More than tubular dysfunction: cystinosis and kidney outcomes.

BACKGROUND: Cystinosis is a lysosomal storage disease that affects many tissues. Its prognosis depends predominantly on kidney involvement. Cystinosis has three clinical forms: nephropathic infantile, nephropathic juvenile and non-nephropathic adult. Proximal tubular dysfunction is prominent in the infantile form, whereas a combination of glomerular and tubular alterations are observed in the juvenile form. METHODS: Thirty-six children with nephropathic cystinosis were included in the study. Clinical features, molecular genetic diagnoses, and kidney outcomes of the patients were evaluated. RESULTS: Twenty-one children (58.3%) were male. The median age at diagnosis was 18.5 months. Twenty-eight patients (77.8%) had infantile nephropathic cystinosis, while eight (22.2%) had juvenile nephropathic cystinosis. An acute rapid deterioration of the kidney function with proteinuria, hypoalbuminemia, and nephrotic syndrome, was observed in 37.5% of patients with the juvenile form. The mean estimated glomerular filtration rate (eGFR) was 82.31 ± 37.45 ml/min/1.73m2 at diagnosis and 63.10 ± 54.60 ml/min/1.73m2 at the last visit (p = 0.01). Six patients (16.6%) had kidney replacement therapy (KRT) at the last visit. The median age of patients with kidney failure was 122 months. Patients with a spot urine protein/creatinine ratio < 6 mg/mg at the time of diagnosis had better kidney outcomes (p = 0.01). The most common allele was c.451A>G (32.6%). The patients with the most common mutation tended to have higher mean eGFR and lower leukocyte cystine levels than patients with other mutations. CONCLUSION: Glomerulonephritis may be a frequent finding in addition to the well-known tubular dysfunction in patients with cystinosis. Furthermore, our results highlight that the presence of severe proteinuria at the time of diagnosis is a relevant prognostic factor for kidney survival.

Sarcoma - correlation between CD73 and PD-L1 and their relationship with prognosis.

This study aimed to evaluate CD73 and PD-L1 and determine their relationship with each other and with overall survival (OS) in sarcoma patients. The paraffin blocks of 101 patients were analysed. 56.4% were female, and the mean age was 51.39 years. The mean OS was 20.73 months, and the Ki-67 proliferative index was 41.45. A positive correlation was found between CD73 tumour and CD73 tumour-infiltrating lymphocyte (TIL) findings. CD73 tumour and TIL findings were also positively correlated with PD-L1 percentages and PD-L1 intensity. An inverse correlation was detected between OS and CD73 tumour and TIL groups of 5-25%, 25-50%, 50-75%, 75-90%, and > 90%, but no such correlation was found for the ≤ 5% group. There was an inverse correlation between OS and the PD-L1 percentages of  50% and the PD-L1 intensity of weak-moderate and strong, but no correlation was found for the negative values. Lastly, an inverse correlation was found between OS and the Ki-67 proliferative index. We found CD73 and PD-L1 positivity to be associated with decreased OS in sarcoma patients and determined a significant correlation between these parameters. This result is promising in terms of achieving better survival and disease control with anti-CD73 and anti-PD-L1 therapy in selected patients.

Primary glomerulonephritis in diabetic patients.

BACKGROUND: Primary glomerulonephritis (PGN) has a significant part in non-diabetic kidney disease (NDKD) in diabetes mellitus (DM) patients. In our study, we compared the clinical, demographic and laboratory features of patients with biopsy-proven diabetic nephropathy (DN) and PGN with type 2 DM. METHODS: In our retrospective study, type 2 DM patients who underwent kidney biopsy between 2011 and 2019 were included. Demographic, clinical and laboratory characteristics of DN and PGN patients were compared. RESULTS: Seventy patients with a mean age of 55.7 ± 9.4 and 43 (61.4%) males were included. About 38 (54.3%) of the patients had DN and 32 (45.7%) had PGN. In the PGN, membranous GN (20, 62.5%) was most common. In DN patients, diabetes duration was longer; complications such as retinopathy, neuropathy, hypertension, coronary artery disease, heart failure were more frequent. At the time of renal biopsy, blood sugar, HbA1C, blood pressure, serum albumin and proteinuria values were similar in two groups. The pathological damage findings of kidney biopsy in DN patients were more severe. In the first year after kidney biopsy decrease in eGFR was higher in DN patients, whereas eGFR did not change in PGN patients. CONCLUSION: In a diabetic patient, fasting blood sugar, hbA1C, serum albumin and proteinuria did not differ in the differential diagnosis of DN and PGN, whereas complications of DM (retinopathy, neuropathy, hypertension, coronary artery disease) were more characteristic in differentiation. Detection of PGN in a diabetic patient is crucial for the success of the treatment, according to DN.

