The Overlap of Kidney Failure in Extrapulmonary Sarcoidosis in Children-Case Report and Review of Literature.

Sarcoidosis is a non-necrotizing granulomatous inflammatory multisystemic disorder of unknown etiology. In children, as in adults, it can involve a few or all organ systems to a varying extent and degree, entailing multisystemic manifestations. Kidney involvement in pediatric-onset adult-type sarcoidosis is rare, with a wide range of renal manifestations, most of them related to calcium metabolism. Children with renal sarcoidosis tend to be more symptomatic than adults, although male patients have a higher prevalence. We present the case of a 10-year-old boy who presented with advanced renal failure with nephrocalcinosis and important hepatosplenomegaly. The diagnosis was established by histopathological examination, with consequent cortisone therapy and hemodialysis. This review emphasizes that sarcoidosis should be considered in the differential diagnosis of pediatric patients with acute kidney insufficiency or chronic kidney disease of an unknown etiology. As far as we know, this is the first study regarding extrapulmonary sarcoidosis in children from Romania.

Clinical, Pathological and Molecular Insights on KRAS, NRAS, BRAF, PIK3CA and TP53 Mutations in Metastatic Colorectal Cancer Patients from Northeastern Romania.

Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer (p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender (p = 0.02) and the absence of lymph node invasion (p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion (p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 (p = 0.006), ulcerated histopathologic type (p = 0.04), and G2 differentiation (p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.

Chemotherapy-related toxicity in childhood neoplasia.

PURPOSE: To evaluate the incidence and time of occurrence of chemotherapy-related toxic events in 100 children admitted to the Hematology-Oncology Ward of "Sfanta Maria" Children's Emergency Hospital in Iasi, Romania, over a 4-year period. METHODS: An analytical, descriptive and comparative, retrospective and prospective study covering a 4-year period on the incidence of chemotherapy side effects, was performed on 100 children admitted for solid tumors or hematologic malignancies. The probability of each adverse event to appear and the time period from chemotherapy initiation to the moment of side effect appearance were assessed. RESULTS: The most frequent toxicity was alopecia (79.5%), followed by medullary aplasia (71.1%), oral candidiasis (65.3%), diarrhea and emesis (64% each), toxic hepatitis (61%), and Cushing's syndrome (21.5%). Oral herpes and thrush were less frequent (13.2% and 12.2%, respectively). Remissions of the underlying disease were achieved in 69.9% of the cases. Alopecia, medullary aplasia and oral candidiasis developed during the first 14 months of treatment. Mucositis, emetic syndrome and toxic hepatitis were diagnosed within the first 12 months of treatment. Diarrhea and oral herpes or thrush appeared during the first 15 months, while Cushing's syndrome developed during the first 6 months. All remissions were obtained during the first 4 months of treatment. CONCLUSIONS: While alopecia and medullary aplasia were the most frequent side effects of chemotherapy in our study group, the earliest were Cushing's syndrome, emetic syndrome and toxic hepatitis.

Hepatocellular carcinoma: insights in the biological treatment beyond sorafenib.

UNLABELLED: Hepatocellular carcinoma has an increasing incidence and an impressive mortality. At present, the only authorized systemic treatment is the multi-kinase inhibitor sorafenib. A multitude of clinical trials are aimed at improving outcomes, both in firstY- and in second-line therapy. In this multitude of clinical trials, the purpose of our article was to familiarize physicians with the mechanisms of action of new biological therapies and to offer an algorithm for optimal trial selection for each patient, based on clinical and biological indicators. The available data were structured as follows: antiangiogenic therapy, c -MET inhibitors, combinations of chemotherapy with sorafenib, immune response modulators, cellular metabolism modulators, mTOR inhibitors, other multi-kinase inhibitors. CONCLUSION: Treatment of advanced hepatocellular carcinoma remains a challenge for oncologists. Choosing the "right" trial may be the only chance of prolonging patient survival and improve his/her clinical status.

Incidence of chemotherapy discontinuation and characteristics of elderly patients with non-small cell lung cancer treated with platinum-based doublets.

