Prognostic value of detection of CD99+ , CD45- cells in peripheral blood by flow cytometry in children with Ewing sarcoma.

BACKGROUND: Early detection of metastasis and recurrence of Ewing sarcoma (ES) is important for early management. This work aimed to detect CD99+ , CD45- cells in peripheral blood by flow cytometry (FC) before and during chemotherapy and evaluate their prognostic significance. PROCEDURE: This prospective cohort study was carried out on 60 children newly diagnosed with ES at Children Cancer Hospital-Egypt 57357 and 40 healthy children control group. Detection of CD99+ , CD45- cells in peripheral blood was accomplished by FC at baseline before treatment and after five cycles of chemotherapy. Samples were classified as positive if they had more than the upper limit of cells observed in the control cases. Correlation between FC results and relapse and overall survival (OS) after one year was performed. RESULTS: Median percentage of CD99+ , CD45- cells was significantly increased in patients compared with controls (0.002% vs 0%, respectively, P < 0.001). Post-cycle 5 CD99+ , CD45- cells were increased in 12 patients, of them 11 patients' disease had either relapsed or progressed. Post-cycle 5 CD99+ ; CD45- cells had a 73.3% sensitivity and 97.8% specificity for predicting relapse or progression, whereas baseline only had 6.7% sensitivity and 77.8% specificity. The hazard ratio for mortality in the post-cycle 5 positive group was 18.4 [95% confidence interval (1.86 to 181.46)] times that of the negative group. One year OS was 91.67%. CONCLUSION: Post-cycle 5 CD99+ , CD45- cells in peripheral blood by FC is a strong predictor for relapse, progression, and mortality whereas baseline is a poor predictor in newly diagnosed patients with ES.

The role of circulating tumor cells and K-ras mutations in patients with locally advanced rectal cancer: a prospective study.

Rectal cancer is a common malignancy with a relatively poor prognosis. We assessed the possible prognostic and predictive role(s) of circulating tumor cells (CTCs) and K-ras mutations in locally advanced rectal carcinoma (LARC) patients. CTCs number and K-ras mutation status were assessed in the Peripheral blood and tumor tissue samples of 60 patients with LARC compared to control group (normal rectal mucosa). Data were correlated to relevant clinico-pathological features, response to treatment, disease free (DFS) and overall survival (OS) rates. K-ras mutations were present in 24/60 (40%) patients. Baseline CTCs (< 5 cells/7 ml blood) were detected in 23/60 (38.3%) patients, and 37 (61.7%) had baseline CTCs (≥ 5 cells/7 ml) blood (P = 0.071). Serial sampling showed a decrease in CTCs levels in 40 (66.7%) patients and increase in 20 (33.3%) patients (P = 0.01). Patients with K-ras mutations had a significantly poor response to treatment, with reduced DFS and OS rates (P = 0.001, 0.004, and 0.001; respectively). Similarly, decreased CTCs levels during treatment associated significantly with better pathological responses (P = 0.003). Multivariate analysis demonstrated that K-ras mutation and baseline CTCs are independent prognostic factors for DFS (P = 0.014 and 0.045; respectively) and OS (P = 0.002 and 0.045; respectively). The presence of mutant K-ras and baseline CTCs ≥ 5 cells associated significantly with poor pathological response, shorter DFS and OS rates compared to those with either K-ras mutation or CTCs ≥ 5 cells only (P = 0.014, 0.005 and 0.001, respectively). K-ras mutations, baseline and serial CTCs changes represent good prognostic and predictive factors for LARC patients.

Pediatric pulmonary multisystem langerhans cell histiocytosis: does lung lesion severity affect the outcome?

