The prognostic value of bone marrow retention index and bone marrow-to-liver ratio of baseline 18F-FDG PET/CT in diffuse large B-cell lymphoma.

OBJECTIVE: To determine prognostic value of bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) measured on baseline dual-phase 18F-FDG PET/CT in a series of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) treated homogeneously with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. PATIENTS AND METHODS: This prospective study enrolled 135 patients with newly diagnosed DLBCL. All patients underwent dual-phase 18F-FDG PET/CT. The following PET parameters were calculated for both tumor and bone marrow: maximum standardized uptake value (SUVmax) at both time points (SUVmax early and SUVmax delayed), SUVmax increment (SUVinc), RI, and BLR. Patients were treated with R-CHOP regimen and response at end of treatment was assessed. RESULTS: The final analysis included 98 patients with complete remission. At a median follow-up of 22 months, 57 patients showed no relapse, 74 survived, and 24 died. The 2-year relapse-free survival (RFS) values for patients with higher and lower RI-bm were 20% and 65.1%, respectively (p < 0.001), and for patients with higher and lower BLR were 30.2% and 69.6%, respectively (p < 0.001). The 2-year overall survival (OS) values for patients with higher and lower RI-bm were 60% and 76.3%, respectively (p = 0.023), and for patients with higher and lower BLR were 57.3% and 78.6%, respectively (p = 0.035). Univariate analysis revealed that RI-bm and BLR were independent significant prognostic factors for both RFS and OS (hazard ratio [HR] = 4.02, p < 0.001, and HR = 3.23, p < 0.001, respectively) and (HR = 2.83, p = 0.030 and HR = 2.38, p = 0.041, respectively). CONCLUSION: Baseline RI-bm and BLR were strong independent prognostic factors in DLBCL patients. CLINICAL RELEVANCE STATEMENT: Bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) could represent suitable and noninvasive positron emission tomography/computed tomography (PET/CT) parameters for predicting pretreatment risk in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. KEY POINTS: • Bone marrow retention index (RI-bm) and bone marrow-to-liver ratio (BLR) are powerful prognostic variables in diffuse large B-cell lymphoma (DLBCL) patients. • High BLR and RI-bm are significantly associated with poor overall survival (OS) and relapse-free survival (RFS). • RI-bm and BLR represent suitable and noninvasive risk indicators in DLBCL patients.

PARP1, BRCA1 and androgen receptor expression in triple-negative breast cancer patients treated with neoadjuvant chemotherapy / Expresión de receptores de PARP1, BRCA1 y andrógenos en pacientes de cáncer de mama triple negativo tratados con quimioterapia neoadyuvante

Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype, where no effective therapies have been established for it. Searching for therapeutic targets for TNBC patients is the aim of the current research. Poly adenosine diphosphate ribose polymerase (PARP1) inhibitors are promising antitumor therapy that have a high potency in BRCA1-deficient breast cancers. Materials and methods: Forty TNBC patients who received neoadjuvant chemotherapy (NAC) were enrolled in this study, and evaluated for PARP1, BRCA1, and Androgen receptor (AR) immunohistochemical expression before and after receiving NAC. Data of patients' clinical and pathological responses to the chemotherapy were collected and finally analyzed. Results: The immunohistochemical results revealed 10 cases (25%) positive for AR, while 18 cases (45%) and 22 cases (55%) expressed PARP1 at low and high levels, respectively. Twelve cases (30%) and 28 cases (70%) expressed BRCA1 at low and high levels, respectively. There was a significant difference between PARP1 expression in normal and malignant tissues (P < 0.001). Higher PARP1 expression was correlated with a better overall clinical response (OAR) and pathological complete response (pCR) (P = 0.018, 0.01 respectively). Co-expression of both PARP1 & BRCA1 was correlated with OAR and pCR. Chemotherapy decreases PARP1 protein levels in matched patient samples (P = 0.015). Positive AR expression was correlated with BRCA1 overexpression. Conclusion: PARP1 is highly expressed in TNBC with a better OAR and pCR especially in cases with high BRCA1, so it might be considered as a therapeutic target for this risky group. (AU)

