What Determines the Success of Closed-Wedge High Tibial Osteotomy: Severity of Malalignment, Obesity, Follow-up Period, or Age?

OBJECTIVES: High tibial osteotomy (HTO) is a well-established procedure for the treatment of medial knee osteoarthritis originating from malalignment of the lower extremity. The current study was designed to evaluate the clinical and radiographic results of closed-wedge HTO for the treatment of medial knee osteoarthritis and to reveal factors affecting the outcome. METHODS: A retrospective study was conducted with 138 patients who were operated on for medial knee osteoarthritis between 2000 and 2007 using closed-wedge HTO. Preoperative and follow-up physical examination findings, body mass index (BMI) values, and Hospital for Special Surgery (HSS) and Lysholm knee scores were reviewed. Radiographic evaluation included measurement of the mechanical axis preoperatively and the most recent follow-up orthoroentgenograms. The follow-up knee scores were evaluated according to preoperative mechanical axis, obesity, age, follow-up period, and gender of the patient. The mechanical axis measurement was assessed based on obesity, age, and follow-up period. RESULTS: The mean preoperative and latest follow-up mechanical axis was 4.92o±4.24o varus and 3.43o±3.74o valgus, respectively (p=0.0001). Improvement in the Lysholm (p=0.0001) and HSS (p=0.0001) knee scores was significant. The preoperative mechanical axis, obesity, follow-up period, and gender had no negative effect on the follow-up knee scores, whereas a preoperative age over 50 years had a negative effect on the follow-up knee score. Obesity and the length of the postoperative follow-up period did not have a negative effect on the postoperative mechanical axis, whereas a preoperative age over 50 had a negative effect on the postoperative mechanical axis. CONCLUSION: The results of this study suggest that medial knee osteoarthritis may be treated successfully with closed-wedge HTO. The analysis indicated that factors such as obesity, the degree of preoperative deformity, and gender do not adversely affect the success of treatment. However, a preoperative age over 50 adversely affected the outcome.

NUT Midline Carcinoma of the Lung in a Six-Year-Old Child.

BACKGROUND: Nuclear protein of the testis (NUT) midline carcinoma is genetically defined by rearrangement of NUT or by immunohistochemical expression of NUT. FINDINGS: A 6-year old child had a NUT midline carcinoma of the lung. Despite aggressive therapy, the child died. CONCLUSION: NUT carcinoma, which can be diagnosed immunohistochemically, remains an aggressive tumor.