BACKGROUND: The pediatric pulmonary multisystem Langerhans cell histiocytosis (PPM LCH) is associated with either low risk or high risk organ(s). The nodulo-cystic lung lesions although pathognomonic, yet are very variable in severity and remain a source of controversy in certifying pulmonary LCH diagnosis. The study aimed to examine the prognostic value of clinical respiratory manifestations and radiological lung lesions severity. This is through associating a CT chest triad of bilateral, extensive and diffuse lesions. It is a retrospective study of 350 LCH patients who received systemic treatment at Children's Cancer Hospital Egypt during the period from 2007 to 2020. RESULTS: Sixty-seven patients (67/350-19.1%) had PPM LCH at presentation. Severe lung lesions were present in 24 of them. The median follow-up period was 61 months (IQR: 3.4-8.3). The 5-year overall survival (OS) and event free survival (EFS) was 89% and 56.6% respectively. The EFS, for severe radiological lesions triad was 38% ± 20.7 versus 66% ± 16.2 for non-severe lesions triad p 0.002, while for presence of chest X-ray changes 27% ± 22.344 versus absence of chest X ray changes 66% ± 14.7 p 0.001, for clinical respiratory manifestations 13% ± 13.9 versus none 62% ± 22.9 p < 0.001, for RO- with severe lung lesions 47% ± 30.4 versus RO- without severe lung lesions 69% ± 5.9 p 0.04. There was a tendency for the independent prognostic impact of severe lung involvement; aHR = 1.7 (95% CI 0.92-3.13, p = 0.09). CONCLUSION: Although the lung is a low -risk organ per se in LCH, our study demonstrates a non negligeable prognostic impact of severe lung involvement in the risk stratification of pediatric LCH. This warrants further study and external validation.

Sonographic prediction of fetal main pulmonary artery (MPA) Doppler indices of lung maturity and neonatal respiratory distress syndrome (RDS) development.

PURPOSE: The aim of this study is to highlight the predictive role of perinatal fetal main pulmonary artery (MPA) Doppler measurements in neonatal respiratory distress syndrome development. Respiratory distress syndrome (RDS) is one of the lead causes of neonatal respiratory distress as well as neonatal death. Thus, it seems logic to evaluate fetal lung maturity before labour. METHODS: The study is a prospective cohort study performed in tertiary hospital over a period of one-year duration. 70 pregnant ladies between 34 and 38 weeks of gestation were referred for fetal echo, when pregnancy was considered a high risk. A trained radiologist using dedicated ultrasound machine with updated obstetric and fetal echo software performed the fetal echo. Doppler mode and curvilinear probe of 5.7 MHz transducer. Pediatric neonatologist observed the neonatal outcome post-natally. RESULTS: A total of 70 pregnant patients with risk factors underwent fetal echo, 26/70 (37.1%) were diagnosed with RDS conforming to the neonatal criteria. The mean acceleration time/ejection time ratio (At/Et ratio) of the fetal pulmonary artery was significantly reduced in fetuses that subsequently developed RDS than those without RDS. Contrarily, the mean pulsatility index (PI), resistance index (RI), and peak systolic velocity (PSV) of the fetal pulmonary artery were significantly high in fetuses who later developed RDS than in those who did not. CONCLUSION: Fetal MPA Doppler measurements have a major role in anticipating the development of neonatal RDS in preterm and early term neonates.

Prognostic significance of the ratio of surgically resected to radiologically detected lung nodules in patients with metastatic osteosarcoma.

The factors that affect the prognosis of patients' metastatic osteosarcoma are still poorly understood. In this study, we investigated a new prognostic factor, the ratio of surgically resected to radiologically detected osteosarcoma lung nodules (SR/RD), which may have predictive value. PATIENTS AND METHODS: Data from patients with metastatic osteosarcoma who underwent metastasectomy between January 2009 and December 2020, in a single center, were reviewed. The relationships between survival and the SR/RD ratio, timing of lung metastases, number of nodules, laterality, and presence of tumor necrosis at first metastasectomy were investigated. RESULTS: Among the 125 metastatic osteosarcoma patients, 80 patients had an SR/RD ratio ≤1. The median duration of follow-up was 72 months, ranging from 6 to 118 months. The five-year overall survival (OS) and postmetastasectomy event-free survival (EFS) for all patients were 36.5% and 18.1%, respectively. The five-year OS of patients with a low SR/RD ratio was 49.6% and that of patients with a high SR/RD ratio was 11.8 (P = 0.001). The two-year postmetastasectomy EFS rates of the high and low ratio groups were 24.1% and 9.4%, respectively (P = 0.001). The SR/RD ratio, number of nodules, and tumor necrosis had significant effects on OS and postmetastasectomy EFS in univariate analysis. A Cox proportional hazard model demonstrated that tumor necrosis and an SR/RD ratio >1 were associated with OS (HR = 1.8 and 2.01) and postmetastasectomy EFS (HR = 1,69 and 1.97). CONCLUSIONS: A high SR/RD ratio of greater than 1 and poor tumor necrosis were significantly associated with poor survival among patients with metastatic osteosarcoma who had lung metastasectomy. The high SR/RD ratio may be a surrogate outcome for incomplete metastatic tumor resection.

