Neoadjuvant nivolumab and cabozantinib in advanced renal cell carcinoma in a horseshoe kidney - how to achieve a safe and radical resection? a case report and review of the literature.

Introduction: Neoadjuvant nivolumab and cabozantinib in locally advanced renal cell carcinoma in a horseshoe kidney is a novel therapeutic approach in the preoperative setting. Methods: We report a case of a 52-year old male who presented with a large inoperable tumor of the horseshoe kidney and achieved major partial radiologic response after neoadjuvant therapy with nivolumab and cabozantinib leading to radical resection of the tumor. The patient remains tumor free on the subsequent follow-up and his renal function is only mildly decreased. The systemic treatment was complicated by hepatotoxicity leading to early nivolumab withdrawal. Results: Currently, the combination therapy based on immune checkpoint inhibitors and tyrosine kinase inhibitors represents the treatment of choice in treatment-naïve patients with metastatic renal cell carcinoma in any prognostic group. The neoadjuvant treatment approach is being tested in prospective clinical trials and results are eagerly awaited. Renal cell carcinoma in a horseshoe kidney is an uncommon finding that is always challenging. Additionally, management guidance in this patient population is lacking. In some patients neoadjuvant therapy could be the only way to preserve kidney function. The initial treatment strategy should be individualized to patient needs aiming at the radical resection of the primary tumor as the only chance of getting the tumor under control in the long term. Conclusion: Herein, we highlight the feasibility of neoadjuvant systemic therapy with nivolumab and cabozantinib allowing the subsequent performance of radical tumor resection with negative margins in a patient with advanced renal cell carcinoma in a horseshoe kidney, removing the primary tumor while sparing the patient from lifelong dialysis.

A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people.

Introduction: Romani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies. Materials and methods: The study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members. Results: In total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%). Conclusion: These two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing.

Antineutrophil Cytoplasmic Autoantibody-Associated Glomerulonephritis as a Complication of Home Parenteral Nutrition.

Patients on long-term home parenteral nutrition (HPN) occasionally develop glomerulonephritis due to chronic central venous catheter (CVC)-related infection. Most previously reported cases were membranoproliferative glomerulonephritis (MPGN). This is a case report of a 16-year-old girl receiving HPN for short bowel syndrome. After 11 years on HPN, she developed acute kidney injury with macroscopic hematuria, nephrotic-range proteinuria, and a reduced glomerular filtration rate (GFR). Initially, MPGN associated with chronic bacteremia was suspected with the assumption that the condition would be treated with antibiotics and CVC replacement. However, her kidney biopsy revealed antineutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAG). This was consistent with the fact that the patient tested positive for proteinase 3-ANCA. Immunosuppressive therapy with methylprednisolone pulses (followed by oral prednisone) and rituximab led to remission. Her GFR and protein excretion returned to normal. Chronic bacteremia as a complication of long-term HPN may cause various types of glomerulonephritis including, rarely, AAG requiring immunosuppressive therapy.

Spherical Robots for Special Purposes: A Review on Current Possibilities.

The review discusses the possibilities of different driving mechanisms and sensors of spherical robots, and a special kind of mobile robots is introduced and discussed. The sensors discussed can expand robots' sensing capabilities which are typically very limited. Most spherical robots have holonomic characteristics and protect the inner environment using a shell. Today, there are a diversity of driving mechanisms. Therefore, this article provides a review of all of them and identifies their basic properties. Accordingly, many spherical robots have only inner sensors for moving, balancing, driving, etc. However, a few of them are also equipped with sensors that can measure environmental properties. Therefore, in this paper, we propose the possibility of using such sensors as cameras, LiDARs, thermocouples, and gas sensors, which can be used for special purposes underground, for example, in mines, underground tunnels, or road tunnels. After combining all components are combined, it is possible to design a special type of spherical robot designed for underground exploration, such as accidents in mines or road tunnels.

Current Status, Prevention and Treatment of BK Virus Nephropathy.

All renal transplant recipients should undergo a regular screening for BK viral (BKV) viremia. Gradual reduction of immunosuppression is recommended in patients with persistent plasma BKV viremia for 3 weeks after the first detection, reflecting the presence of probable or suspected BKV-associated nephropathy. Reduction of immunosuppression is also a primary intervention in biopsy proven nephropathy associated with BKV (BKVN). Thus, allograft biopsy is not required to treat patients with BKV viremia with stabilized graft function. There is a lack of proper randomised clinical trials recommending treatment in the form of switching from tacrolimus to cyclosporin-A, from mycophenolate to mTOR inhibitors or leflunomide, or the additive use of intravenous immunoglobulins, leflunomide or cidofovir. Fluoroquinolones are not recommended for prophylaxis or therapy. There are on-going studies to evaluate the possibility of using a multi-epitope anti-BKV vaccine, administration of BKV-specific T cell immunotherapy, BKV-specific human monoclonal antibody and RNA antisense oligonucleotides. Retransplantation after allograft loss due to BKVN can be successful if BKV viremia is definitively removed, regardless of allograft nephrectomy.

