Targeting Myc and Hdac8 with a Combination of SiRNAs Inhibits Tumor Growth in a Murine Neuroblastoma Xenograft Model

Neuroblastoma is a common tumor of the peripheral nervous system in children. Highly aggressive MYC-drivenneuroblastoma is defined by increased MYC and/or MYCN expression. HDAC8 overexpression is associated with advanced neuroblastoma. Previously, we have demonstrated that transient knockdown of both Myc and Hdac8 using siRNA significantly suppressed neuroblastoma cells proliferation compared to knockdown of either target in vitro. In this study, we further investigated whether combinational targeting Myc and Hdac8 in neuroblastoma xenograft mice model is consistent with our previous findings. Intratumoral treatment with siRNA-MYC and siRNA-HDAC8 reduced the levels of the target MYC protein by 64% and HDAC8 by 85%; in addition, we found that the average tumor growth was reduced by 80% compared to that of control tumors treated with NC-siRNA. Our results suggest the potential therapeutic effect of the combination of siRNA-MYC and siRNA-HDAC8 for neuroblastoma treatment.

Percutaneous Biopsy under Simultaneous Ultrasound and Computer Tomography Guidance in Diagnosis of Isolated Pancreatic Metastasis of Clear Cell Renal Cell Carcinoma

Cancers of the kidney are a various group of tumors, most of which are of epithelial origin and malignant. Renal cell carcinoma (RCC) classically referred to as clear cell carcinoma is the most common kidney cancer (70- 80% of all kidney cancers). The most common primary cancer site resulting in pancreatic metastases is liver, followed by colorectal cancer, melanoma, breast cancer, lung carcinoma and sarcoma. 65 year old man six years after nephrectomy due to clear cell renal cell carcinoma (ccRCC), attended regular abdominal CT examination, which revealed 28.9 mm focal lesion located in pancreatic tail. No other pathological lesions were detected. Patient underwent US guided biopsy preceded by CT pre-biopsy planning. Histopathological analysis of the obtained material confirmed clear cell carcinoma. The authors being aware of other than renal possible sites of clear cell carcinoma origin, additional tests such as membranous immunoreactivity with renal cell carcinoma (RCC), and immunohistochemical staining applied to identify the cellular origin and confirm the renal origin of the metastasis. This innovative, combined method of US guided biopsy supported by CT pre-biopsy planning can be helpful in the diagnosis of atypically located metastases of RCC. Our described case shows that in contrast to other well-known biopsy methods, our assay enables to obtain material for complete histopathological diagnosis and consequently start treatment. Moreover, presented method is based on diagnostic tools that are routinely available in every hospital such as US and CT. The only required modification is the installation of programme that enables to upload CT images containing marked planned needle path to the biopsy room, and simultaneous display of both - static CT image and US image performed in real time.

Examination of Factors Influencing the Success Rates of an In Vitro Chemosensitivity Test for Lung Cancer Using Collagen Gel Droplet-Embedded Cultures

Objective: We evaluated the success rates and factors influencing the success rates of the Collagen Gel Droplet-Embedded Culture Drug Sensitivity Test (CD-DST) for pleural effusate in lung cancer patients with carcinomatous pleurisy.Materials and methods: Thirty-two patients with lung cancer having carcinomatous pleurisy were enrolled in this study between January 2014 and May 2017. Their pleural effusions were analysed by CD-DST, and the subjects were classified into two groups: successful cases and unsuccessful cases, based on whether the test was able to successfully determine drug sensitivity. We investigated whether the properties of the pleural effusate might influence the success rate of CD-DST. We observed that the CD-DST tended to have good success rates in patients with higher pH, higher percentage of lymphocytes, higher cell counts, and lower percentage of neutrophils in their pleural effusate. The red blood cell count was higher in the effusate of unsuccessful than successful cases.Conclusion: Our results suggest that the diagnostic success rates of CD-DST for pleural effusion from patients with lung cancer might improve by appropriate sample selection.