The egyptian clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease.

The landscape of chronic liver disease in Egypt has drastically changed over the past few decades. The prevalence of metabolic-associated fatty liver disease (MAFLD) has risen to alarming levels. Despite the magnitude of the problem, no regional guidelines have been developed to tackle this disease. This document provides the clinical practice guidelines of the key Egyptian opinion leaders on MAFLD screening, diagnosis, and management, and covers various aspects in the management of MAFLD. The document considers our local situations and the burden of clinical management for the healthcare sector and is proposed for daily clinical practical use. Particular reference to special groups was done whenever necessary.

Metabolic-associated fatty liver disease and autoimmune hepatitis: an overlooked interaction.

INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) is the most common liver disease globally, and affects about a quarter of the general population. Autoimmune hepatitis (AIH) is a severe (sometimes fatal) liver disease that affects children and adults, with a rising prevalence. Thus, not surprisingly, both conditions can frequently coexist, with potential synergistic impact on the course of the disease and response to therapy of both entities. AREAS COVERED: In this work, the authors aimed to provide a narrative updated review on this interaction, diagnosis, and management of MAFLD/AIH and the current challenges. EXPERT OPINION: Clarifying the nature of the complex interaction between the two diseases was hampered by a myriad of factors, particularly the previous diagnosis of exclusion for fatty liver disease associated with metabolic dysfunction. The recent redefinition of fatty liver disease that led to the development of positive diagnostic criteria for MAFLD has the premise to help in circumventing some of these challenges.

Surgical Resection of Hepatoblastoma: Factors Affecting Local Recurrence.

INTRODUCTION: This study aimed to investigate potential factors contributing to local recurrence after surgical resection of hepatoblastoma (HB). MATERIALS AND METHODS: This retrospective study involving all patients with HB who underwent nontransplant surgery at our tertiary center between July 2007 and July 2018. Data were analyzed regarding microscopic surgical resection margin, tumor multifocality and extracapsular tumor extension in correlation with local recurrence. These relations were assessed by logistic regression. RESULTS: The study included 133 patients with a median age of 1.3 years (range: 0.5-12.8 years). They were classified into 99 cases (74.44%) standard risk and 34 cases (25.56%) high risk. Delayed surgical resection was adopted in all patients. Follow-up to July 2019 revealed that 23 patients (23/133, 17.3%) developed local recurrence, whereas the remaining 110 were locally disease free. Microscopic positive margin (R1) was detected in 29 patients, 8 of them had local recurrence (p = 0.097). Regarding tumor multifocality, there were 12 patients who had multifocal lesions, 3 of them developed local recurrence (p = 0.459). Forty-four patients had extracapsular tumor extension in their pathological reports, 12 of them had local recurrence (p = 0.032). CONCLUSION: Extracapsular tumor extension was a significant prognostic factor of local recurrence after surgical resection of HB. R1 margin does not necessarily require a second resection, and it could achieve accepted results when combined with adjuvant platinum-based chemotherapy. However, patients who are not eligible for surgical resection must be transferred for primary transplantation to obtain favorable outcome.

Validation of acute kidney injury prediction scores in critically ill patients.

Prediction of acute kidney injury (AKI) in critically ill patients allows prompt intervention that improves outcome. We aimed for external validation of two AKI prediction scores that can be bedside calculated. A prospective observational study included patients admitted to medical and surgical critical care units. Performance of two AKI prediction scores, Malhotra score and acute kidney injury prediction score (APS), was assessed for their ability to predict AKI. The best cutoff point for each score was determined by Youden index. Area under the receiving operation characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were used to assess performance of each score. Univariate and multivariate regression analyses were done to detect the predictability of AKI. Goodness-of-fit and kappa Cohen agreement tests were done to show whether the expected score results fit well and agree with the observed results. AKI prevalence was 37.6%. The best cutoff values were 5 and 4 for Malhotra score and APS, respectively. Area under the curve for Malhotra 5 was 0.712 and for APS 4 was 0.652 with nearly similar sensitivity and specificity. Regression analysis demonstrated that Malhotra 5 was the independent predictor of AKI. Goodness-of-fit test showed significant results denoting lack of fit between the scores and the actual results. Kappa test showed moderate agreement for Malhotra 5 and fair agreement for APS 4. Both scores showed moderate performance for AKI prediction. Malhotra 5 showed better performance compared to APS 4. Multicenter international study is warranted to develop a universal model that can predict AKI in critically ill patients.

