Renal oncocytoma: a challenging diagnosis.

PURPOSE OF REVIEW: The aim of the review is to provide an update on the current and evolving approaches to diagnosing the challenging clinical entity of renal oncocytoma. RECENT FINDINGS: Renal oncocytoma is being increasingly recognized among patients with renal masses, and it can be found in up to 50% of benign small renal masses (SRMs) less than 4 cm. Renal oncocytomas have benign clinical biology but distinguishing them from some of the other renal masses with more malignant potential can be challenging due to overlapping imaging, histologic, and immunophenotypic characteristics. Increasing integration of various imaging modalities, histologic characteristics, cytogenetics, and molecular and metabolic signatures is helping better define and characterize renal masses. SUMMARY: Evolving and complementary diagnostic approaches, including at the molecular level, are continuing to help refine the classification of renal tumors, with implications on their clinical behavior and ultimately clinical management.

The incidence and outcome of severe hyperlactatemia in critically ill patients.

This study aimed to assess the incidence, persistence, and associated mortality of severe hyperlactatemia in a large cohort of unselected critically ill patients. Also, we evaluated the association between 12 h lactate clearance, the timing of severe hyperlactatemia, and the maximum lactate levels with ICU mortality. In this retrospective, single-center study, we used data from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database. Data extracted to screen 23,598 ICU patients for severe hyperlactatemia. A total of 23,598 critically ill patients were eligible for this study. Overall, ICU mortality in the 23,598 ICU patients was 12.1%. Of these, 760 patients had lactate concentration [Formula: see text] 10 mmol/L and ICU mortality in this group was 65%. Our findings confirm the association between hyperlactatemia and ICU mortality [odds ratio 1.42 (95% CI 1.35; 1.49; P < 0.001)]. Data for 12 h lactate clearance was available for 443 patients (276 nonsurvivable vs. 167 survival). 12 h lactate clearance yielded a high area under the curve (AUC) of 0.78, (95% CI 0.74 and 0.83). Severe hyperlactatemia is associated with extremely high ICU mortality in a heterogeneous ICU population. Lactate derived variables (the timing and persistence of severe hyperlactatemia, maximum level, and 12 h clearance) are shown to be associated with ICU mortality in patients with severe hyperlactatemia. Our results suggest that maximum lactate level and 12 h lactate clearance were clinically useful prognostic parameters for patients with severe hyperlactatemia.

Wnt-pathway Activating Mutations Are Associated with Resistance to First-line Abiraterone and Enzalutamide in Castration-resistant Prostate Cancer.

BACKGROUND: Wnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10-20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients. OBJECTIVE: To determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints. RESULTS AND LIMITATIONS: Of 137 patients evaluated, 11% (n=15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6mo, hazard ratio [HR] 2.34, p=0.003), as was OS (23.6 vs 27.7mo, HR 2.28, p=0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p=0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p=0.007) and use of previous chemotherapy (aHR 1.83, p=0.004) were both independently associated with increased hazard of progression. CONCLUSIONS: Patients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients. PATIENT SUMMARY: In this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations.

Genomic and clinical characterization of pulmonary-only metastatic prostate cancer: A unique molecular subtype.