AIM OF THE STUDY: To compare patient's characteristics, clinical data, and rates of chemotherapy discontinuation in advanced NSCLC (non-small cell lung cancer) patients treated with platinum-based association chemotherapy (elderly vs. younger counterparts). To evaluate if there are certain factors that can predict discontinuation of chemotherapy. MATERIAL AND METHODS: A retrospective analysis of all cases of advanced NSCLC treated with either cisplatin-gemcitabine or cisplatin-vinorelbine at the Regional Institute of Oncology Iasi between January 2012 and December 2013 was performed. Patients were divided into two groups: over 70 years old and under 70 years old. Patient's characteristics and clinical data (including whether or not the patient discontinued treatment) were recorded for each case. RESULTS: The elderly patients had more comorbidities (p = 0.003), were prescribed a larger number of pills (p = 0.02), and had longer periods of hospitalisation (p = 0.005). No difference in toxicity was noted between the two groups. Five patients chose to discontinue chemotherapy in the elderly group. Only two patients made the same choice (p = 0.02) in the younger group. Correlation analysis revealed that refusal of further chemotherapy was associated with the length of hospital stay, number of pills per day, and smoking status. CONCLUSIONS: Geriatricians should minimise iatrogeny and polypharmacy by optimising long-term treatment. This will increase the chance that elderly patients will not discontinue chemotherapy. Hospital stay should be reduced to a minimum. As life span increases so does the number of elderly patients with cancer; it is vital to understand and prevent the causes of chemotherapy discontinuation in order to achieve optimal therapeutic results.

Real Check RIO: A Real-World Analysis of Nivolumab in First Line Metastatic Melanoma Assessing Efficacy, Safety and Predictive Factors.

We performed a retrospective study on 51 metastatic melanoma patients treated with Nivolumab in first line, at the Regional Institute of Oncology (RIO) Iasi, Romania between April 2017 and December 2019. We studied the efficacy and safety of anti-PD-1 immune checkpoint inhibitor therapy on a treatment-naive population. After a median follow-up of 36 months, the median progression free survival (PFS) was 26 months (95% CI, 15-36) and the median overall survival (OS) was 31 months (95% CI, 20.1-41.8). At 12 months after the initiation of immunotherapy, the percentage of patients alive was 70%, and at 24 months 62.5%. The most common adverse events observed were dermatological (23.5%) and grade ≥3 was identified in 4 (6.8%) patients. Multivariate analysis indicated that the presence of liver metastases (HR 4.42; 95% CI: 1.88-10.4, p = 0.001) and a neutrophils/lymphocytes ratio (NLR) were associated with poor survival (HR 3.21; 95% CI: 1.04-9.87, p = 0.04). Although retrospective data on a small group of patients were analyzed, we can conclude that our results in RIO are similar to those described in clinical trials and other real-world studies. Our study highlights the potential usefulness of liver metastases and NLR as novel predictive factors in clinical decision-making.

Pediatric COVID-19 and Diabetes: An Investigation into the Intersection of Two Pandemics.

Coronavirus disease 2019 (COVID-19) is a complex infectious disease caused by the SARS-CoV-2 virus, and it currently represents a worldwide public health emergency. The pediatric population is less prone to develop severe COVID-19 infection, but children presenting underlying medical conditions, such as diabetes mellitus, are thought to be at increased risk of developing more severe forms of COVID-19. Diabetic children face new challenges when infected with SARS-CoV-2. On one hand, the glycemic values become substantially more difficult to manage as COVID-19 is a predisposing factor for hyperglycemia. On the other hand, alongside other risk factors, high glycemic values are incriminated in modulating immune and inflammatory responses, leading to potentially severe COVID-19 cases in the pediatric population. Also, there are hypotheses of SARS-CoV-2 being diabetogenic itself, but this information is still to be confirmed. Furthermore, it is reported that there was a noticeable increase in the number of cases of new-onset type 2 diabetes among the pediatric population, and the complications in these patients with COVID-19 include the risk of developing autoimmune diseases under the influence of stress. Additionally, children with diabetes mellitus are confronted with lifestyle changes dictated by the pandemic, which can potentially lead to the onset or exacerbation of a potential underlying anxiety disorder or depression. Since the literature contains a series of unknowns related to the impact of COVID-19 in both types of diabetes in children, the purpose of our work is to bring together the data obtained so far and to identify potential knowledge gaps and areas for future investigation regarding COVID-19 and the onset of diabetes type 1 or type 2 among the pediatric population.

Gastroesophageal Reflux in Children with Asthma.

Background: Nowadays it is considered that a specific causal relationship exists between asthma and gastroesophageal reflux (GER), because of the aspiration of gastric refluate which leads to and maintain spasticity even real crisis of paroxystic expiratory dyspnea. This study explores this relationship and evaluates the results after treatment. Methods: 56 children diagnosed with asthma, hospitalized in a regional center of pediatric gastroenterology in Northeast Romania, underwent 24-hour continuous esophageal pH monitoring in order to establish the presence of GER. The Boix-Ochoa score was used to interpret the results. Proton pump inhibitors were administered to those with GER and the patients were reevaluated after 2 months. Results: 39 patients (69.64%) had GER, with a Boix-Ochoa score above normal (N < 11.99), and 17 patients (30.36%) had normal score. After administering proton pump inhibitors for 2 months, 7 patients still had high Boix-Ochoa score (17.95%). The result of this analysis shows that the presence of asthma increases the chance of GER by 2.86 times. Conclusions: In children with asthma we have to look for GER in order to treat, because it can help the treatment of asthma or even solve some cases resistant to standard treatment.