Skeletal involvement in children with Langerhans cell histiocytosis: healing, complications, and functional outcome.

INTRODUCTION: Skeletal involvement in children with Langerhans cell histiocytosis (LCH) is a common feature of the disease. Several options for the treatment of these skeletal lesions have been reported. We describe our experience in the treatment of skeletal involvement of LCH in this retrospective case series study, entailing anatomic distribution, pattern of healing, skeletal deformities, and functional outcome of skeletal LCH. METHODS: A retrospective analysis was conducted for patients diagnosed with LCH and having skeletal lesions in the period between 2007 and 2015. Out of a total of 229 cases, 191 (83.4%) had skeletal involvement. Bone healing was divided into partial and complete based on the size of lesion and cortical changes in plain radiograph. Skeletal deformities were serially measured. Time to pain control, resumption of weight bearing, and the final functional status of the patient were reviewed. RESULTS: The mean age at presentation was 4.4 years (3 m-14.8 y) and the mean follow-up period was 53.3 months (0.2-120.7). After screening of skeletal and extra-skeletal lesions, 59 patients (31%) had M-S (Multisystem) LCH and 132 (69%) had S-S (Single system) LCH. Unifocal bone lesions were found in 81 (42.5%) patients, and multifocal bone lesions in 110 patients (57.5%). Single or multiple bone lesions were found in the craniofacial bones in 152 patients (79.5%), femur in 19 patients, (10%), ribs in 18 patients (9.4%), spine in 15 patients (8.1%), pelvis in 14 patients (7.3%), scapula in 8 patients (4.1%), humerus in 6 (3.1%), clavicle in 6 patients (3.1%), tibia in 3 patients (1.5%), radius in 3 patients (1.5%), and the ulna in 2 patients (1%) patients. No lesions were found in the fibula, hand, or foot. Out of all skeletal lesions, 179 (93.7%) patients were treated either medically or conservatively and 12 patients (6.2%) were treated surgically. The mean time to complete healing was 5.2 months (2-12). Skeletal complications included: pathologic fractures (9 vertebra plana, 5 long bone, 1 iliac bone), deformities (9 thoracolumbar kyphosis, 2 cervical spine subluxations, 2 coxa vara deformity of the proximal femur and one flattening of iliac bone). CONCLUSION: Non-operative treatment can lead to adequate bone healing in few months period. Partial or complete remodeling of bone deformities can be observed without surgical correction. However, surgical intervention might be indicated when cervical spine affection may lead to instability and subsequent neurological affection. Functional impairment is rarely caused by skeletal lesions in LCH.

Effect of timing of pulmonary metastasis occurrence on the outcome of metastasectomy in osteosarcoma patients.

BACKGROUND: Complete metastasectomy is the best predictor of survival in patients with osteosarcoma pulmonary metastases. There has been some controversy in the literature regarding the prognostic significance of the timing of occurrence of lung metastasis. METHODS: We reviewed the clinical course of all osteosarcoma patients with pulmonary metastases treated by metastasectomy in our hospital from January 2008 through December 2016. Each patient who underwent metastasectomy was placed into one of three groups based on whether lung metastases were present at initial presentation (Group 1), developed during chemotherapy (Group 2), or appeared after completion of chemotherapy (Group 3). Data were obtained retrospectively and follow-up was obtained until the end of June 2017. RESULTS: We identified 170 patients with pulmonary nodules of whom 99 (58.2%) underwent at least one metastasectomy (149 thoracotomies). Eleven patients had benign pulmonary nodules and were excluded. The other 88 patients were classified as Group 1 (37), Group 2 (18) or Group 3 (33). The median follow-up was 35 months (range 8 to 99). Postmetastasis 5-year overall survival (OS) was 38.1 ±â€¯6.4%; event-free survival (EFS) was 25 ±â€¯5.3%. By group, postmetastasis 5-year OS and EFS were 34.3 ±â€¯13% and 18 ±â€¯9.3% in Group 1, 8 ±â€¯6.5% and 6.5 ±â€¯5% in Group 2, and 52 ±â€¯11.4% and 25 ±â€¯9% in Group 3 (P < 0.001). In univariate analysis, the only significant factors associated with survival were timing of occurrence of lung metastasis and the number of lung nodules found. CONCLUSION: The timing of occurrence of lung metastasis is an important prognostic factor among osteosarcoma patients eligible for metastasectomy. Patients whose metastases occurred during chemotherapy had the worst survival. LEVEL OF EVIDENCE: Level II.