BACKGROUND: Isolated pulmonary involvement is uncommon in metastatic hormone-sensitive prostate cancer (mHSPC). To characterize outcomes and molecular alterations of this unique patient subset, we conducted a retrospective review of patients with hormone-naïve prostate cancer presenting with lung-only metastases. METHODS: This was a retrospective single-institution study. Medical records of 25 patients presenting with pulmonary-only metastases before receiving androgen deprivation therapy (ADT) were analyzed. Germline and/or somatic genomic results, where available (n = 16), were documented. Tumor tissue was analyzed using clinical-grade next-generation DNA sequencing assays. Clinical endpoints included complete prostate-specific antigen (PSA) response to ADT (<0.1 ng/mL), median overall survival (OS) from time of ADT initiation, median PSA progression-free survival (PSA-PFS), and failure-free survival (FFS) at 4 years. RESULTS: Baseline characteristics were notable for 48% of men (12 of 25) having first or second-degree relatives with prostate cancer, compared with 20% expected. Complete PSA responses to ADT were noted in 52% of men, with a median PSA-PFS of 66 months, a 4-year FFS rate of 72%, and a median OS that was not reached after 190 months. In evaluable patients, molecular drivers were enriched for mismatch repair mutations (4 of 16, 25%) and homologous-recombination deficiency mutations (4 of 16, 25%). These results are limited by the small sample size and retrospective nature of this analysis. CONCLUSIONS: This exploratory study represents one of the largest cohorts of lung-only mHSPC patients to-date. The prevalence of actionable DNA-repair gene alterations was higher than anticipated (any DNA-repair mutation: 8 of 16, 50%). Compared to historical data, these patients appear to have exceptional and durable responses to first-line ADT. This study suggests that pulmonary-tropic mHSPC biology may be fundamentally different from nonpulmonary mHSPC.

A rare case of bilateral breast lobular carcinoma coexisting with primary breast follicular lymphoma.

CLINICAL PRACTICE POINTS ● Co-existence of breast cancer and lymphoma is a rare condition. A few cases of synchronous breast ductal carcinoma and lymphoma have been reported in the literature. However, to our knowledge this is the first case report of a bilateral breast lobular carcinoma co-presenting with follicular lymphoma. ● Little is known about the pathophysiology of synchronous cancers of different tumor types, especially solid tumors co-existing with hematologic malignancies. In-depth review of these cases can shed light on underlying mechanism leading to synchronous cancer development.

Concentration- Dependent Effects of Curcumin on 5-Fluorouracil Efficacy in Bladder Cancer Cells

Purpose: Curcumin (Cur), a herbal ingredient with anticancer properties, has been shown to inhibit growth of malignant cells in vivo and in vitro. However, studies on combination therapy of Cur with chemotherapeutic drugs have been limited. Here, effects of Cur on the cytotoxicity of 5-Fluorouracil (FU) were investigated with epithelial bladder cancer cells (EJ138) in vitro. Methods: EJ138 cells were treated with 5 and 15 µM of Cur and/ or 100 µM of FU. Cell viability was measured by sulforhodamine B colorimetric assay. The glucose concentration as an index of cell metabolism was evaluated by an enzymatic method. Total oxidant and antioxidant capacities were estimated by the ferrous oxidation-xylenol (FOX1) method and ferric reducing antioxidant power assay (FRAP), respectively. Results: Combination of 5 µM Cur with FU significantly reduced its cytotoxicity in EJ138 cells, while 15 µM Cur caused an opposite increase. Significant increase in glucose concentration at 24 h and decrease in the FRAP value at 48 h incubation was observed in cells treated with FU in combination with Cur. There were no significant changes in total oxidant capacity with the combination therapy. Conclusion: Our findings suggest a crucial role of Cur concentration in regulating chemotherapeutic agent-induced cytotoxicity. Further investigations are needed to understand the precise mechanisms of action of Cur and determine appropriate doses with combination therapy for clinical application against human cancers.

MSH2 Loss in Primary Prostate Cancer.

Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2 Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; P = 0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r = 0.72, P = 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts. Clin Cancer Res; 23(22); 6863-74. ©2017 AACR.

Paraneoplastic Galactorrhea in Childhood T-ALL: An Evaluation of Tumor-derived Prolactin.

T-cell acute lymphoblastic leukemia (T-ALL) comprises 15% of childhood leukemia. Although multiagent pulse chemotherapy has improved event-free survival in recent decades, the lack of reliable prognosticators and high rate of relapse remain a challenge. Described is a novel discovery of tumor-derived hyperprolactinemia in childhood T-ALL through a case associated with paraneoplastic galactorrhea. Prolactin production by tumor cells, although a rare phenomenon, is previously demonstrated in several adult cancers and 2 pediatric malignancies with unknown implications. This is the first report demonstrating tumor-derived prolactin in pediatric T-ALL and offers potential as a disease marker and therapeutic drug target.