The relationship between chronic lung diseases and lung cancer - a narrative review.

Lung cancer and chronic lung diseases are currently two of the main causes of death in the world. Both conditions have common etiological factors and multiple research directions in the last decades demonstrated the presence of some common relevant biological mechanisms which can explain why patients with chronic respiratory diseases are at higher risk of developing lung cancer. In this review, we discuss the role of chronic pulmonary diseases, such as chronic obstructive pulmonary disease, tuberculosis, sarcoidosis, asthma, pneumoconioses, idiopathic pulmonary fibrosis and their impact on lung cancer development. We also summarize the possible mechanisms involved in this relationship and how these chronic diseases influence the prognosis of patients with lung cancer. Our aim was to inform the clinicians in this respect for a careful follow-up of this category of patients and for the application of a personalized treatment approach.

The Coexistence of RAS and BRAF Mutations in Metastatic Colorectal Cancer: A Case Report and Systematic Literature Review.

BACKGROUND AND AIMS: The coexistence of RAS and BRAF mutations is extremely rare, occurring in approximately 0.05% of patients with metastatic colorectal cancer (mCRC). Starting from a case presentation, this review aims to examine the prevalence, clinical, histopathological and molecular features of tumors with concomitant mutations. METHODS: Case report and systematic review. We performed a systematic literature search in PubMed and EMBASE using the following MeSH terms: "coexistence" OR "concomitant" AND "RAS" AND "BRAF" AND "colorectal cancer" from the inception of the databases onwards. RESULTS: We present the case of a 53-year-old man diagnosed with metastatic rectal adenocarcinoma with both a KRAS and a BRAF mutation. The review included eleven papers reporting on a total of 30 mCRC cases with concomitant RAS and BRAF mutations. The male/female ratio was 11/5. The average age was 58.5 years. The tumor was located in nine cases on the right colon and in two cases in the left colon. 43.3% of subjects had liver metastases, and 6.6% had lung metastases. Next-generation sequencing (NGS) was used in 36.6% of cases and polymerase chain reaction (PCR) in 16.6% of cases. KRAS mutations were present in 83.3% of patients and NRAS mutations in 16.6% of patients. Survival could be assessed in 10 patients and the median was 21.1 months (about 30% lower than the survival in the general mCRC population). CONCLUSION: The results of this systematic review suggest the need to design a cohort study (either prospective or retrospective) to better characterize the patients with concomitant RAS and BRAF mutations and to establish the optimal treatment for this rare situation.

Experimental Investigation of Thermal and Pressure Performance in Computer Cooling Systems Using Different Types of Nanofluids.

A modern computer generates a great amount of heat while working. In order to secure appropriate working conditions by extracting the heat, a specific mechanism should be used. This research paper presents the effect of nanofluids on the microchannel heat sink performance of computer cooling systems experimentally. CeO2, Al2O3 and ZrO2 nanoparticles suspended in 20% ethylene glycol and 80% distilled water are used as working fluids in the experiment. The concentration of the nanoparticles ranges from 0.5% to 2%, mass flow rate ranges from 0.028 kg/s to 0.084 kg/s, and the ambient temperature ranges from 25 °C to 40 °C. Regarding the thermal component, parameters such as thermophysical properties of the nanofluids and base fluids, central processing unit (CPU) temperature, heat transfer coefficient, pressure drop, and pumping power have been experimentally investigated. The results show that CeO2-EG/DW, at a concentration of 2% and a mass flow rate of 0.084 kg/s, has with 8% a lower temperature than the other nanofluids and with 29% a higher heat transfer coefficient compared with the base fluid. The Al2O3-EG/DW shows the lowest pressure drop and pumping power, while the CeO2-EG/DW and ZrO2-EG/DW show the highest. However, a slight increase of pumping power and pressure drop can be accepted, considering the high improvement that the nanofluid brings in computer cooling performance compared to the base fluid.

KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer - practical implications for the clinician.

Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.

A very rare presentation of lung cancer: Metastases to the distal phalanx of index-case report.