Renal expression of PLA2R, THSD7A, and IgG4 in patients with membranous nephropathy and correlation with clinical findings.

BACKGROUND: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in nondiabetic adults. M-type phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A) are known as target podocyte antigens in membranous nephropathy (MN). Antibodies against these podocyte antigens are used in the initiation of treatment and response monitoring. However, the relationship between renal podocyte antigens and treatment response is not clear yet. We evaluated the relationship between immunohistochemical PLA2R, THSD7A and IgG4 staining, clinical findings and treatment response in kidney biopsies. METHODS: Fifty-eight patients with MN were included in this retrospective study. In the renal biopsy samples of the patients, PLA2R, THSD7A and IgG4 were stained immunohistochemically and evaluated by light microscopy. The clinical, laboratory and treatment results of the patients were obtained from the hospital records. RESULTS: The study included a total of 58 patients with MN and a mean follow-up period of 32.3 ± 19.7 months. In patients with primary MN; PLA2R, THSD7A and IgG4 were positive in 57.1% (n = 28), 12.2% (n = 6) and 69.4% (n = 34), respectively. Only PLA2R staining was distinctly higher in patients with primary MN than secondary MN (P = .025). Dual positivity (PLA2R + THSD7A) was detected in five (10.2%) of patients with primary MN. We did not determine any relationship between the PLA2R, THSD7A and IgG4 staining patterns and treatment response of the patients. CONCLUSION: It was found no correlation between PLA2R, THSD7A and IgG4 staining in kidney tissue and treatment response. Interestingly, dual positivity (PLA2R + THSD7A) was detected only in primary MN.

Therapy-Induced Neural Differentiation in Ewing's Sarcoma: A Case Report and Review of the Literature.

Ewing's sarcoma (ES) is a small round cell tumor of adolescents or young adults that usually arises in the deep soft tissues of the extremities. The tumor cells have uniform round nuclei, fine powdery chromatin and indistinct nucleoli. CD99 (O13) is a product of the MIC 2 gene that is highly sensitive to ES but not specific. A panel of markers should be used for the differential diagnosis of small round cell tumors because nearly all others, on occasion, show membranous staining for CD99. One of the defining feature of ES is the presence of 22q12 gene rearrangement. The presented case is a 6 year-old boy complaining of swelling on his right leg. The biopsy was compatible with classic ES in terms of histopathological, immunohistochemical and cytogenetic criteria. Wide surgical resection was performed after chemotherapy. The posttreatment specimen was composed of uniformly small round cells mixed with areas of ganglion cells embedded in neurophil-like fibrillary background. Immunohistochemically, neoplastic cells revealed strong CD99 (O13) and NSE staining and the tumor had EWSR1 gene rearrangement. Morphologic alterations due to treatment are commonly seen in pediatric tumors. Single case reports have defined neural differentiation in ES but to the best of our knowledge this is the first report of ES in the literature with all histopathological, immunohistochemical, and cytogenetic criteria evaluated in both pretreatment and posttreatment specimens.

A congenital soft tissue Ewing sarcoma in a newborn patient.