Dual targeting of androgen receptor and mTORC1 by salinomycin in prostate cancer.

Androgen receptor (AR) and PI3K/AKT/mTORC1 are major survival signals that drive prostate cancer to a lethal disease. Reciprocal activation of these oncogenic pathways from negative cross talks contributes to low/limited success of pathway-selective inhibitors in curbing prostate cancer progression. We report that the antibiotic salinomycin, a cancer stem cell blocker, is a dual-acting AR and mTORC1 inhibitor, inhibiting PTEN-deficient castration-sensitive and castration-resistant prostate cancer in culture and xenograft tumors. AR expression, its transcriptional activity, and androgen biosynthesis regulating enzymes CYP17A1, HSD3ß1 were reduced by sub-micro molar salinomycin. Estrogen receptor-α expression was unchanged. Loss of phosphorylated AR at serine-81, which is an index for nuclear AR activity, preceded total AR reduction. Rapamycin enhanced the AR protein level without altering phosphoAR-Ser81 and CYP17A1. Inactivation of mTORC1, evident from reduced phosphorylation of mTOR and downstream effectors, as well as AMPK activation led to robust autophagy induction. Apoptosis increased modestly, albeit significantly, by sub-micro molar salinomycin. Enhanced stimulatory TSC2 phosphorylation at Ser-1387 by AMPK, and reduced inhibitory TSC2 phosphorylation at Ser-939/Thr-1462 catalyzed by AKT augmented TSC2/TSC1 activity, which led to mTORC1 inhibition. AMPK-mediated raptor phosphorylation further reduced mTOR's kinase function and mTORC1 activity. Our novel finding on dual inhibition of AR and mTORC1 suggests that salinomycin is potentially active as monotherapy against advanced prostate cancer.

Assessing the percent of necrosis after neoadjuvant chemotherapy with 24hr infusional cisplatin/3 days Doxorubicin intermittent with Ifosfamide-Doxorubicin for osteosarcoma.

INTRODUCTION: Osteosarcoma is the most common primary bone tumor in children and young adults and appropriate chemotherapy can increase limb sparing and overall survival. Yet, the toxicity of chemotherapy regimens including MTX can be life threatening. Therefore; we tried another chemotherapy regimen for these patients. METHOD AND MATERIALS: We investigated 15 patients aged 15 to 40 years old and used continuous infusion of cisplatin, doxorubicin intermittently with ifosfamide, doxorubicin as neoadjuvant chemotherapy. Percent of necrosis and toxicities was recorded for each patient. RESULTS: Out of 15 patients investigated, 13 were males and 2 females. Tumor necrosis≥ 90% (defined as good necrosis) was observed in 60% of patients. 26.7% of the patients showed leucopenia grade three or four, 26.7% had anemia grade three or four, and 20% showed thrombocytopenia grade three or four. CONCLUSION: The above chemotherapy regimen can cause as good necrosis as the chemotherapy regimens including high dose of MTX with reduced toxicity and less nursing cares and laboratory tests. Of course small sample size limits extension of our result to all patients but trying this regimen is recommended in more patients to see more reliable results.

SULT2B1b sulfotransferase: induction by vitamin D receptor and reduced expression in prostate cancer.