Mathematical Modelling of Temperature Distribution in Selected Parts of FFF Printer during 3D Printing Process.

This work presented an FEM (finite element method) mathematical model that describes the temperature distribution in different parts of a 3D printer based on additive manufacturing process using filament extrusion during its operation. Variation in properties also originate from inconsistent choices of process parameters employed by individual manufacturers. Therefore, a mathematical model that calculates temperature changes in the filament (and the resulting print) during an FFF (fused filament fabrication) process was deemed useful, as it can estimate otherwise immeasurable properties (such as the internal temperature of the filament during the printing). Two variants of the model (both static and dynamic) were presented in this work. They can provide the user with the material's thermal history during the print. Such knowledge may be used in further analyses of the resulting prints. Thanks to the dynamic model, the cooling of the material on the printing bed can be traced for various printing speeds. Both variants simulate the printing of a PLA (Polylactic acid) filament with the nozzle temperature of 220 °C, bed temperature of 60 °C, and printing speed of 5, 10, and 15 m/s, respectively.

Nephrotoxicity of calcineurin inhibitors as a risk factor for BK polyomavirus replication after kidney transplantation.

BK polyomavirus-associated nephropathy (PyVAN) is responsible for a significant percentage of transplanted kidneys prematurely terminating their function. Its occurrence is closely related to the intensity of immunosuppressive therapy. In a group of 161 newly transplanted patients, we prospectively evaluated 457 protocol renal biopsies performed within the first year after transplantation. Using the calcineurin inhibitors (CI) nephrotoxicity score, the incidence of nephrotoxicity was monitored as a manifestation of excessive immunosuppression. Findings were correlated with clinical evidence of active BK polyomavirus (BKPyV) replication and PyVAN. Compared to the normal histology, nephrotoxicity was associated with more frequent BKPyV viremia and viruria (p = .01 and p < .01, respectively) and more common occurrence of PyVAN. The persistence of toxicity in the subsequent biopsy proved to be a negative risk factor of viremia and viruria (p = .03 and p < .01, respectively), independently of the initial BKPyV status. Toxicity could also be used as a predictor of viremia and viruria (p = .04 and p < .01, respectively) even in the absence of viral replication at the time of initial biopsy. The early histological manifestation of CI nephrotoxicity was associated with significant BKPyV reactivation in the risky first posttransplant year.

Description of the twelfth species of the genus Thermistis Pascoe, 1867 (Coleoptera: Cerambycidae: Lamiinae: Saperdini).

Thermistis Pascoe, 1867 (Cerambycidae: Lamiinae: Saperdini) is a large and brightly coloured Oriental saperdine genus. It was thoroughly revised by Lin et al. (2012), with 11 species from the Oriental region. After that, only some new locality reports were added to this genus (Lin Vives 2012).

Dabrafenib monotherapy in BRAF+ non-small cell lung cancer - our experience.

BACKGROUND: Activating BRAF mutations result in constitutive activation of the MAP kinase signaling cascade, stimulating cell proliferation. BRAF mutations are typical for malignant melanoma, but occur less frequently in other tumors, including in 1-2% cases of non-small cell lung cancer (NSCLC) [1,2]. CASE: We present two case reports of BRAF+ NSCLC patients, treated with 3rd line dabrafenib monotherapy on our department, and also brief review of available information about dabrafenib and its use in monotherapy of BRAF+ NSCLC. CONCLUSION: Monotherapy with BRAF inhibitors presents a viable alternative for BRAF+ NSCLC patients, incapable of combined therapy with trametinib. The lack of proper indication and reimbursement for NSCLC cases remains a problem, and individual treatment approval is required.

Enhanced Oral Bioavailability of 2-(Phosphonomethyl)-pentanedioic Acid (2-PMPA) from its (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL)-Based Prodrugs.

