Non-oncological Diseases Research Articles

ORAL ULCERS CAUSED BY THE USE OF METHOTREXATE IN A PATIENT WITH RHEUMATOID ARTHRITIS

Methotrexate is a chemotherapy originally used in oncology that is also applied in several nononcologic diseases, such as rheumatoid arthritis, because it has an anti-inflammatory effect in low doses. A 68-year-old leucoderm man attended our service with complaint of oral sores for 1 month. As a personal background he had rheumatoid arthritis, diabetes, hypertension, and hypothyroidism. The patient said the ulcers began to appear after the dose of methotrexate had been changed. Clinical history and anamnesis as well as a conversation with his physician led to the conclusion that a possible methotrexate toxicity was related to the oral ulcers despite the use of the medication in low doses (25 mg weekly). Extensive sore of the oral mucosa, especially in the labial lips region, was observed with a yellowish membrane. This case report aims to demonstrate that the toxic effects of methotrexate are seen even in low doses.

Smoking and gut microbiota: a cross sectional study involving students

Abstract Background Cigarette smoking is associated with oncological and non-oncological diseases. Tobacco smoking causes more than 7 million deaths per year worldwide. Cigarette smoking could impact not only on human tissues and organs, but also on the gut microbiota, i.e. the community of microorganisms in the gastrointestinal tract. The aim of this study is to evaluate the composition of gut microbiota among smoker and non-smoker university students. Methods Students from Sapienza University of Rome were asked to fill a questionnaire about smoking attitude and to provide a fecal sample. Students undergoing therapy which could affect gut microbiota were excluded. Differences in microbial composition and variability between smokers and non-smokers were assessed. Results A total of 107 students (43.9% males, mean age 21.96±2.52 years, 30,0% smokers) were enrolled so far. As for microbial composition, Firmicutes/Bacteroidetes ratios (F/B ratio) differed between smokers and non-smokers (5.34±16.66 vs 2.47±2.28). As for variability measures, smokers had lower Shannon index (3.43±0.26 vs 3.46±0.29). At Genus level, Prevotella was significantly more abundant in smokers (10.97±15.87 vs 4.86±10.86; p = 0.027) in comparison to non-smokers. Conclusions Our preliminary results seem to suggest that smoking habit affects gut microbiota. Smokers had higher Firmicutes/Bacteroidetes ratio and Prevotella Genus, while lower Shannon index. These preliminary data suggest that smoking habit may cause changes in gut microbiota pattern, but further research is needed. Key messages Smoking may cause changes in gut microbiota pattern. Smoking seems increases F/B ratio and Prevotella, while reduces gut microbiota variability.

PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response.

It is being increasingly appreciated that the immunomodulatory functions of PARP1 inhibitors (PARPi) underlie their clinical activities in various BRCA-mutated tumors. PARPi possess both PARP1 inhibition and PARP1 trapping activities. The relative contribution of these two mechanisms toward PARPi-induced innate immune signaling, however, is poorly understood. We find that the presence of the PARP1 protein with uncompromised DNA-binding activities is required for PARPi-induced innate immune response. The activation of cGAS-STING signaling induced by various PARPi closely depends on their PARP1 trapping activities. Finally, we show that a small molecule PARP1 degrader blocks the enzymatic activity of PARP1 without eliciting PARP1 trapping or cGAS-STING activation. Our findings thus identify PARP1 trapping as a major contributor of the immunomodulatory functions of PARPi. Although PARPi-induced innate immunity is highly desirable in human malignancies, the ability of 'non-trapping' PARP1 degraders to avoid the activation of innate immune response could be useful in non-oncological diseases.

P-02-66 Emergency Sperm and Spermatogonial Stem Cell Retrieval in Oncological Context

Fertility preservation(FP) must be considered in all patients undergoing high risk treatment for oncological/haematological disease. In men, semen cryopreservation is a straightforward step however if men are found to be azoospermic or unable to masturbate choices have been historically limited. However, in those men involving a Urologist for surgical sperm retrieval should be considered. Retrospective study. Almost half a thousand patients are referred yearly to our reproductive department for sperm banking prior to undergoing high risk chemotherapy or bone marrow transplant, out of which 10.5% present azoospermia. From December 2017 to October 2019, 34 patients (median age of 16.0 years old and median testosterone at 3.7 nmol/L) chose to go forward with surgical sperm/stem cell retrieval which could be offered for oncological cases within 4.5 days from semen-analysis and preceding one day from chemotherapy start date (medians reported). Primary diagnoses were: sarcoma in 8 patients, leukaemia in 8 patients, lymphoma in 8 patients, testicular tumour in 5 patients, other cancers in 2 patients, while 3 patients had non-oncological haematological diseases.