Introducción: El cáncer de mama triple negativo (TNBC) es un subtipo agresivo, donde no se han establecido terapias efectivas para este cáncer. La búsqueda de dianas terapéuticas para pacientes con TNBC es el objetivo de la investigación actual. Los inhibidores de la poli adenosina difosfato ribosa polimerasa (PARP1) son prometedores terapia antitumoral que tienen una alta potencia en los cánceres de mama deficientes de BRCA1. Materiales y métodos: Cuarenta pacientes de TNBC que recibieron quimioterapia neoadyuvante (NAC) se inscribieron en este estudio y se evaluaron para la expresión inmunohistoquímica de PARP1, BRCA1 y receptores de andrógenos (AR) antes y después de recibir NAC. Se recogieron y finalmente se analizaron los datos de las respuestas clínicas y patológicas de los pacientes a la quimioterapia. Resultados: Los resultados inmunohistoquímicos revelaron 10 casos (25%) positivos para AR, mientras que 18 casos (45%) y 22 casos (55%) expresaron PARP1 en niveles bajos y altos, respectivamente. Doce casos (30%) y 28 casos (70%) expresaron BRCA1 en niveles bajos y altos, respectivamente. Hubo una diferencia significativa entre la expresión de PARP1 en tejidos normales y malignos (P 0.001). Una mayor expresión de PARP1 se correlacionó con una mejor respuesta clínica global (OAR) y una respuesta patológica completa (pCR) (P = 0,018, 0,01 respectivamente). La co-expresión de ambos PARP1 y BRCA1 se correlacionó con OAR y pCR. La quimioterapia disminuye los niveles de proteína PARP1 en muestras de pacientes emparejadas (P = 0,015). La expresión positivos de AR se correlacionó con la expresión de BRCA1. Conclusión: El PARP1 está muy expresado en TNBC con una mejor OAR y pCR especialmente en casos con BRCA1 alto, por lo que podría ser considerado como una diana terapéutica para este grupo de riesgo. (AU)

Prognostic impact of immunohistochemical expression of claudin-4 and epithelial mesenchymal-related markers (Snail-1) in breast invasive duct carcinoma / Impacto pronóstico de la expresión inmunohistoquímica de Claudin-4 y marcadores epiteliales-mesenquimales relacionados (Snail-1) en el carcinoma ductal infiltrante de la mama

Introduction: Although the molecular profile of the breast provides prognostic indicators, risk stratification in breast cancer continues to be a challenge. Therefore, it is mandatory to seek new prognostic markers that could aid the early diagnosis of potential metastases in biopsy samples from breast cancer; among these are increased Snail-1 and Claudin-4 expression.Objectives: The aim of this study was to analyze the correlation between Snail-1 and Claudin-4 with other clinical-pathological parameters and distinct molecular subtypes.Methods: This study included 110 patients with invasive ductal carcinoma from 2009 to January 2015. Snail-1 and Claudin-4 were assessed by immunohistochemistry in formalin-fixed paraffin-embedded tissue blocks and the data were correlated with clinical-pathological data and survival.Results: A total of 65 patients (68.2%) were positive for Snail-1 and 85 patients (77.3%) were positive for Claudin-4. High Snail-1 and high Claudin-4 were detected in high-grade tumors and were associated with lymphovascular infiltration and lymph node metastases (p<0.001 for each). There was a highly significant correlation between Snail-1, Claudin-4 expression and the molecular subtype of breast cancer (p<0.001), with higher Snail-1 expression in TNBC and Her 2/neu cases (p=0.001). Claudina-4 expression in the Her2/neu enriched subtype, Snail-1-positivity and high Claudin-4 expression were associated with recurrence (p=0.001; 0.004 respectively) among the cases studied. Snail-1 and Claudin-4 were inversely related with overall survival (p=0.001) and disease-free survival (p=0.001).Conclusion: High Snail-1 and Claudin-4 levels were associated with adverse outcomes in patients with breast cancer. (AU)