RATIONALE: Acrometastases of the hand are an unusual sign of lung cancer onset and may often be mistaken for other benign disorders, thus delaying diagnosis and treatment. PATIENT CONCERNS: A 58-year-old man presented at the Rheumatology Clinic with a lump in the distal phalanx of the right index finger associated with intense pain, swelling, rib pain, and hemoptysis. DIAGNOSES: Given the clinical manifestations, an x-ray of the right hand was performed, and it revealed an osteolytic lesion in the distal phalanx of the right index finger. The subsequent CT of the thorax and abdomen showed a lung tumor, osteolytic lesions in the ribs, sternum, and the thoracic spine. INTERVENTIONS: Amputation of the phalanx was decided on account of intense pain refractory to NSAIDs and opioids. Pathology assessment established the diagnosis of bone metastases secondary to lung adenocarcinoma. The patient underwent 6 cycles of first-line palliative chemotherapy with cisplatin and gemcitabine with partial response according to the RECIST 1.1. criteria. EGFR and ALK testing were not available at the time. A year later, the patient presented with progressive disease, which lead to 6 more cycles of chemotherapy with docetaxel. The disease progressed during chemotherapy and the patient was switched to erlotinib. OUTCOMES: After 7 months of anti-EGFR treatment, the patient passed away due to disease progression, thus having an overall survival of 25 months. LESSONS: On rare occasions, acrometastases of the hand may be the first manifestation of a lung cancer and, as such, they must be taken into consideration in the differential diagnosis of rheumatologic disorders. They are a poor prognosis marker, but some cases like this one can have a better survival than reported in the literature, most likely due to that particular cancer's biology.

A case report of pediatric calciphylaxis-a rare and potentially fatal under diagnosed condition.

RATIONALE: Though to be rare, calcific uremic arteriolophathy (CUA) is an ectopic calcification entity causing pain and disabilities in patients with chronic renal insufficiency, thus increasing the morbidity and mortality. PATIENT CONCERN: We report a case of four years old boy admitted with acute respiratory failure. Physical examination revealed: irritability, purple subcutaneous hard nodules, tachypnea, dry spasmodic cough, respiratory rate 45/min, heart rate 110/min, blood pressure 100/60 mmHg, with normal heart sounds, no murmurs, hepatomegaly with hepato-jugular reflux. He was diagnosed at 2 years old with stage 5 chronic kidney disease due to untreated posterior urethral valve, and subsequently started peritoneal dialysis. He developed severe renal osteodystrophy, refractory to standard phosphate binders. DIAGNOSES: Pathology examination revealed the presence of diffuse calcifications involving the skin, brain, heart, lung, kidney, stomach and pancreas, consistent with the underlying diagnosis of CUA. INTERVENTION: Apart from standard treatment for end stage renal disease and associated co-morbidities, intensive care procedures have been initiated: oxygen therapy, continuous positive airway pressure, inotropic medication (Dopamine, Dobutamine), anticonvulsants (Diazepam), and antiedematous therapy (Dexamethasone). OUTCOME: His pulmonary function rapidly deteriorated up to the severe hypoxemia, seizures and cardio-respiratory arrest, despite the initiation of intensive care measures. LESSONS: A careful follow up of small children might detect in time an abnormal urinary pattern. The diagnosis of growth failure should also trigger urgent further investigation.

Silent presentation of multiple metastasis Burkitt lymphoma in a child: A case report and review of the literature.

RATIONALE: The Burkitt lymphoma (BL) is a very aggressive B-cell non-Hodgkin's lymphoma. It accounts for 34% of lymphoma cases in children. PATIENT CONCERNS: We present the case of a 6-year-old boy diagnosed with BL, who presented multiple contrasting elements of the disease: silent symptomatology, without involvement of the bone marrow at first, but with multiorgan infiltration and a fast evolution, despite starting the treatment shortly after the symptoms appeared. DIAGNOSES: He was diagnosed with BL after immunophenotyping from the pleural fluid. INTERVENTIONS: After a week from admission, chemotherapy was initiated according to protocol NH-BFM therapeutic group III-cytoreductive phase in the acute care ward and subsequently the AA 24 treatment. OUTCOMES: Following the treatment, the patient developed medullary aplasia and cutaneous toxicity. The patient's general state remained severe during the hospitalization. LESSONS: Even though the prognosis of BL has improved over time (up to 90% survival rate), in this case the evolution was unfavorable. In our patient, the symptoms appeared abruptly. They appeared late in the phase of multiple-organ dissemination, which generated the pessimistic prognosis.

Immunohistochemical significance of ER alpha, inhibin A, calretinin, and Ki67 expression in granulosa cell ovarian tumors.