2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) is a potent (IC50 = 300 pM) and selective inhibitor of glutamate carboxypeptidase II (GCPII) with efficacy in multiple neurological and psychiatric disease preclinical models and more recently in models of inflammatory bowel disease (IBD) and cancer. 2-PMPA (1), however, has not been clinically developed due to its poor oral bioavailability (<1%) imparted by its four acidic functionalities (c Log P = -1.14). In an attempt to improve the oral bioavailability of 2-PMPA, we explored a prodrug approach using (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL), an FDA-approved promoiety, and systematically masked two (2), three (3), or all four (4) of its acidic groups. The prodrugs were evaluated for in vitro stability and in vivo pharmacokinetics in mice and dog. Prodrugs 2, 3, and 4 were found to be moderately stable at pH 7.4 in phosphate-buffered saline (57, 63, and 54% remaining at 1 h, respectively), but rapidly hydrolyzed in plasma and liver microsomes, across species. In vivo, in a single time-point screening study in mice, 10 mg/kg 2-PMPA equivalent doses of 2, 3, and 4 delivered significantly higher 2-PMPA plasma concentrations (3.65 ± 0.37, 3.56 ± 0.46, and 17.3 ± 5.03 nmol/mL, respectively) versus 2-PMPA (0.25 ± 0.02 nmol/mL). Given that prodrug 4 delivered the highest 2-PMPA levels, we next evaluated it in an extended time-course pharmacokinetic study in mice. 4 demonstrated an 80-fold enhancement in exposure versus oral 2-PMPA (AUC0-t: 52.1 ± 5.9 versus 0.65 ± 0.13 h*nmol/mL) with a calculated absolute oral bioavailability of 50%. In mouse brain, 4 showed similar exposures to that achieved with the IV route (1.2 ± 0.2 versus 1.6 ± 0.2 h*nmol/g). Further, in dogs, relative to orally administered 2-PMPA, 4 delivered a 44-fold enhanced 2-PMPA plasma exposure (AUC0-t for 4: 62.6 h*nmol/mL versus AUC0-t for 2-PMPA: 1.44 h*nmol/mL). These results suggest that ODOL promoieties can serve as a promising strategy for enhancing the oral bioavailability of multiply charged compounds, such as 2-PMPA, and enable its clinical translation.

Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.

Sphingosine 1-phosphate (S1P) is a bioactive lipid metabolite associated with cancer cell proliferation, survival, migration and regulation of tumor angiogenesis in various cellular and animal models. Sphingosine kinase-1 (SphK1) and S1P lyase are the main enzymes that respectively control the synthesis and degradation of S1P. The present study analyzed the prognostic and predictive value of SphK1 and S1P lyase expression in patients with non-small cell lung cancer (NSCLC), treated with either surgery alone or in combination with adjuvant carboplatin and navelbine. Formalin-fixed, paraffin-embedded tissue samples from 176 patients with NSCLC were stained immunohistochemically using antibodies against SphK1 and S1P lyase, and their expression was correlated with all available clinicopathological factors. Increased expression of SphK1 was significantly associated with shorter overall and disease free survival in patients treated with adjuvant platinum-based chemotherapy. No prognostic relevance for S1P lyase expression was observed. Collectively, the results suggest that the immunohistochemical detection of SphK1 may be a promising predictive marker in NSCLC patients treated with adjuvant platinum-based chemotherapy.

Cochlear Implantation.

Historically, cochlear implants are the first substitute for a sensory modality, hearing. In past decades, they have become a standard method of a compensation for a hearing loss, both for children and adults. Because of restored hearing by cochlear implants, people were able to keep their jobs, marriages and other social ties. Many children born deaf could attend standard schools from basic education to universities, together with their hearing peers, the fact which had influenced greatly their future lives. Unfortunately, not all suitable candidates for cochlear implants get them. Paradoxically, not due to insufficient financing as before or in undeveloped countries nowadays, but due to lack of a correct information and a lack of interest both in patients and specialists. In our contribution, a principle of the cochlear implant is explained, together with proper indications, modes of application and results of its usage. Because of a limited text span, a history of development of cochlear implants is skipped completely. Nevertheless, we believe that the information proper will reach all those, who could benefit from it.

Exposure criteria for evaluating lumbar spine load.