Introducción: Aunque el perfil molecular de la mama proporciona indicadores de pronóstico, la estratificación del riesgo de cáncer de mama sigue siendo un desafío y es obligatoria para buscar nuevos marcadores de pronóstico que puedan facilitar el diagnóstico temprano de metástasis potenciales en las muestras de biopsia de cáncer de mama; entre estos se encuentra la expresión creciente de Snail-1 y Claudin-4.Objetivos: El objetivo de este trabajo es estudiar la correlación de Snail-1 y Claudin-4 con otros parámetros clínico-patológicos y diferentes subtipos moleculares.Métodos: Se inscribieron 110 pacientes con carcinoma de conducto invasivo en este estudio durante el período de enero de 2009 a enero de 2015. Snail-1 y Claudin-4 fueron evaluados por inmunohistoquímica (IHC) en bloques de parafina y los datos se correlacionaron con características clínico-patológicas y de supervivencia.Resultados: Fueron positivos 75 casos (68,2%) para Snail-1 y 85 (77,3%) positivos para Claudin-4. High Snail-1 y High Claudin-4 se detectaron en tumores de alto grado y se asociaron con invasión linfovascular y metástasis en los ganglios linfáticos (p < 0,001 para cada uno). Se detectó una correlación altamente significativa entre Snail-1, la expresión de Claudin-4 y el subtipo molecular de cáncer de mama (p < 0,001), con la mayor expresión de Snail-1 en los casos de cáncer de mama triple negativo (TNBC) y Her 2/neu (p = 0,001). La expresión de Claudina-4 en subtipo Her2/neu enriched, Snail-1 positivo y alta expresión de Claudin-4 se asoció con recaída (p = 0,001; 0,004, respectivamente) entre los casos estudiados. La expresión de Snail-1 y Claudin-4 se relacionó inversamente con la SG (p = 0,001) y la SSE (p = 0,001).Conclusión: Los niveles altos de proteínas Snail-1 y Claudin-4 se asocian con resultados adversos en pacientes con cáncer de mama. (AU)

Clinicopathological Features and Treatment Challenges in Triple Negative Breast Cancer Patients: A Retrospective Cohort Study.

OBJECTIVE: As the genetic and molecular profiles of triple negative breast carcinoma (TNBC) are elucidated, multiple therapeutic targets have been produced. TNBC with less than 1% androgen receptor (AR) expression may respond to enzalutamide with greater response association in higher levels. A metronomic dose of capecitabine and docetaxel are effective developed drugs for angiogenic process inhibition. We aimed to demonstrate the treatment outcome of triple-negative breast cancer patients in correlation to their clinicopathological features. MATERIALS AND METHODS: A retrospective cohort study of 80 TNBC patients was conducted. The patients underwent proper observation with the reporting of their treatment and follow-up data. Patients with a metastatic disease, neoadjuvant chemotherapy, follow-up drop or data shortage were excluded from the survival analysis. RESULTS: The study results revealed a significant association between negative androgen expression and younger age ≤35 years, premenopausal status, higher grade, extracapsular extension, lymphovascular invasion, Ki 67, and CA15-3 (p=0.003, 0.02, < 0.001, 0.001, 0.027, 0.005, 0.009 respectively). The three-year overall survival (OS) in patients who received bicalutamide was better than those patients who received capecitabine or docetaxel but of no significance (p=0.46). The three-year disease free survival (DFS) was significantly better in the bicalutamide arm versus the other two groups (p=0.012). CONCLUSIONS: We concluded that extended adjuvant antiandrogen such as bicalutamide and metronomic capecitabine are well tolerated with accepted compliance and affordability compared to docetaxel and are warranted for problem-solving and better DFS and OS in some TNBC patients.

Ascitic Calprotectin as an early predictor of hepatocellular carcinoma in patients with cirrhotic ascites.