Akçali M, Yapicioglu H, Akay E, Özlü F, Kozanoglu B, Erdogan K, Gönlüsen G, Satar M. A congenital soft tissue Ewing sarcoma in a newborn patient. Turk J Pediatr 2017; 59: 76-79. < p < Congenital Ewing sarcoma is extremely rare. Here we present a newborn baby born with a mass on the left shoulder. Immunohistochemical staining showed congenital Ewing sarcoma. Chemotherapy and then surgical operation were planned, however the patient died before initiation of chemotherapy on the 30th day of life.

Clinical and pathological results of denosumab treatment for giant cell tumors of bone: Prospective study of 14 cases.

OBJECTIVE: Giant cell tumor of bone (GCT) is a primary, osteolytic, benign tumor of the bone. Surgery is the commonly used treatment; however, recurrence remains a problem. Receptor activator of nuclear factor kappa B (RANKL) is responsible for the formation of osteoclastic cells. Discovery of RANKL and its human monoclonal antibody, denosumab, led to use of denosumab for treatment of GCT. The aim of this study was to evaluate clinical and pathological results of treatment of GCT with denosumab and to assess adverse effect profile and recurrence rate. METHODS: Thirteen patients with 14 lesions were enrolled in the study. Mean age was 38.3 years. Patients were given subcutaneous injections of denosumab (120 mg) every 4 weeks (with additional doses on days 0, 8 and 15 in cycle 1 only) and were radiologically evaluated for tumor response. Pain and functional status were measured using Visual Analog Score (VAS) and Musculoskeletal Tumor Society Score (MSTS). Adverse effects were analyzed after each cycle. RESULTS: Participants were 5 men and 8 women. Mean follow-up was 17 months. One lesion was Campanacci grade I, 8 were grade II, and 5 were grade III. Eight lesions were recurrent, and remaining were primary lesions. After average of 9 cycles (range: 4-17 cycles), all tumors underwent radiological regression. Ten lesions were removed surgically. More than 90% of giant cells were found to have regressed in all pathological specimens. On last follow-up, average VAS was 1 and MSTS was 87%. Fatigue and joint and muscle pain after injections was reported by 46% of patients, and mild hypocalcaemia was seen in 1 patient. CONCLUSION: Denosumab has been shown to be a successful drug in treatment of GCT. Denosumab can be used as neoadjuvant for all recurrent lesions, grade II lesions with high surgical risk, grade III lesions, and metastatic cases of GCT. LEVEL OF EVIDENCE: Level IV, Therapeutic study.

Clinical and prognostic significance of PD-1 and PD-L1 expression in sarcomas.

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are new targets in cancer immunotherapy in recent years. The aim of this study is to evaluate the PD-1/PD-L1 expressions in sarcomas and to determine association between PD-1/PD-L1 expressions and clinical/pathological properties in some sarcoma subtypes. Formalin-fixed, paraffin-embedded tissue samples from 65 cases with sarcomas were analyzed. Immunohistochemical staining was performed to detect the PD-1 and PD-L1 expressions in tumor tissue and microenvironment, separately. PD-1 expression in tumor tissue and microenvironment was detected in 11 (17 %) and 8 (12 %) cases, respectively. PD-L1 expression in tumor tissue and microenvironment was detected in 19 (29 %) and 20 cases (30 %), respectively. None of the 5 Ewing sarcomas involving bone showed PD-1/PD-L1 expression, while 2 of 3 cases with Ewing sarcomas involving soft tissue showed PD-1 and PD-L1 expression. Among 5 cases with Kaposi sarcoma, four showed PD-1 and/or PD-L1 expression in tumor or microenvironment. PD-1/PD-L1 expressions were detected 3 of 6 cases with pleomorphic sarcoma, 2 of 4 cases with peripheral nerve sheath tumors and 1 of 4 cases with synovial sarcoma. Interestingly, strongest PD-1/PD-L1 expressions in our study group were detected in 2 sarcoma cases with the history of giant cell tumor. PD-1 and PD-L1 expressions are up to 30 % of the cases with sarcomas. It may be rational to target programmed death pathway in Kaposi sarcoma, pleomorphic sarcoma and peripheral nerve sheath tumors. Strong expression of PD-1/PD-L1 in cases with previous giant cell bone tumor has been found to be interesting and must be studied in giant cell tumor samples.