In vitro phototherapeutic effects of indolenine-based mono- and dithiosquaraine cyanine dyes against Caco-2 and HepG2 human cancer cell lines.

Photodynamic therapy is a noninvasive approach for the treatment of oncological and nononcological diseases which has attempted to address the shortcomings and disadvantages of conventional cancer therapies. Given the scarcity of photosensitizers that exhibit desirable characteristics for its potential application in this therapeutic strategy, the main aims of this work were the study of the photophysical and photochemical properties, and the in vitro photobiological activity of several squaraine cyanine dyes. Thus, herein, the synthesis of indolenine-based N-methyl and N-ethyl mono- and dithiosquaraine dyes, the study of their spectroscopical properties, aggregation behavior, photodegradation and singlet oxygen production ability, and the further application of the previously synthesized dyes in colorectal adenocarninoma and hepatocellular carcinoma cell lines to evaluate their phototherapeutic effects, are described. Thionation significantly favored the ability to singlet oxygen production, and moderate photostability was observed for squaraine and monothionated dyes. Squaraine and monothiosquaraine cyanine dyes showed high promise within the tested concentration range regarding their potential application as cancer photodynamic therapy photosensitizers. Squaraine dyes' monothionation resulted in the preparation of compounds with poor photocytotoxicity, which was an undesirable effect on their phototherapeutic application.

Aberrant Telomere Length in Circulating Cell-Free DNA as Possible Blood Biomarker with High Diagnostic Performance in Endometrial Cancer.

To investigate the diagnostic performance of relative telomere length (RTL) in cell-free DNA (cfDNA) for endometrioid endometrial cancer (EC). We measured RTL in cfDNA of 40 EC patients (65 ± 12years) and 31 healthy controls (HC) (63 ± 13years), excluding in both groups other oncologic and severenon-oncologic diseases to limit confounders. Circulating cfDNA was extracted from serum using the QIAamp DNA Blood Mini kit (Qiagen, Hilden, Germany). After the quantitative real-time polymerase chain reaction, telomere repeat copy number to single-gene copy number ratio was calculated. RTL in cfDNA was found to be significantly lower in EC patients than in HC (p < 0.0001). The diagnostic performance of cfDNA RTL was estimated with receiver operating characteristics (ROC) curve analysis, which showed a diagnostic accuracy for EC of 0.87 (95% CI: 0.79-0.95, p < 0.0001). The cutoff cfDNA RTL value of 2.505 (T/S copy ratio) reported a sensitivity of 80.0% (95% CI: 64.35-90.95) and a specificity of 80.65% (95% CI: 62.53-92.55). Significant differences of RTL among EC stages or grades (p = 0.85 and p = 0.89, respectively) were not observed. Our results suggest that cfDNA RTL analysis may be a diagnostic tool for EC detection since the early stage, whilst its diagnostic performance seems unsatisfactory for cancer progression, staging, and grading. However, further studies are needed to confirm these preliminary findings. In particular, future investigations should focus on high-risk patients (such as those with atypical endometrial hyperplasia) that may benefit from this tool, because TL shortening is not specific for EC and is influenced by other oncologic and non-oncologic diseases.

Drivers and barriers to clinical trials (CTs) participation among oncological and non-oncological patients in Poland: A cross sectional survey.