Association of Aggresomes with Survival Outcomes in Pediatric Medulloblastoma.

Aggresomes are inclusion bodies for misfolded/aggregated proteins. Despite the role of misfolded/aggregated proteins in neurological disorders, their role in cancer pathogenesis is poorly defined. In the current study we aimed to investigate whether aggresomes-positivity could be used to improve the disease subclassification and prognosis prediction of pediatric medulloblastoma. Ninety three pediatric medulloblastoma tumor samples were retrospectively stratified into three molecular subgroups; WNT, SHH and non-WNT/non-SHH, using immunohistochemistry and Multiplex Ligation Probe Amplification. Formation of aggresomes were detected using immunohistochemistry. Overall survival (OS) and event-free survival (EFS) were determined according to risk stratification criteria. Multivariate Cox regression analyses were carried out to exclude confounders. Aggresomes formation was detected in 63.4% (n = 59/93) of samples. Aggresomes were non-randomly distributed among different molecular subgroups (P = 0.00002). Multivariate Cox model identified aggresomes' percentage at ≥20% to be significantly correlated with patient outcome in both OS (HR = 3.419; 95% CI, 1.30-8.93; P = 0.01) and EFS (HR = 3; 95% CI, 1.19-7.53; P = 0.02). The presence of aggresomes in ≥20% of the tumor identified poor responders in standard risk patients; OS (P = 0.02) and EFS (P = 0.06), and significantly correlated with poor outcome in non-WNT/non-SHH molecular subgroup; OS (P = 0.0002) and EFS (P = 0.0004).

Outcome of resectable pediatric Ewing sarcoma of the ribs.

PURPOSE: Was to evaluate the outcome of multimodality treatment in resectable primary Ewing sarcoma/primitive neuroectodermal tumor ES/PNET of the ribs and role of thoracoscopy in facilitating resection of these tumors. PATIENTS AND METHODS: This was a retrospective study including 22 patients with primary ES/PNET of the ribs surgically treated at Children's Cancer Hospital Egypt (CCHE) between January 2008 until the end of December 2014. RESULTS: Median age was 8.5years (range 5months to 16years.). All patients received neoadjuvant chemotherapy. Thoracoscopic exploration was performed in 15 (68%) patients. Resection included 1,2,3 and 4 ribs in (7,4,8 and 3 patients) respectively, parts of the diaphragm (3 patients), wedge resection of the lung (10 patients) and pleural nodules (2 patients). Primary closure was feasible in 11 patients and rib transposition was done in one patient. Reconstruction by proline mesh covered by muscle flap was done in 10 patients. Margins were microscopically positive in 3 patients and close in 2 patients. Postoperative radiotherapy was given in 8 patients. With a median follow-up of 38.5months, the 3-year event -free survival (EFS) and overall survival(OS) rates were 31.6% and 55.6%, respectively. CONCLUSION: Multimodality treatment is essential in the management of ES-PNET of the ribs. Neoadjuvant chemotherapy facilitates adequate resection. The role of thoracoscopy and the indications of postoperative radiotherapy need further evaluation.

TAp73 and ΔNp73 relative expression in Egyptian patients with lymphoid neoplasms.