An elevated tumor tissue androgen level, which reactivates androgen receptor in recurrent prostate cancer, arises from the intratumor synthesis of 5α-dihydrotestosterone through use of the precursor steroid dehydroepiandrosterone (DHEA) and is fueled by the steroidogenic enzymes 3ß-hydroxysteroid dehydrogenase (3ß-HSD1), aldoketoreductase (AKR1C3), and steroid 5-alpha reductase, type 1 (SRD5A1) present in cancer tissue. Sulfotransferase 2B1b (SULT2B1b) (in short, SULT2B) is a prostate-expressed hydroxysteroid SULT that converts cholesterol, oxysterols, and DHEA to 3ß-sulfates. DHEA metabolism involving sulfonation by SULT2B can potentially interfere with intraprostate androgen synthesis due to reduction of free DHEA pool and, thus, conversion of DHEA to androstenedione. Here we report that in prostatectomy specimens from treatment-naive patients, SULT2B expression is markedly reduced in malignant tissue (P < .001, Mann-Whitney U test) compared with robust expression in adjacent nonmalignant glands. SULT2B was detected in formalin-fixed specimens by immunohistochemistry on individual sections and tissue array. Immunoblotting of protein lysates of frozen cancer and matched benign tissue confirmed immunohistochemistry results. An in-house-developed rabbit polyclonal antibody against full-length human SULT2B was validated for specificity and used in the analyses. Ligand-activated vitamin D receptor induced the SULT2B1 promoter in vivo in mouse prostate and increased SULT2B mRNA and protein levels in vitro in prostate cancer cells. A vitamin D receptor/retinoid X receptor-α-bound DNA element (with a DR7 motif) mediated induction of the transfected SULT2B1 promoter in calcitriol-treated cells. SULT2B knockdown caused an increased proliferation rate of prostate cancer cells upon stimulation by DHEA. These results suggest that the tumor tissue SULT2B level may partly control prostate cancer growth, and its induction in a therapeutic setting may inhibit disease progression.

Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin.

The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents of natural product origin. We previously reported anti-proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC-3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase-3-dependent pathway that is activated due to dysregulated mitochondrial function. DPT-treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Ca (i)(2+) surge, increased mitochondrial membrane potential (MMP, ΔΨ(m)), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase-3 activation, which in turn induced apoptosis. The antioxidant N-acetylcysteine (NAC) reduced ROS accumulation, MMP and Ca (i)(2+) surge, on the other hand the Ca(2+) chelator BAPTA inhibited the Ca( i)(2+) overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca(2+) flux. This suggested that both ROS and Ca( i)(2+) signaling play roles in the increased MMP via Ca (i)(2+)-dependent and/or -independent mechanisms, since ΔΨ(m) elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS- and Ca( i)(2+)-activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca(2+) flux homeostasis.

Evaluation of agar films in the prevention of postoperative peritoneal adhesions in an animal model.

BACKGROUND: Peritoneal adhesions cause significant long-term postoperative morbidity. This study evaluates the efficacy of agar plates as the physical barrier in reducing adhesion formation after abdominal surgery in an animal model. METHODS: Adhesions were induced, by cecum abrasion, in 20 C57/BL6 mice during a laparotomy procedure. Agar plates were used in 10 mice as the experimental group. At a second operation, 28 days later, the adhesions were graded, in two groups. Data were analyzed by using Student t test. RESULTS: There was no significant difference in weight gain of the two groups during the study period. A comparison of the morphological appearances of the adhesions demonstrated that there was no evident difference between the two groups. There was also no significant difference in the incidence ratio of adhesions or postoperative adhesion scores between the two groups (p value >0.05). CONCLUSION: Despite the hydrogel properties of agar, it was not successful in practice in the reduction of adhesion formation after peritoneal surgery. Since agar is a biological product, it may cause a hyperreactivity induced by the innate immune system in peritoneum. Therefore, agar does not appear to be useful in clinical practice for the reduction of adhesion formation after peritoneal surgery.

Idiopathic thrombocytopenic purpura in women with breast cancer.

The association of solid tumors with idiopathic thrombocytopenic purpura (ITP) is rare. However, there have been some case reports indicating an association between breast cancer and ITP. In this article four patients with breast cancer and ITP are mentioned. The diagnosis of breast cancer was based on the results of biopsy or surgical sample. The ITP diagnosis criteria were 1) exclusion of drug induced thrombocytopenia, 2) platelet count less than 140 × 109 /l with normal or increased number of megakaryocytes on bone marrow samples, and 3) absence of splenomegaly. In this case report an association of breast cancer and ITP is shown.

The comparative study of serum iron, copper, and zinc levels between bladder cancer patients and a control group.