e24191 Background: Understanding patients decision-making process regarding participation in a clinical trial (CT) is crucial for research associates. It enables efficient recruitment and timely completion of a study. The patients perspective is becoming increasingly important worldwide however Polish patients attitudes to CTs have not been studied well enough yet. This study analyses multiple factors influencing oncological (onco) and non-oncological (non-onco) patients decisions to participate in CTs. Methods: Total of 401 hospitalized adults who have never participated in a CT were recruited to take a paper and pencil interview survey. 211 patients (52.6%) were diagnosed or treated for cancer and 190 (47.4%) for non-oncological diseases. The majority of respondents were: (1) women: 256 (63.8%), (2) people with secondary education: 223 (55.6%), (3) at the age of 60-69: 147 (36.7%), (4) living in cities over 100k inhabitants: 179 (44.8%). Results: If proposed, 49.9% of all respondents would agree to be enrolled in a CT (non-onco 52.1% vs onco 47.8%, p = 0.61); 14.9% would refuse (13.3% vs 16.3% respectively) and 35.2% were not certain about the decision (34.6% vs 35.9%). Top two drivers for participation in CTs of non-onco patients were: chance of receiving a new drug (78.6%) and better access to medical care (74.5%), while for oncological respondents: better access to medical care (77.0%) and to additional diagnostic tests (76.0%). Altruism was declared by a total of 54.5% respondents. Main reasons for not participating were: concerns about toxicity – 57.6% (p = 0.14), about lack of efficacy – 44.1% (p = 0.01) and refusal to be a “guinea pig” – 59.3% (p = 0.23). For uncertain respondents, the most convincing factors for enrollment was a terminal phase of the disease: 57.1% in total (onco 69.3% vs non-onco 43.1%, p = 0.01). The results of subanalyses based on demography and type of diagnosis were not of statistical significance. Conclusions: The willingness to participate in CTs is high, which is mainly driven by a chance for a better access to medical care and additional diagnostic tests. Improved access to state-financed care and innovative medicines for chronically ill patients in Poland are needed.

Mitochondrial Protection by PARP Inhibition.

Inhibitors of the nuclear DNA damage sensor and signalling enzyme poly(ADP-ribose) polymerase (PARP) have recently been introduced in the therapy of cancers deficient in double-strand DNA break repair systems, and ongoing clinical trials aim to extend their use from other forms of cancer non-responsive to conventional treatments. Additionally, PARP inhibitors were suggested to be repurposed for oxidative stress-associated non-oncological diseases resulting in a devastating outcome, or requiring acute treatment. Their well-documented mitochondria- and cytoprotective effects form the basis of PARP inhibitors’ therapeutic use for non-oncological diseases, yet can limit their efficacy in the treatment of cancers. A better understanding of the processes involved in their protective effects may improve the PARP inhibitors’ therapeutic potential in the non-oncological indications. To this end, we endeavoured to summarise the basic features regarding mitochondrial structure and function, review the major PARP activation-induced cellular processes leading to mitochondrial damage, and discuss the role of PARP inhibition-mediated mitochondrial protection in several oxidative stress-associated diseases.

Ribociclib mitigates cisplatin-associated kidney injury through retinoblastoma-1 dependent mechanisms

Aberrant cell cycle activation is a hallmark of carcinogenesis. Recently three cell cycle targeting cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for the treatment of metastatic breast cancer. CDK4/6 inhibitors suppress proliferation through inhibition of CDK4/6-dependent retinoblastoma-1 (Rb1) phosphorylation and inactivation, a key regulatory step in G1-to-S-phase transition. Importantly, aberrant cell cycle activation is also linked with several non-oncological diseases including acute kidney injury (AKI). AKI is a common disorder caused by toxic, inflammatory, and ischemic damage to renal tubular epithelial cells (RTECs). Interestingly, AKI triggered by the anti-cancer drug cisplatin can be mitigated by ribociclib, a CDK4/6 inhibitor, through mechanisms that remain unclear. Employing in vivo cell cycle analysis and functional Rb1 knock-down, here, we have examined the cellular and pharmacological basis of the renal protective effects of ribociclib during cisplatin nephrotoxicity. Remarkably, siRNA-mediated Rb1 silencing or RTEC-specific Rb1 gene ablation did not alter the severity of cisplatin-associated AKI; however, it completely abrogated the protective effects conferred by ribociclib administration. Furthermore, we find that cisplatin treatment evokes CDK4/6 activation and Rb1 phosphorylation in the normally quiescent RTECs, however, this is not followed by S-phase entry likely due to DNA-damage induced G1 arrest. The cytoprotective effects of ribociclib are thus not a result of suppression of S-phase entry but are likely dependent on the maintenance of Rb1 in a hypo-phosphorylated and functionally active form under stress conditions. These findings delineate the role of Rb1 in AKI and illustrate the pharmacological basis of the renal protective effects of CDK4/6 inhibitors.

Correlation of synovial caspase-3 concentration and the photodynamic effectiveness in osteoarthritis treatment.