BACKGROUND: Calprotectin is a heterodimer formed by S100A8 and S100A9 proteins which are enhanced during hepatic carcinogenesis and the increased expression of both proteins promotes malignant progression of hepatocellular carcinoma. The potential correlation between ascitic Calprotectin and HCC was not studied. METHODS: 100 patients were stratified into a case group which enrolled 50 patients with cirrhotic ascites and documented HCC and a control group consisted of 50 patients with cirrhotic ascites without HCC. They were evaluated by liver function tests, abdominal ultrasound and routine ascitic fluid examination including ascetic Calprotectin and results were validated in another group (n = 100). RESULTS: Calprotectin level was significantly higher in the HCC group with insignificant difference regarding total cell count, PNLs, ascitic albumin, LDH, CEA and SAAG. It correlated with serum creatinine (r = 0.245, p = 0.014) and number of focal hepatic lesions (r = 0.309, p = 0.002). In the validation group, 28 patients had elevated ascitic Calprotectin of which 21 patients had developed HCC (75%) after a mean period of 3.8 ± 1.54 months. A cut of value 126 ng/ml was accurate to predict HCC in liver cirrhosis with ascites with a sensitivity of 93.3% specificity 94%, AUC 0.950, Youden's J value = 0.873, p = 0.0001. CONCLUSION: Ascitic Calprotectin may offer an easy, affordable marker that can predict the early occurrence of HCC.

Outcome of Core Binding Factor Acute Myeloid Leukemia by Receptor Tyrosine Kinase Mutation.

BACKGROUND: Core binding factor acute myeloid leukemia (CBF-AML) encodes 2 recurrent cytogenetic abnormalities, t(8;21) and inv(16), which carries an overall good prognosis. However, some patients will develop a relapse. We sought define the unfavorable group of CBF-AML by analysis of (c-KIT and FLT3-ITD) and to correlate them with treatment outcome. PATIENTS AND METHODS: We performed a prospective study of 70 patients with CBF-AML diagnosed and managed at the medical oncology department of the (National Cancer Institute), Cairo University, with analysis of c-KIT and FLT3 mutations. All patients had received "3 + 7" induction, followed by 3 to 4 courses of high-dose cytarabine consolidation. The institutional review board approved the present study. RESULTS: The median patient age was 31 years (range, 18-60 years), with a male/female ratio of 4:3. Of the 70 patients, 42 (60%) had t(8;21) and 28 had inv(16) (40%). c-KIT mutations (exons 8 and 17) were detected in 10 of 52 tested patients, and FLT3-ITD was detected in 3 of 70 patients. Patients with inv(16) experienced more lymphadenopathy and splenomegaly, had a higher median initial leukocyte count. Hepatitis C antibody positivity (8 of 42) was exclusively present in patients with t(8;21). The median overall survival (OS) was 19.5 months, and the median disease-free survival (DFS) was not reached. Patients with inv(16) had near-significant (P = .07) better DFS than patients with t(8;21). c-KIT mutations had no significant effect on OS or DFS. However, reverse tyrosine kinase mutations had a negative effect on DFS but not OS (P = .04). CONCLUSION: CBF-AML with reverse tyrosine kinase mutation conveys a worse prognosis. Hepatitis C virus antibody positivity might be associated with t(8;21) AML and inv(16) with more extramedullary disease.

ERCC1, PARP-1, and AQP1 as predictive biomarkers in colon cancer patients receiving adjuvant chemotherapy.