Immunohistochemical Determination of ATAD2 Protein Overexpression for Predicting Prognostic Value in Patients with Different Types of Cancer: A Meta-Analysis

Background: Increasing number of studies has reported that Atpase family AAA domain-containing 2 (ATAD2) is nuclear coactivator, which is associated with tumor cell proliferation and invasion. Previous studies have demonstrated conflicting results on the relationship between high ATAD2 expression and clinicopathological characteristics of the tumors or patients’ survival outcomes. Considering the discordant results of published studies, we performed a metaanalysis to evaluate the ATAD2 expression in predicting prognosis, and to assess the relationship between high ATAD2 expression and clinicopathological parameters.Methods: We systematically searched electronic database of PubMed, Web of Science and Embase, and selected all immunohistochemical studies of hepatocellular cancer specimens for ATAD2, to analyze the relationship between high ATAD2 expression and prognosis of hepatocellular cancer patients. Pooled data of eligible studies together from individual studies and analyzed data using STATA software to perform this meta-analysis.Results: A total of 5 studies with 719 liver cancer patients were included. ATAD2 protein overexpression wassignificantly correlated with poorer overall survival (HR 3.53, 95% CI: 1.87-6.63, P = 0.000). In addition, high ATAD2 expression was also negatively related with tumor stage [RR, relative risk: 1.46 (95% CI: 1.30-1.64); P < 0.001], as well as tumor size [RR: 1.23(95% CI: 1.06-1.43); P < 0.001], and tumor recurrence [RR: 1.34 (95% CI: 1.05-1.72); P < 0.001].Conclusions: These data suggested that immunohistochemical determination of ATAD2 Protein might be aprognostic biomarker for the patients of hepatocellular cancer.

Postoperative Wound Complications in Fungating Extremity Soft Tissue Sarcomas

Background: Among deep extremity soft tissue sarcomas, skin ulceration is infrequent. Fungating sarcomas may lead to infection or clinically significant bleeding. Data regarding management of ulcerating sarcomas is lacking. We sought to evaluate the outcomes of different treatments for these tumors.Patients and methods: A retrospective review of patients treated at two sarcoma referral centers with histologically confirmed extremity soft tissue sarcoma was performed from 2000-2018. Patient demographics, clinicopathologic, and treatment factors were analyzed in terms of method of resection, receipt of radiation, and wound complications.Results: Overall, 22 patients had fungating lesions. Most patients were male with tumors of the distal extremity.Median tumor size was 8 cm. Half had undifferentiated pleomorphic sarcoma histology, followed by myxofibrosarcoma (n=5), leiomyosarcoma (n=3), or other (n=3). Fifteen patients (68%) underwent limb-preserving resection, of which 7 underwent adjuvant radiation. Six patients (27%) developed wound complications, which occurred equally between amputation versus local excision (p = 0.93). Among local excision patients, one who received adjuvant radiation developed a wound complication (14%), which was not significantly different from those who did not undergo radiation (n=3 of 8, 38%; p = 0.31).Conclusions: Similar rates of wound complications were seen between amputation and limb-preserving groups.Among patients who underwent local excision, the administration of adjuvant radiation therapy did not significantly increase wound complication rates.

Bone Complications in Allogenic Hematopoietic Stem Cell Transplantation

Allogenic hematopoietic stem cell transplantation (allogenic HSCT) is employed to treat benign and malignanthematologic disorders. Increased use of allogenic HSCT has improved outcomes and patient survival, but has led to increased complications. Bone complications following HSCT include osteopenia, osteoporosis, avascular necrosis (AVN) and fracture. These complications decrease patient quality of life and increase morbidity. Allogenic HSCTassociated bone loss is linked to multiple factors including pre-transplant physiologic risk, myeloablative regimens, total-body irradiation, graft-versus-host disease (GVHD), immunosuppressive regimens, secondary hypogonadism, intestinal malabsorption and renal dysfunction. However, the precise molecular causes of HSCT-associated bone loss remain to be determined. Herein, we summarize the epidemiology, risk factors, and pathophysiology of allogenic HSCT-related bone loss and fracture. Also, review is made of the current modalities for prevention and treatment of these complications.

KRAS and NRAS Mutations in Moroccan Patients with Colorectal Cancer

Objective: Activating mutations in the RAS proto-oncogene (KRAS, HRAS and NRAS) play a crucial role in carcinogenesis and drug resistance in many cancers including, colorectal cancer. The aim of the present study was to evaluate the frequencies of KRAS and NRAS oncogenic mutations in Moroccan CRC patients.Patients and methods: In the present study, formalin-fixed paraffin-embedded CRC specimens from 114 Moroccan CRC patients were analyzed. To detect mutations in codons 12, 13 and 61 of the KRAS and NRAS genes, the pyrosequencing technique was used.Results: 114 colorectal cancer patients were included in this study, 64 were males and 50 were females, the primary tumor was the most frequent type (78.1%) and the commonest histological type was ADK (77.2%). KRAS mutation was found in 49 of all CRC patients and the most frequent KRAS mutations were 35G>T, 35G>A and 38G>A. On the other hand NRAS mutation was detected only in 6 patients. No statistically significant relationship between CRC patient’s characteristics and RAS mutations was found.Conclusion: Our results suggest that the KRAS mutation is more frequent among Moroccan patients with CRC, which is in agreement with the most previous studies. Further studies, with a larger number of CRC patients, are needed to confirm our findings.