The present study focuses on investigation of Intra-articular PDT mechanisms for OA treatment. Also, a search for determination of the most effective dose of chlorin e6 (Ce6) for anti-inflammatory PDT of OA was carried out. The study was carried out on laboratory animals (11 Chinchilla rabbits, 1 year, 2.5 kg) with a gonarthritis model of post-traumatic OA. According to the instructions for using Photoditazin (Ce6 based PS) for PDT of human oncological and non-oncological diseases, the recommended dose is 0.7-1.2 mg/kg. For studies on rabbits, taking into account the conversion coefficient (3.2), the PS doses of 2.4, 3.2 and 6.4 mg/kg were selected. Fluorescence spectra were measured intra-articular before and after PDT using spectrometer with fiber-optic probe. The intrajoint PDT was carried out using a laser (662 ± 10 nm) and a fiber-optic catheter with a cylindrical diffuser inside a sapphire needle for a uniform distribution of the laser radiation. The immunohistochemical study was carried out by staining the samples with caspase-3. Histological and immunohistochemical analysis showed that the best PS dose for intravenous administration for PDT of rabbit gonarthritis is 3.2 mg/kg. The PS concentration directly in the synovial tissue was 0.5 mg/kg, and this was enough to achieve the most positive results to reduce the caspase-3 level. The caspase-3 level correlates well with other signs of inflammation in the synovial membrane (edema, etc.). Therefore, to assess the PDT effectiveness in the treatment of gonarthritis accompanied by synovitis, it is sufficient to analyze only for caspase-3. The efficacy of PDT with Ce6 showed that 3.2 mg/kg PS dose (1 mg/kg for a human) is the most effective.

Artificial intelligence and neural networks in urology: current clinical applications.

As we enter the era of "big data," an increasing amount of complex health-care data will become available. These data are often redundant, "noisy," and characterized by wide variability. In order to offer a precise and transversal view of a clinical scenario the artificial intelligence (AI) with machine learning (ML) algorithms and Artificial neuron networks (ANNs) process were adopted, with a promising wide diffusion in the near future. The present work aims to provide a comprehensive and critical overview of the current and potential applications of AI and ANNs in urology. A non-systematic review of the literature was performed by screening Medline, PubMed, the Cochrane Database, and Embase to detect pertinent studies regarding the application of AI and ANN in Urology. The main application of AI in urology is the field of genitourinary cancers. Focusing on prostate cancer, AI was applied for the prediction of prostate biopsy results. For bladder cancer, the prediction of recurrence-free probability and diagnostic evaluation were analysed with ML algorithms. For kidney and testis cancer, anecdotal experiences were reported for staging and prediction of diseases recurrence. More recently, AI has been applied in non-oncological diseases like stones and functional urology. AI technologies are growing their role in health care; but, up to now, their "real-life" implementation remains limited. However, in the near future, the potential of AI-driven era could change the clinical practice in Urology, improving overall patient outcomes.

Vascular Endothelial Growth Factor (VEGF) in Abdominal Fluid in Dogs with Oncological and Non-Oncological Diseases

Abstract The vascular endothelial growth factor (VEGF) is a multifunctional cytokine stimulating the growth of vascular endothelial cells, survival and proliferation, inhibiting apoptosis. It is one of the most potent stimulants of vascular permeability. VEGF is found at high levels in inflammatory and tumour-associated pleural and abdominal effusions and is involved in their occurrence. In the present study, the blood plasma and abdominal fluid VEGF levels were assayed in thirty-one client-owned dogs with neoplastic and non-neoplastic diseases by means of enzyme-linked immunosorbent assay (ELISA). The VEGF concentration in abdominal fluid of dogs (n=6) with ascites was 190.70±34.35 pg/ml, in dogs (n=6) with peritonitis: 1449.81±365.42 pg/ml and in dogs (n=9) with tumour-associated effusion: 1993.13±202.56 pg/ml. Blood plasma VEGF of healthy dogs (control group, n=10) was 36.79±5.72 pg/ml, in dogs with ascites: 57.92±2.88 pg/ml, in dogs with peritonitis: 76.98±7.24 pg/ml and in dogs with tumour-associated effusion: 173.50±40.9 pg/ml. There were substantial differences between blood plasma and abdominal fluid VEGF levels.

Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration.