BACKGROUND: The recognition of high-risk colon cancer patients prone to chemoresistant and recurrent disease is a challenge. OBJECTIVES: We aimed to assess the immunohistochemical expression of ERCC1, PARP-1, and AQP1 in 60 cases of stage II and III colon cancer who underwent curative resection and adjuvant chemotherapy. Their predictive role of tumor progression and disease-free survival (DFS) was analyzed. METHODS: The immunohistochemical expression of ERCC1, PARP-1, and AQP1 in 60 cases of stage II and III colon cancer who underwent curative resection and adjuvant chemotherapy was studied. The collected data on the overall survival (OS), disease-free survival (DFS), and the response to the chemotherapy were analyzed. RESULTS: Positive nuclear ERCC1 expression was identified in 58.3% of the patients, ERCC1 expression was significantly associated with left-sided tumors (P< 0.01). Moreover, its expression was significantly associated with the aggressive tumor characteristics including high grade, lymph node metastasis and advanced tumor stage (P< 0.001 for each). High nuclear PARP-1 expression was observed in 63.3% of the cases, and its expression was significantly associated with tumor grade and lymph node metastasis (P= 0.003 for each). Positive membranous AQP1 expression was identified in 41.7% of patients, and it was associated with high grade, lymph node metastasis and advanced tumor stage (P< 0.001 for each). During the follow-up period, 23 patients (38.3%) exhibited a tumor progression; this was significantly associated with positive ERCC1, high PARP-1, and negative AQP1 expression. Statistics of the survival data revealed that shorter DFS was significantly associated with positive ERCC1, high PARP-1, and positive AQP1 expression (P= 0.005, 0.016, 0.002, respectively). CONCLUSIONS: ERCC1, PARP1, and AQP1 are adverse prognostic biomarkers in stage II-III colon cancer. Moreover, adjuvant chemotherapy may not be beneficial for patients with positive ERCC1, high PARP1, and AQP1-negative tumors. Therefore, we recommend that ERCC1, PARP-1, and AQP1 should be assessed during the selection of the treatment strategy for stage II-III colon cancer patients.

Upregulation of microRNA-21 is a poor prognostic marker in patients with childhood B cell acute lymphoblastic leukemia.

OBJECTIVES: Many studies have demonstrated that microRNA-21 (miR-21) is an oncogene and is upregulated in tumor tissue. However, its association with B-cell acute lymphoblastic leukemia (B-ALL) remains poorly understood. METHODS: The expression of miR-21 was detected by real-time quantitative PCR in 75 children with de novo B-ALL as well as in 50 healthy controls. This study was conducted to evaluate the miR-21 as a biomarker for risk assessment, diagnosis and prognosis. RESULTS AND DISCUSSION: Compared with normal controls, miR-21 expression was significantly upregulated in childhood B-ALL patients. Using the receiver operating characteristic curve 3.23 was selected as the cut-off value of miR-21 expression in distinguishing patients from controls. Patients group with High miR-21 expression was significantly associated with those aged <2 and >10 years, lower platelets count, more incidence of CNS infiltration and poorer treatment outcome also, they showed a significantly poorer disease-free survival (DFS) and overall survival (OS) compared to those with low miR-21 expression group. Its expression was an independent prognostic marker according to multivariate analysis. CONCLUSION: This is the first report demonstrating the upregulation of miR-21 in childhood B-ALL, and its association with poor response to induction therapy, shorter DFS and OS. These results suggest that miR-21 upregulation represent an unfavorable prognostic marker in Childhood B-ALL.

The fear of using tramadol for pain control (tramadolophobia) among Egyptian patients with cancer.

OBJECTIVES: The fear of using tramadol for pain control (tramadolophobia) by Egyptian patients with cancer is a frequent problem in our practice. This study was conducted to explore the prevalence of and the reasons behind tramadolophobia among Egyptian patients with cancer. METHODS: A structured interview including open-ended and closed questions. The study included 178 adult patients with cancer from two cancer centers in Cairo and Sharkia, Egypt. RESULTS: The source of information about tramadol was a non-healthcare-related source in 168 (94 percent) patients, mainly the media (50 percent). The believed uses of tramadol were abuse related in 94 (53 percent) patients, stimulant (physical, sexual, and to boost alertness) in 59 (33 percent), and analgesic in 55 (31 percent). Twenty-six (15 percent) patients gave history of tramadol use, largely (69 percent) as a stimulant. In case tramadol was prescribed for pain control, 90 (51 percent) patients refused to take it, 59 (33 percent) patients agreed to take it with concern about addiction, and only 29 (16 percent) patients agreed without concerns. Among those who refused taking tramadol for pain, the mentioned reason of refusal was addiction-related fears in 57 percent. CONCLUSIONS: The stigmatization and misconceptions about tramadol may have resulted in tramadolophobia among the majority of Egyptian patients with cancer. This further complicates the barriers to cancer pain control in Egypt. Being the only available World Health Organization step-II analgesic in Egypt, interventions to overcome tramadolophobia should be taken.