OBJECTIVE: As a part of regular revision of the List of Occupational Diseases in the Czech Republic, efforts have been made to add a new item so that lumbar spine disease caused by overload may be recognized as occupational one, with adherence to the valid national rules, that is, clinical criteria are met and objective assessment confirms working conditions under which, according to recent scientific knowledge, such an occupational disease develops. The aim is to provide information on the use of a proposed method for working condition assessment in a real setting, based on the initial experiences gained from a pilot study carried out to validate the method. METHODS: Working conditions were assessed in 55 individuals with chronic low back pain (25 males, 30 females; mean age 45.6 years; mean length of employment 15.6 years). The assessment was based on estimating compressive force on the L4/L5 intervertebral disc when performing potentially high-risk work tasks which were entered into four types of checklists throughout their work shifts. The compression values were calculated using a special module that was developed. RESULTS: In 24 cases comprehensive assessment of all tasks performed showed fulfillment of the proposed criteria of working conditions needed for recognition of occupational disease. Those included healthcare, foundry and forest workers, production operators, cabinetmakers, locksmiths, bricklayers, etc. In all the cases, lumbar spine overload was associated with work tasks requiring combinations of manual handling of objects and trunk rotation or bending. The criteria were not met in 31 subjects. The mean length of employment was 15.4 and 15.8 years in patients who met and did not meet the proposed criteria, respectively. CONCLUSION: The proposed method proved to be applicable in occupational hygiene evaluation in a real setting.

Real life adjuvant chemotherapy uptake and survival in patients with non-small cell lung cancer after complete resection.

OBJECTIVES: Adjuvant chemotherapy (AC) in non-small cell lung cancer (NSCLC) has become a standard of care in patients with stages IIA, IIB, and IIIA after complete tumor resection. Utilization and outcome of AC in routine practice is described in a few studies, with non-conclusive results. MATERIALS AND METHODS: This retrospective study included consecutive patients with NSCLC who underwent curative-intent surgery. Data of AC uptake in stages IB (tumor of ≥4 cm in diameter), II, and IIIA, and reasons of AC omission were evaluated according to medical records. Mortality risk among patients treated with surgery (only) and different types of AC in routine practice was compared. RESULTS: AC was applied to 79% of patients with stages IB (tumor of ≥4 cm in diameter), II, and IIIA, and was associated with an improved median of overall survival (HR = 0.69; 95% CI = 0.44-1.06). Significantly longer survival was achieved in the sub-group treated with platinum and oral vinorelbine (HR = 0.575, 95% CI = 0.339-0.974), and the longest survival was among patients treated with oral vinorelbine and cisplatin (HR = 0.371, 95% CI = 0.168-0.820). CONCLUSIONS: AC utilization should be based on co-operation between surgeons, pneumo-oncologists, and patients. Rational use of AC offers better survival in routine practice.

BK virus-induced renal allograft nephropathy.

BK virus nephropathy (BKVN) is a serious opportunistic infection threatening renal function especially during the first year after transplantation. Its incidence is now on the rise and is closely related to the level of the recipient's immune system inhibition. This is more intensive with current trends in transplantation medicine, where more potent immunosuppressive protocols are used and more aggressive antirejection therapy is applied. In the absence of BK virus (BKV) specific therapy and limited treatment options for advanced BKVN, active screening of BKV replication and subsequent preemptive adjustment of immunosuppression are essential measures to prevent BKVN. However, it remains unclear how to modify immunosuppressive protocols as well as how to address initial stages of BKV replication. This comprehensive review summarizes the currently applied and not completely uniform procedures for the detection, prophylaxis and therapy of BKV replication and BKVN. The pitfalls brought by reduced immunosuppression, as a typical response to a significant viral replication or a developed BKVN, are also mentioned, particularly in the form of graft rejection. The paper also outlines the authors' experiences, and lists currently ongoing studies on the subject. The perspectives of new, especially immune-based, procedures in the treatment of complications associated with BKV infections are highlighted. Different views on the management of patients indicated for kidney re-transplantation whose previous graft failed because of BKVN are also discussed.

N-Substituted Prodrugs of Mebendazole Provide Improved Aqueous Solubility and Oral Bioavailability in Mice and Dogs.

Mebendazole (MBZ) was developed as a broad-spectrum anthelmintic but has recently shown efficacy as an anticancer agent. The use of MBZ for cancer, however, is challenging due to its poor solubility leading to poor bioavailability. Herein, we developed a prodrug approach with various N-linked promoieties including acyloxymethyl, aminoacyloxymethyl, and substituted phosphonooxymethyl in attempt to improve these characteristics. Compound 12, containing an (((((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl promoiety, showed a >10 000-fold improvement in aqueous solubility. When evaluated in mice, 12 displayed a 2.2-fold higher plasma AUC0- t and a 1.7-fold improvement in brain AUC0- t with a calculated oral bioavailability of 52%, as compared to 24% for MBZ-polymorph C (MBZ-C), the most bioavailable polymorph. In dogs, 12 showed a 3.8-fold higher plasma AUC0- t with oral bioavailability of 41% compared to 11% for MBZ-C. In summary, we have identified a prodrug of MBZ with better physicochemical properties and enhanced bioavailability in both mice and dog.