The enzyme poly-ADP-ribose-polymerase (PARP) has important roles for many forms of DNA repair and it also participates in transcription, chromatin remodeling and cell death signaling. Currently, some PARP inhibitors are approved for cancer therapy, by means of canceling DNA repair processes and cell division. Drug repurposing is a new and attractive aspect of therapy development that could offer low-cost and accelerated establishment of new treatment options. Excessive PARP activity is also involved in neurodegenerative diseases including the currently untreatable and blinding retinitis pigmentosa group of inherited retinal photoreceptor degenerations. Hence, repurposing of known PARP inhibitors for patients with non-oncological diseases might provide a facilitated route for a novel retinitis pigmentosa therapy. Here, we demonstrate and compare the efficacy of two different PARP inhibitors, BMN-673 and 3-aminobenzamide, by using a well-established retinitis pigmentosa model, the rd1 mouse. Moreover, the mechanistic aspects of the PARP inhibitor-induced protection were also investigated in the present study. Our results showed that rd1 rod photoreceptor cell death was decreased by about 25-40% together with the application of these two PARP inhibitors. The wealth of human clinical data available for BMN-673 highlights a strong potential for a rapid clinical translation into novel retinitis pigmentosa treatments. Remarkably, we have found that the efficacy of 3 aminobenzamide was able to decrease PARylation at the nanomolar level. Our data also provide a link between PARP activity with the Wnt/β-catenin pathway and the major intracellular antioxidant concentrations behind the PARP-dependent retinal degeneration. In addition, molecular modeling studies were integrated with experimental studies for better understanding of the role of PARP1 inhibitors in retinal degeneration.

Comparison between PROFUND and PALIAR indexes in polypathological patients with advanced non-oncologic chronic diseases

Background and objectiveTo compare the discrimination power of PROFUND and PALIAR indexes for predicting mortality in polypathological patients with advanced non-oncologic chronic disease. Material and methodsProspective multicentre cohort study. We included polypathological patients with advanced non-oncologic chronic disease, who were admitted to internal medicine departments between July 1st and December 31st, 2014. Data was collected from each patient on age, sex, categories of polypathology, advanced disease, comorbidity, functional and cognitive assessment, terminal illness symptoms, need for caregiver, hospitalisation in the past three and 12 months and number of drugs. We calculated the PROFUND and PALIAR indexes and conducted a 12-month follow-up. We assessed mortality with the Kaplan–Meier survival curves and the discrimination of indexes with the ROC curves. ResultsWe included 213 patients with a mean (standard deviation) age of 83.0 (7.0) years, 106 (49.8%) of whom were female. Mortality at six months was 40.4% and at 12 months 50.2%. Deceased patients scored higher scores on the PROFUND [11.2(4.2) vs 8.5(3.9); p<0.001] and PALIAR [6.7 (4.6) vs 3.6(3.1); p<0.001] indexes. The discrimination of PALIAR index at six months (under the curve area 0.734 95%CI 0.665–0.803) was higher than of PROFUND, and there was no difference at 12 months. ConclusionsIn polypathological patients with advanced non-oncologic chronic disease, the PALIAR index had better discrimination power than PROFUND index at 66 months and there were no differences at 12 months.

Optimal care at the end of life (OPAL): study protocol of a prospective interventional mixed-methods study with pretest-posttest-design in a primary health care setting considering the view of general practitioners, relatives of deceased patients and health care stakeholders

BackgroundAt the end of life, about 85–90% of patients can be treated within primary palliative care (PC) provided by general practitioners (GPs). In Germany, there is no structured approach for the provision of PC by GPs including a systematic as well as timely identification of patients who might benefit from PC, yet. The project “Optimal care at the end of life” (OPAL) focusses on an improvement of primary PC for patients with both oncological and non-oncological chronic progressive diseases in their last phase of life provided by GPs and health care services.MethodsOPAL will take place in Hameln-Pyrmont, a rural region in Lower Saxony, Germany. Target groups are (a) GPs, (b) relatives of deceased patients and (c) health care providers. The study follows a three-phase approach in a mixed-methods and pre-post design. In phase I (baseline, t0) we explore the usual practice of providing PC for patients with chronic progressive diseases by GPs and the collaboration with other health care providers. In phase II (intervention) the Supportive and Palliative Care Indicators Tool (SPICT) for the timely identification of patients who might benefit from PC will be implemented and tested in general practices. Furthermore, a public campaign will be started to inform stakeholders, to connect health care providers and to train change agents. In phase III (follow-up, t1) we investigate the potential effect of the intervention to evaluate differences in the provision of PC by GPs and to convey factors for the implementation of SPICT in general practices.DiscussionThe project OPAL is the first study to implement the SPICT-DE regionwide in general practices in Germany. The project OPAL may contribute to an overall optimisation of primary PC for patients in Germany by reducing GPs’ uncertainty in initiating PC, by consolidating their skills and competencies in identifying patients who might benefit from PC, and by improving the cooperation between GPs and different health care stakeholders.Trial registrationThe study was retrospectively registered at the German Clinical Trials Register (Deutsches Register Klinischer Studien; trial registration number: DRKS00015108; date of registration: 22th of January 2019).