BACKGROUND AND AIMS: The p73 gene has different isoforms with opposing anti- and pro-apoptotic functions. The pro-apoptotic activities are inhibited by overexpression of the dominant ΔNp73 isoform. The aim of this study was to detect the expression of the TAp73 and ΔNp73 isoforms in Egyptian patients with malignant lymphoid neoplasms. Their expression was analyzed by quantitative RT-PCR. PATIENTS AND METHODS: The study included 30 B-NHL patients, 24 T-NHL patients, 16 ALL patients, 18 CLL patients, 22 patients with reactive lymphoid hyperplasia, and 6 healthy control subjects. RESULTS: ALL and CLL patients expressed both isoforms at higher levels compared to lymphoma patients. Higher expression of TAp73 was found in both B-NHL and T-NHL (around 4-fold and 16-fold, respectively) in comparison to ΔNp73 (2-fold and 14-fold, respectively). In CLL patients both isoforms showed higher expression levels in comparison to normal peripheral blood lymphocytes controls: nearly 27-fold for TAp73 and 233-fold for ΔNp73. All ALL patients showed higher expression of both studied isoforms than controls (9-fold for TAp73 and 386-fold for ΔNp73). The highest ΔNp73 expression along with a higher ΔNp73/TAp73 ratio (67-fold) was found in ALL patients compared with CLL patients (21-fold). CONCLUSIONS: A considerable number of lymphoma patients lacked the expression of either or both isoforms, while all lymphoid leukemia patients expressed both isoforms. The expression pattern differences of p73 isoforms may reflect differences in the biology of these malignancies.

Outcome of Muscle-Invasive Urothelial Bladder Cancer After Radical Cystectomy.

UNLABELLED: We aimed at clarification of reasons for recurrence of urothelial carcinoma after radical cystectomy in a retrospective study that included 189 patients. Presence of lymphovascular invasion even in node-negative cases, high tumor grade, and high nodal stage appeared to be independent predictors for recurrence. This raises the necessity for postoperative multimodality treatment to improve disease-free survival. BACKGROUND: Radical cystectomy remains the gold standard for local control of muscle-invasive bladder cancer. Despite that, a significant proportion of patients develop disease recurrence. Several predictors for recurrence have been described and the implication of such factors on development of recurrence will help in modification of treatment strategies to improve the prognosis of bladder cancer patients. PATIENTS AND METHODS: This is a retrospective study carried on patients with muscle-invasive urothelial carcinoma who underwent radical cystectomy at the National Cancer Institute in 3 years; January 2007 to December 2009, and analyzed for the development of recurrence and potential risk factors. RESULTS: The 3-year disease-free survival (DFS) rate was 56%. Seventy patients (37%) developed disease recurrence during the follow-up period. Of these recurrences, 17 patients (24.3%) developed local and/or regional recurrences, 45 patients (64.3%) developed distant metastasis, and 8 patients (11.4%) developed local and/or regional and distant recurrences. In univariate analysis, lymph node metastasis (P < .001), lymphovascular invasion (LVI) (P < .001), high grade (P = .005), and advanced tumor stage (P = .002) were significantly associated with development of recurrence. In multivariate analysis, lymph node metastasis, LVI, and high grade were significantly associated with tumor recurrence and poor DFS. CONCLUSION: Lymph node metastasis, LVI, and high tumor grade were independent prognostic factors that affected tumor recurrence and DFS. LVI status should be reported in radical cystectomy specimens to help in risk assessment of patients especially in node-negative cases.

ssociation of Cytochrome P450-1B1 Gene Polymorphisms with Risk of Breast Cancer: an Egyptian Study.

It is thought that population characteristics of breast cancer may be due to a variation in the frequency of different alleles of genes such as CYP1B1. We aimed to determine the association of CYP1B1 polymorphisms in 200 breast cancer cases and 40 controls by PCR-RFLP. Frequencies were assessed with clinical and risk factors in Egyptian patients. The genotype LV and the Leu allele frequencies for patients and controls were 42.9% and 50%, and 52.9% and 53.3%, respectively), with no significant differences observed (P values = 0.8 and 0.6, respectively). There was also no significant association between genotypes and any risk factors for cases (>0.05) except laterality and metastasis of the tumor (P values=0.006 and 0.06, respectively). The CYP1B1 polymorphism Val432Leu was not associated with breast cancer in Egypt, but may provide clues for future studies into early detection of the disease.

Ki-67 is a powerful tool for grading neuroendocrine tumors among Egyptian patients: a 10-year experience.