A Giant Aggressive Angiomyxoma of the Pelvis Misdiagnosed as Incarcerated Femoral Hernia: A Case Report and Review of the Literature.

Aggressive angiomyxoma (AA) is an uncommon mesenchymal tumor that is mostly derived from the female pelvic and perineal regions. AA is a locally infiltrative slow growing tumor with a marked tendency to local recurrence. Painless swelling located around the genitofemoral region is the common symptom; thus, it is often misdiagnosed as a gynecological malignancy or a groin hernia. A 35-year-old female patient who previously underwent surgery for left femoral hernia operation resulting in surgical failure was reoperated for a giant AA located in the pelvis. The tumor was completely excised with free margins. Histopathologic examination revealed an AA. The tumor size was measured as 24 × 12 × 6 cm with a weight of 4.2 kg. Immunohistochemically, the cells show positive staining with vimentin, desmin, estrogen, and progesterone receptor. S100, MUC4, CD34, and SMA were negative in the tumor cells. AA should be considered in the differential diagnosis of any painless swelling located in the genitofemoral region, particularly in women of reproductive age. The principle treatment should be complete surgical excision with tumor-free margins. Long-term follow-up and careful monitoring are essential due to its high tendency of local recurrence in spite of wide excision of the tumor. Adjuvant antihormonal therapy yields promising results for preventing recurrence.

Morphologic evaluation of the effect of denosumab on giant cell tumors of bone and a new grading scheme.

Giant cell tumor (GCT) is a rare, usually benign but locally aggressive neoplasm. Recent studies suggest new approaches in light of the elucidation of molecular pathways in bone. The osteolytic nature of GCT is caused by the receptor for activating nuclear factor-kB ligand (RANKL) associated osteoclasts. Denosumab is a monoclonal antibody that affects GCT through RANKL and it prevents normal and neoplastic osteolysis. The aim of this study is to evaluate the histopathologic alterations due to denosumab treatment and the efficiency of this drug in GCT therapy. Ten patients had been treated with denosumab and were included in the study. Pretreatment biopsies were interpreted as conventional GCTs and posttreatment biopsies of the ten patients' GCTs were classified in accordance with the grading system. Only one patient had tumor remaining after treatment. There is limited data on histopathologic alterations that follow denosumab treatment. The bone pathologist should keep these changes in mind because they mimic different types of bone tumors. Furthermore, there is no widely accepted grading system to evaluate the effect of denosumab in GCT. Our study suggested a scheme that would be helpful to evaluate the efficiency of denosumab treatment in GCT.

Vertical Bone Augmentation Using Bone Marrow-Derived Stem Cells: An In Vivo Study in the Rabbit Calvaria.

PURPOSE: To evaluate the bone regeneration capacity of bone marrow-derived stem cells (BMSCs) in vertical guided augmentation of bone tissue. MATERIAL AND METHODS: The calvaria of 20 rabbits were vertically augmented with autogenous bone graft (ABG); collagen/beta-tricalcium phosphate (ß-TCP) linked scaffold transplanted with 15 × 10 BMSCs; or scaffold alone (control). The augmentation materials were covered with stainless steel domes. BMSCs were isolated with Ficoll-Paque technique and applied directly without in vitro expansion. The newly formed bone was evaluated using radiodensitometric, histomorphometric, histological, and micro-computed tomographic (micro-CT) analyses after a 12-week healing period. The data excluding micro-CT assessments were compared statistically. RESULTS: Radiodensitometric and bone volume parameters demonstrated increased bone formation in both BMSC group and ABG group compared with control group (P < 0.01), but difference between the BMSC and ABG groups was not significant (P > 0.05). The mean histological scores for the BMSC, ABG, and control groups were 7.44 ± 1.03, 8.44 ± 0.81, and 6.00 ± 1.10, respectively, indicating significant difference among the groups (P < 0.05). CONCLUSION: BMSCs delivered with a collagen/ß-TCP linked scaffold can provide improved new bone formation that is comparable with autogenous bone block graft through vertical guided bone regeneration technique.