How do hospital-based nurses and physicians identify the palliative phase in their patients and what difficulties exist? A qualitative interview study

BackgroundEarly start of palliative care improves the quality of life of eligible patients and their relatives. However, in hospital, patients who could benefit from palliative care are often not identified timely. The aim of this study is to assess how hospital-based nurses and physicians define the palliative phase, how they identify the palliative phase and what difficulties they face.MethodsSemi-structured interviews were held with ten nurses and 18 physicians working at seven hospitals in the Netherlands. Data was analysed using thematic analysis.ResultsNurses and physicians feel insecure about how to define the palliative phase and differentiate between an acute and extended phase. Great variation existed in what life expectancy is attributed to each phase. A variety of ways to identify the palliative phase were described: 1) Prognostication. 2) Treatment trade-off. 3) Assessment of patients’ preferences and needs. 4) Interprofessional collaboration. Professionals base prognostication on their experience but also search for clinical indicators. When benefits of treatment no longer outweigh the negatives, this was considered an, albeit late, identification point. To start a conversation on a patients’ palliative care needs was found to be difficult. Therefore, some respondents wait for patients to vocalize preferences themselves. Many professionals rely on interprofessional collaboration for identification, however uncertainty exist about responsibilities. Difficulties in identification occurred because of variance in definitions, unpredictability of non-oncological diseases, focus on treatment and difficulties in communication and collaboration.ConclusionThese results provide insight into the challenges and difficulties hospital-based professionals experience in timely identification of patients with palliative care needs.

Update on Whole-body MRI in Musculoskeletal Applications.

Whole-body magnetic resonance imaging (WB-MRI) is a powerful tool increasingly used to assess oncologic and nononcologic diseases. WB-MRI provides information about diffuse multifocal pathologies with excellent anatomical definition through high soft tissue contrast and spatial resolution as well as valuable functional information from diffusion-weighted images. In addition to its roles in establishing the diagnosis and assessing the extent and severity of disease, WB-MRI is also useful for monitoring the response to treatment for malignant and benign systemic diseases affecting the musculoskeletal system. This article reviews and updates the applications of WB-MRI in current practice, discussing the role of this helpful tool in various conditions involving the musculoskeletal system including bone metastases, hematologic cancers, inflammatory processes, infections, and multisystemic-multifocal bone, nerve, vascular, and muscle/soft tissue disorders, as well as other idiopathic conditions.

Clinical utility of genomic analysis in adults with idiopathic liver disease

Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US. Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB. Genomic analysis yielded an actionable diagnosis in a substantial number (∼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice. We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.

Challenges of fertility preservation in non-oncological diseases.

Clinicians should provide fertility counseling to all patients receiving gonadotoxic treatment. International scientific societies have mainly focused on oncological patients, and fewer efforts have been made to apply these recommendations to women diagnosed with benign disease (eg benign hematological diseases, autoimmune diseases, and gynecological or genetic disorders). However, these indications account for 8%-13% of the demand for fertility preservation. The risk of premature ovarian failure due to treatment, or to the disease itself, can be considered fairly high for many young women. Counseling and adequate management of these women require particular attention due to the severe health conditions that are associated with some of these diseases. In this review, we address specific issues related to providing adequate fertility counseling and management for women who have been diagnosed with the major non-oncological indications, based on the literature and on our clinical experience.

KIT as a therapeutic target for non-oncological diseases.

KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT. This is the case for the lung, heart, nervous system, gastrointestinal tract, pancreas, kidney, liver, and bone. For this reason, the tyrosine kinase inhibitors that were originally developed for the treatment of hemato-oncological diseases are being currently investigated for the treatment of non-oncological disorders such as asthma, rheumatoid arthritis, and alzheimer's disease, among others. The beneficial effects of some of these tyrosine kinase inhibitors have been proven to depend on KIT inhibition. This review will focus on KIT expression and regulation in healthy and pathologic conditions other than cancer. Moreover, advances in the development of anti-KIT therapies, including tyrosine kinase inhibitors, and their application will be discussed.