BACKGROUND: Neuroendocrine tumors (NETs) arise in most organs of the body and share many common pathologic features. However, a variety of organ-specific systems have been developed for nomenclature, grading and staging of NETs, causing much confusion. In collaboration with WHO, the European Neuroendocrine Tumor Society (ENETS) recommended the use of either mitotic rate or Ki-67 labeling index (LI) for grading and classification. We aim to explore the profile of NETs in Egyptian patients and apply the ENETS system. MATERIALS AND METHODS: This retrospective study was carried out on all cases of NETs diagnosed at the Pathology Department, National Cancer Institute, Cairo University, during the period from January 2000 to December 2009. Data about age, sex, anatomic site of tumor, tumor size, tumor stage and presence of nodal metastasis were retrieved. Ki-67 immunostaining and grading according to ENETS were done. RESULTS: There was a trend toward increased mean age and tumor size and grade according to Ki-67, with significant statistical difference (p < 0.001 and 0.036, respectively). Estimation of mitotic count and Ki-67 LI was strongly associated with NET histopathologic types, but this association was stronger regarding Ki-67 LI than mitotic count (p = 0.002 and 0.035, respectively). On the other hand, there was discordance between grading according to mitotic count and grading according to Ki-67 LI in relation to NET histopathologic subtypes. Concordance between mitotic rate and Ki-67 LI was reported in 18.89% of cases, while discordance occurred in 81.11% of cases and was more prevalent in G3. CONCLUSION: Ki-67 is a reliable and reproducible marker for grading of NETs and more superior than mitotic rate.

A case of synchronous double primary breast carcinoma and osteosarcoma: Mismatch repair genes mutations as a possible cause for multiple early onset malignant tumors.

BACKGROUND: Simultaneous or consequent development of multiple solid tumors might be faced in some patients, especially the young. These tumors might be related to certain hereditary cancer syndromes or certain genetic predispositions. CASE REPORT: We present the case of a 19-year-old woman with metastatic breast cancer to the contralateral axillary lymph node, associated with simultaneous osteosarcoma of the left lower femur. As she did not fit into any of the familial cancer syndromes, genetic predisposition was suspected. We detected MLH1 and MSH2 promotor methylation (PM), microsatellite instability (MSI), and different mutational events in both tumors. BRCA1 gene mutations were detected in the breast tumor, with reduced mRNA expression of BRCA1&2. ERCC1, MLH1 and MSH2, especially in OS, and RRM1 was overexpressed in both tumors. CONCLUSIONS: Aberrations in MMR genes could explain simultaneous or consequent development of multiple solid tumors, especially in a young patient. We recommend detecting these defects, close follow-up for those patients, and genetic counseling for their family members. Further studies in a larger population are essential to support our results.

Evaluation of nuclear unrest and p53 immunostaining in Wilms' tumor.

BACKGROUND: Nuclear unrest is a term applied to Wilms' tumors (WT) that show nuclear abnormalities close to anaplasia but without abnormal mitoses. p53 is claimed to be associated with anaplasia and poor prognosis. This study was undertaken to evaluate the clinical significance of nuclear unrest and p53 immunostaining in Wilms' tumor. MATERIAL AND METHODS: This is a retrospective study of 63 patients who presented at NCI with Wilms' tumors, and underwent preoperative chemotherapy followed by nephrectomy. Histopathologic assessment and p53 immunohistochemistry were done. RESULTS: WT with nuclear unrest grade III closely resembled anaplastic tumors and both of them (group 1) constituted 19% of cases. Group 1 constituted 29% of cases showing blastema dominant morphology compared to 9.4% of cases without blastema dominant morphology with significant statistical difference (p=0.047). Almost 83% of cases that achieved 1st complete remission were stages I, II and III, while 17% were stages IV and V with significant statistical difference (p<0.001). Stage affected the 3-year relapse-free-survival (RFS) significantly (p=0.014) as it was more in stages I, II and III than in stages IV and V (75.4% versus 50%). Blastema dominant morphology and high risk state significantly lowered the 3-year overall survival (OS) into 54.8% in comparison to 80.9% for cases with non-blastema dominant morphology (p=0.042). Regarding p53 immunohistochemistry, group 1 tumors showed positive p53 more than group 2 with significant statistical difference (p=0.014). p53 Positive immunostaining was significantly associated with high risk nephroblastoma (p=0.004). CONCLUSION: Tumor stage and blastema dominant morphology are potent prognostic factors. p53 is linked to blastema dominant morphology. WT with nuclear unrest grade III closely resembles anaplastic WT. It may be appropriate to group tumors with nuclear unrest grade III with anaplastic histology regarding treatment stratification.