[30 years of the cochlear implantations in the Czech Republic]. / 30 let kochleárních implantací v Ceské republice.

Cochlear implant is the unique sensory neuroprosthesis and still the only one used in clinical praxis. The function of the inner ear is replaced with direct electrical stimulation of the cochlear nerve. It is 30 years since the first cochlear implantation has been performed with the Czech single-channel cochlear neuroprosthesis. There are more than one thousand users of cochlear implants in the Czech Republic nowadays. Cochlear implants have become a standard of care of patients with severe hearing loss. It allows user inclusion to the society with only a minimum of obstacles.Key words: cochlear implant, history, neuroprosthesis, severe hearing loss.

Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain.

4-Carboxy-α-[3-(hydroxyamino)-3-oxopropyl]-benzenepropanoic acid 1 is a potent hydroxamate-based inhibitor of glutamate carboxypeptidase II. In an attempt to improve its poor oral pharmacokinetics, we synthesized a series of prodrugs by masking its hydrophilic hydroxamate group. Prodrugs were evaluated for oral availability in mice and showed varying degree of plasma exposure to 1. Of these, para-acetoxybenzyl-based, 4-(5-(((4-acetoxybenzyl)oxy)amino)-2-carboxy-5-oxopentyl)benzoic acid, 12, provided 5-fold higher plasma levels of 1 compared to oral administration of 1 itself. Subsequently, para-acetoxybenzyl-based prodrugs with additional ester promoiety(ies) on carboxylate(s) were examined for their ability to deliver 1 to plasma. Isopropyloxycarbonyloxymethyl (POC) ester 30 was the only prodrug that achieved substantial plasma levels of 1. In vitro metabolite identification studies confirmed stability of the ethyl ester of benzoate while the POC group was rapidly hydrolyzed. At oral daily dose-equivalent of 3 mg/kg, 12 exhibited analgesic efficacy comparable to dose of 10 mg/kg of 1 in the rat chronic constrictive injury model of neuropathic pain.

A New Approach to the Evaluation of Local Muscular Load while Typing on a Keyboard.

OBJECTIVE: The aim of this study was to assess the contribution of using keystroke dynamics (KD) in combination with integrated electromyography (iEMG) for the objective evaluation of local muscular load of hands and forearms while typing on a computer keyboard and to compare it with results of the commonly used method. METHOD: Study was performed on 12 subjects. Data were collected using our own application for capturing KD data and using EMG Holter for detecting electromyographic potentials to determine local muscular load. RESULTS: The results of our study revealed that currently used methods for assessment of the workload while typing on a computer keyboard are not entirely accurate. In particular, the real total number of keystrokes performed during processing of a text is significantly higher than the count of characters the text is consisting of. In addition to this count, also the so-called invisible keys, keyboard shortcuts, and especially corrections in the typed text must be taken into consideration. CONCLUSIONS: The results indicated that all probands in our study exceeded the valid hygienic limits for the total amount of the small repetitive movements of the hands and forearms and the total amount of the keyboard typing movements. Most of the probands in our study also exceeded the valid hygienic limit for the highest average time-weighted value of the percent maximum voluntary contraction (%MVC). This implies that the keystroke dynamics method has a great potential to increase the accuracy of evaluation of local muscular load when using the keyboard and thus to improve the existing methodology for investigation of occupational diseases resulting from overload while working on the computer.

Prognostic Influence of Internal Mammary Node Drainage in Patients with Early-stage Breast Cancer.

BACKGROUND: The management of internal mammary nodes (IMNs) during multidisciplinary treatment of breast cancer has been debated for the last four decades without unequivocal conclusion. PATIENTS AND METHODS: We retrospectively reviewed patients with breast cancer who underwent sentinel lymph node biopsy at our center from 2008 until 2012. IMN drainage was assessed as a potential risk factor for local and distant disease recurrence. RESULTS: We identified 712 patients, with incidence of drainage to IMNs of 18.4%. No detrimental effect of the pattern of drainage to IMNs was found after a median follow-up of 58 months. A similar outcome was observed when drainage to IMNs was evaluated as a risk factor for patient survival. The potential risk factors for drainage to IMNs during sentinel lymph node biopsy were younger age (p=0.002) and tumor location in lower-outer, lower-inner, and upper-inner versus upper-outer quadrant (p<0.0001). CONCLUSION: The drainage to IMNs is unlikely to have a detrimental effect on patient outcome.