Medullary nephrocalcinosis in Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is a rare hereditary disease characterized by skeletal dysplasia, immune deficiency and progressive renal disease. Kidney involvement mainly determines the prognosis. The most common renal pathology is focal segmental glomerulosclerosis (FSGS). Medullary nephrocalcinosis refers to the diffuse deposition of calcium salts in renal medulla and has not previously been identified in SIOD. Here we report the first case of a pediatric patient having typical features of SIOD with medullary nephrocalcinosis.

Membranous nephropathy presenting with nephrotic syndrome in a child with thalassemia major.

Few data on the renal effects of thalassemia syndrome are available in the literature. Recent clinical studies identified proximal tubular damage and glomerular filtration abnormalities in thalassemia. Iron-chelating agents might be nephrotoxic as well, but proven glomerular injury, either due to anemia or chelating therapy, has not previously been demonstrated in thalassemia patients. Here, we report the first thalassemia patient presenting with nephrotic syndrome to be diagnosed with membranous nephropathy in the literature.

Well-differentiated papillary mesothelioma of the tunica vaginalis: a case study and review of the literature.

Well-differentiated papillary mesothelioma is an uncommon tumor of the testes that usually presents as a hydrocele. Here, we present the case of one patient who did not have a history of asbestos exposure. The tumor was localized in the tunica vaginalis and was composed of three pedunculated masses macroscopically. Microscopically, branching papillary structures with focal coagulative necrosis were present. In addition to immunohistochemistry, simian virus 40 DNA was also tested by polymerase chain reaction. This report presents one case of this rare entity, its clinical and macroscopic features, and follow-up results.

Crescentic glomerulonephritis in a child with Heiner syndrome.

Heiner syndrome is a food-induced pulmonary hypersensitivity disease that predominantly affects infants. Chronic respiratory symptoms with pulmonary infiltrates on radiography, positive milk precipitins and resolution of findings upon removal of cow's milk constitute the main features. Severe cases may present with pulmonary hemosiderosis. Few renal manifestations associated with this syndrome have been reported so far. Here we report the first case of Heiner syndrome complicated by crescentic glomerulonephritis after 5 years of follow-up.

Ultrastructural evaluation of the effect of N-acetylcysteine on methotrexate nephrotoxicity in rats.

The aim of this study is to investigate the possible protective effect of N-Acetylcysteine (NAC) against the likely methotrexate (MTX) toxicity on the kidney using ultrastructural together with biochemical data. Moreover, the immunohistochemical detection of Ki67 nuclear antigen is to be evaluated. Fifteen male Wistar albino rats, weighing 240-290 g, were divided into three equal groups: Rats receiving MTX alone, rats receiving MTX plus NAC treatment, and rats comprising the control group. MTX (18 mg/kg/day, body weight) in dissolved physiologic saline was administered intraperitoneally to rats during 3 days. For the MTX plus NAC group, N-Acetylcysteine (300 mg/kg/day, body weight) was administered together with MTX. At the end of the third day, all the rats were killed with cervical dislocation to obtain blood and tissue samples. Application of MTX principally induced prominent large vacuolization in the proximal convoluted tubule cells, and focal thickening in the glomerular basal lamina of some glomeruli. A decrease in tissue SOD (superoxide dismutase) and GSH-Px (glutathione peroxidase), and an increase in serum urea nitrogen and creatinine and in tissue MDA (malondialdehyde) levels were also seen in the MTX group. These changes were significantly reversed in the MTX-plus-NAC-treated group. Most of the vacuoles in the proximal convoluted tubule cells disappeared. Furthermore, an increase in antioxidant enzyme activities, a decrease in serum urea nitrogen and creatinine, and tissue MDA levels were all significant. Additionally, an increase in the number of Ki67 positive-stained cells in proximal tubules was also noted. In conclusion, NAC may be a promising substance against MTX-induced renal damage. It might be useful to use NAC supplementally to minimize MTX-induced nephrotoxicity.