Phase I/II Clinical Trial of Weekly Intraperitoneal Paclitaxel (IP-PTX) with Monthly Intravenous Carboplatin (IV-CBDCA) for Minimal Residual Disease of Ovarian, Tubal, and Peritoneal Carcinoma

We conducted weekly intraperitoneal administration of paclitaxel (IP-PTX) with monthly intravenous administration of carboplatin (IV-CBDCA), as a prospective phase 1/2 setting. The purpose of this study was to assess the pharmacokinetics and to decide the recommended dose (RD) according to modified Fibonacci method. Patients aged 20-75 years old with histological confirmed mullerian cancers (epithelial ovarian cancer; EOC, fallopian tubal cancer; FTC, and primary peritoneal cancer; PPC) from stage IC to IV or the patients with recurrent disease with small residual disease (including retention of ascetic fluid, para-aortic nodes recurrence after optimal debulked after interval debulking surgery; IDS) were eligible. The protocol regimen consisted of IP-PTX on day1 (D1), 8, and 15, at a starting dose level 1(DL1) of 45 mg/m2, with 15 mg/ m2 incremental, and IV-CBDCA was fixed dose AUC 5.0 mg/mL.min on D1, monthly. The accrual period was from August 2000 until September 2005. As for result, twelve patients were enrolled. No dose limiting toxicity (DLT) was observed in DL1. In dose level 2 (DL2, 60 mg/m2), one grade 3 (G3) hypersensitive reaction to CBDCA was detected. Further 5 patients had been enrolled but additional DLT was not identified. The RD was decided as DL2, which was the same dose of RD in weekly IP-PTX reported by Francis et al. The serum AUCs of PTX in DL1 and DL2 were 1605 nM.min and 2365 nM.min, respectively. By serum CA125, five complete responses were observed out of 8 evaluable patients by Rustin’s criteria. In conclusion, the combination of weekly IP-PTX and monthly IV-CBDCA at AUC 5.0 mg/mL.min was feasible and the recommended dose of IP-PTX was 60 mg/m2. The therapy was moderate effective for optimal debulking mullerian carcinomas. From our pharmacokinetic results, as for the patients with extra-pelvic lesions, additional IV-PTX would be necessary like GOG 172 experimental arm.

Antimicrobial Peptides and Cancer: Potential Use of Antimicrobial-Like Peptides in Chemotherapy

Antimicrobial peptides (AMPs) constitute host defense peptides found among insects, fish, amphibians, and mammals including man. The targets of AMPs are gram-negative and gram-positive bacteria, fungi, enveloped viruses, and transformed/cancerous cells. The AMPs are broad spectrum antibiotics which display the propensity to serve as therapeutic agents not only in infectious disease, but also in human cancer. AMPs demonstrate unique properties which include cell membrane penetration, destabilization of biological membranes, ability to form and/or interact with membrane channels, and the capability to modulate host immune responses. The three types of AMPs consists a) naturally-occurring; b) artificially synthesized; and c) cleaved peptide fragments from blood and extracellular matrix proteins. The present treatise presents one such example of an AMP-like peptide derived from a naturally-occurring human protein as a potential candidate for future cancer therapy. The biological activities of human AMP-like peptides as cancer therapeutic agents are reviewed and reported in multiple in vitro and in vivo cancer assays. The possibility of using such human protein-derived peptides as primary and adjunct cancer therapeutic agents is addressed.

Complete Response to Anti-PD-1 Antibody Monotherapy in Metastatic Melanoma-Can Therapy be Discontinued? A Review of Current Literature

Newer immunotherapeutic agents such as Nivolumab and Pembrolizumab have changed the landscape of management of metastatic melanoma, with a subset of patients achieving durable responses. The ideal duration of therapy in patients who achieve a complete response with these agents has not been determined. We report a case of a 68 year old man with metastatic melanoma who progressed with Ipilimumab and BRAF-directed therapies, but achieved a complete response with Nivolumab monotherapy and continues to be in remission at almost 2 years after discontinuation of treatment. Review of the current data indicates that discontinuation of anti-PD-1 antibodies after complete response is achieved is feasible. The majority of these patients maintain their responses long-term. In those who relapse, re-treatment with the same agent is effective in most cases according to the current data. Prospective studies are necessary to determine the optimal duration of therapy and strategies to maximize the benefit of these drugs.