Adult granulosa cell tumors (AGCTs) have a heterogeneous morphology and an unpredictable behavior, which can lead to a misinterpreted diagnosis. The aim of our study was to assess the immunoexpression of estrogen receptor (ER) alpha, Ki67, calretinin, and inhibin A in AGCTs, in order to evaluate their value in diagnosis and prognosis of this type of tumor. Immunohistochemical stainings for these markers were performed in 21 cases of AGCTs. The immunopositivity evaluation of calretinin and inhibin A was scored according to the percentage of staining intensity and the extent of positive cells, of ER alpha was scored based on the percentage of positive cells, and Ki67 score was recorded as the percentage of positively stained nuclei across the tumor, without taking in consideration the staining intensity. ER was positive in nine cases, Ki67 was expressed in 12 cases, calretinin showed positive immunoreactivity in 16 cases, and inhibin A was positive in 14 cases. Stromal cells presented also immunopositivity for inhibin A and calretinin in the negative cases. ER alpha and calretinin immunoexpression can help in identification of cell components of AGCT. Our results regarding Ki67 expression emphasize the potential utility of this marker in tumor behavior prediction. Inhibin A immunopositivity has an important value in AGCT diagnosis, in association to the other evaluated markers. Additional studies are needed to identify new specific and sensitive markers for AGCT or, at least, of a panel of markers which might contribute to a more accurate characterization of these tumors.

Diagnostic Difficulties in a Pediatric Insulinoma: A Case Report.

Insulinomas are functional neuroendocrine pancreatic tumors rarely encountered in pediatric pathology. Insulinomas are usually solitary and sporadic, but may occur in association with multiple endocrine neoplasia type 1. Whipple's triad-hypoglycemia, simultaneous compatible adrenergic and/or neurological signs, and relief of symptoms upon the administration of glucose-remains the fundamental diagnostic tool. We report a case of insulinoma in an 11-year-old boy with malnutrition and mild psychic retardation. History revealed neuroglycopenic symptoms associated with hypoglycemia that returned to normal values after glucose intravenous infusion; before admission in our unit, the levels of circulating insulin, as well as the abdominal ultrasound and abdominal computed tomography scan, were reported within normal range. During hospitalization in our service, the glycemic curves showed recurring low values associated with low glycated hemoglobin, positive fasting test, and elevated C-peptide. The pancreatic ultrasound was inconclusive, but the magnetic resonance imaging revealed a high signal focal area with a diameter of 1 cm, located in the tail of pancreas. Conventional enucleation of the lesion prompted a spectacular normalization of glucose metabolism and the alleviation of the main clinical symptoms. The child had a favorable evolution in the clinical follow-up, presenting with weight gain and progressive remission to complete disappearance of most symptoms-except for the mental impairments. Although in our case Whipple's triad was apparent from the beginning, the diagnosis was delayed due to the failure of conventional imaging methods in locating the tumor. Weight loss and mental impairment contributed to the diagnosis pitfalls. Pediatricians should be aware of confusing and nonspecific symptoms, especially when children with insulinoma present mental or neurological retardation. Despite the existence of medical regimens, surgery remains the gold standard for the therapeutic approach to this condition.

BRCA1 5382insC founder mutation has not a significative recurrent presence in Northeastern Romanian cancer patients.

Developed two decades ago, oncogenetic medical practice mainly concern breast, ovarian and colorectal cancers, and is targeting the hereditary risk factor, the only one that shows positive predictive value justifying the molecular diagnosis. Screening for BRCA1 and BRCA2 gene mutations is standard practice today for hereditary breast and ovarian cancer (HBOC) families in developed countries, offering the possibility of medical follow-up. The gold standard for molecular diagnosis is Sanger sequencing of all exons and exon-intron boundaries, which is expensive and time consuming. More than 3000 BRCA sequence variants are reported in international databases, but in some populations or ethnic groups a few founder mutations showed to have a recurrent presence. This may be very useful in establishing a combined technical approach for mutation detection, including rapid and cheap pre-screening methods for most common mutations. The BRCA1 5382insC mutation has an Ashkenazi founder effect and is also the second most recurrent mutation in Eastern European populations, having been already identified in several Romanian HBOC patients. Here we present a complete screening of consecutive series of breast and ovarian cancer patients for the presence of BRCA1 5382insC. The presence of the mutation was investigated by allele specific multiplex-PCR on genomic DNA extracted from peripheral blood. No mutation carrier was identified among breast or ovarian cancer patients. Our findings suggest that BRCA1 5382insC may not have a strong recurrent effect in Romanian population comparing to neighboring countries. This may be particularly useful in establishing further pre-screening strategies.