OBJECTIVE: A relatively wide range of trace elements are known to play important roles in biological processes, including the oxidative processes. Oxidative processes are one of the mechanisms involved in both incidence and recurrence of bladder cancer. In the present study, the concentration of iron (Fe), copper (Cu) and zinc (Zn) were determined in the serum of patients with bladder cancer in comparison to healthy subjects. MATERIALS AND METHODS: This cross-sectional study was conducted on 51 patients with bladder cancer and 58 healthy volunteers after age, sex, and smoking habits were matched. After overnight fasting, samples were collected. The concentrations of Fe, Cu, and Zn were measured by flame atomic absorption spectroscopy and comparisons were made using Student's t-test. RESULTS: There was a significant increase in mean Cu and Cu/Zn serum level in bladder cancer patients compared to the control group (P < 0.001). In contrast, the serum zinc level in patients having bladder cancer was significantly lower than in the control group (P < 0.05). Moreover, the serum iron level was significantly lower in the patients than the control group (P < 0.001). CONCLUSIONS: In the present study, a relationship was seen between the level of trace elements and the occurrence of bladder cancer, suggesting that an increase in the serum level of Cu and a decrease in the levels of Zn and Fe might be important causes of bladder cancer occurrence; however, defining such a cause-and-effect relationship needs several prospective studies to be done, which seems necessary with regard to the high prevalence of this cancer.

Standard oral rehydration solution as a new storage medium for avulsed teeth.

OBJECTIVES: Immediate tooth replantation is the choice of treatment in tooth avulsion. When it is impossible to replant immediately an appropriate medium must be used to maintain periodontal ligament (PDL) cell viability. The purpose of this study was to investigate the effect of standard Oral Rehydration Solution (ORS) as a new storage medium for the preservation of PDL cell viability. METHODS: 75 young adult premolar teeth without periodontal disease were used (25 teeth for each medium). Teeth were placed in the experimental media including standard ORS, HBSS and tap water for intended incubation periods. After that, PDL cells were separated and cell viability was determined by Trypan blue staining. The results were analysed by one way ANOVA. RESULTS: There was no significant difference between HBSS and Standard ORS in supporting the maintenance of PDL cell viability. A significant difference between the effect of Standard ORS and water and HBSS and water was observed in maintaining PDL cell viability. CONCLUSIONS: Standard ORS is a suitable transport medium to support the maintenance of PDL cell viability. Regarding its inexpensiveness and availability, standard ORS has preference over some other approved transport media like HBSS.

Bilateral invasive ductal carcinoma in a woman with neurofibromatosis type 1.

A 51-year-old woman with neurofibromatosis type 1 presented to our department for investigation of a left breast lump (50 x 50 x 30 mm); a mass in the right breast (40 x 40 x 20 mm) was also detected on physical examination. The lumps were suspected to be malignant based on physical examination and ultrasonography. Biopsy and frozen sections subsequently confirmed a diagnosis of bilateral invasive ductal carcinoma. A standard bilateral radical mastectomy was performed, followed by postoperative chemoendocrine therapy. Tumor recurrence has not been observed within the first 23 months following the surgery.

A new storage medium for an avulsed tooth.

AIM: The purpose of this study is to determine the efficacy of egg white in maintaining the viability of human periodontal ligament (PDL) cells on avulsed teeth. METHODS AND MATERIALS: The experimental media were: egg white, milk, Hanks' Balanced Salt Solution (HBSS) as the positive control, and tap water as the negative control. The storage times were 1, 2, 4, 8, and 12 hours. Extracted premolar teeth of healthy individuals were rinsed in the media. After trypsinization and subsequent treatment in collagenase, cell viability was determined using trypan blue staining. The two-way analysis of variance (ANOVA) statistical test was used to compare the results among different media. RESULTS: There was no difference in the cell viability between egg white and HBSS media, but there was a statistically significant difference between the viability of PDL cells in egg white medium in comparison with milk (P<0.05) and water (P<0.05). CONCLUSION: Egg white could be suggested as a suitable storage medium. Its principle advantage is its availability.