Physical Activity among Colorectal Cancer Patients and Survivors in Egypt.

INTRODUCTION: Understanding physical activity (PA) levels is important when developing tertiary cancer prevention interventions, especially in Egypt where colorectal cancer (CRC) is more often diagnosed at later stages and at a younger age of onset (≤40 years). METHODS: We assessed PA levels among CRC patients and survivors in Alexandria, Egypt. All participants completed two self-reported PA assessments: Global Physical Activity Questionnaire (GPAQ) and Godin Leisure-Time Exercise Questionnaire (GLTEQ). Participants could opt to wear an accelerometer for seven days. Results were compared against WHO recommendations of ≥150 minutes or ≥600 metabolic equivalents of tasks (METs) of moderate-to-vigorous PA weekly. RESULTS: Of 86 participants enrolled, all completed the surveys and 29 agreed to accelerometer use. Prevalence of meeting PA recommendations was 62.8% based on the GPAQ, 14.0% based on GLTEQ, and 41% based on accelerometer. Based on the GPAQ, very few respondents reported vigorous occupational, vigorous recreational, or moderate recreational activity (median = 0 with interquartile range [IQR] of 0 - 0 weekly minutes for all three) while most activity resulted from moderate occupational and transportation (median [IQR] of 60 [0-840] and 60 [0-187.5] weekly minutes, respectively). Participants meeting PA recommendations were less likely to be married (p = 0.043) according to GPAQ and more likely to be female (p=0.047) and early cancer stage (p=0.007) by GLTEQ. CONCLUSION: Non-leisure free-living PA is a major contributor to meeting PA recommendations while leisure-time PA is a potential target for future interventions that increase PA in this population.

Comparable Efficacy of Submucosal Platelet-Rich Plasma and Combined Platelet-Rich Plasma Noncrosslinked Hyaluronic Acid Injections in Vulvovaginal Atrophy: A Cancer Survivorship Issue.

Background: Cancer survivors are often reluctant to discuss sexual complaints with their oncologists and treatment is frequently unsatisfactory due to paucity of controlled studies and inapplicability of vaginal estrogen. We aimed to evaluate efficacy and tolerability of platelet-rich plasma (PRP) injections alone or in combination with noncrosslinked hyaluronic acid compared with standard therapy with topical hyaluronic acid gel in the management of cancer therapy-induced or aggravated vulvovaginal atrophy. Materials and Methods: This prospective, parallel-group comparative study was conducted on 45 female patients with a history of cancer and complaining of symptoms of vulvovaginal atrophy either induced or aggravated by cancer treatment. Patients were randomly divided into three groups (A, B, and C). Group A patients received two submucosal vaginal PRP injections, group B patients received two similar injections of PRP combined with noncrosslinked hyaluronic acid, and group C received a topical vaginal hyaluronic acid gel applied three times weekly for 2 months. Main outcome measures were vulvovaginal atrophy symptom severity and vaginal health index (VHI) scores before treatment (v0), 1 month from baseline (v1), 2 months from baseline (v2), and 3 months after the last visit (v3). Results: Both groups A and B showed greater improvement of frequency of intercourse avoidance than group C. Group A showed greater improvement of dyspareunia than group C. Groups A and B demonstrated greater improvement of vaginal pH, fluid volume, and total VHI scores than group C. Short-term topical hyaluronic acid (HA) was not associated with any significant improvement of vaginal elasticity. Group B showed greater improvement of vaginal dryness and moisture scores than group C. Reported adverse events were injection-related pain in all patients of groups A and B and vaginal spotting in groups A and B. Conclusion: Both PRP and PRP-HA have comparable efficacy and patient-reported treatment satisfaction. PRP injections were better tolerated by patients than PRP-HA. Clinical trial registration number: NCT05782920.

Evaluation of the Effect of Axillary Radiotherapy Dose and the Development of Lymphedema in Breast Cancer Patients.

Purpose: The present study is aiming to correlate different radiotherapy techniques, fractionations, and doses received by each axillary LN level and axillary vessels with the development of breast cancer-related lymphedema (BCRL). Methods and Materials: We retrospectively studied 181 female breast cancer patients who were diagnosed and treated by radiation therapy during the period from January 2012 to December 2017. The radiotherapy treatment plans were recalled from the archives. The axillary LN levels I, II, III, supraclavicular LN were contoured as well as axillary vessels. New dose volume histograms were generated to correlate between the radiotherapy dose t and the development of BCRL. Results: The study included 162 patients treated with a 3D radiotherapy technique and 19 treated with a 2D radiotherapy technique; 124 patients underwent MRM, while 57 patients underwent BCS; 117 patients were treated with a hypofractionated technique, while 64 patients were treated with a conventional radiotherapy technique. The cumulative incidence of BCRL after radiotherapy was 20.4%. There was a statistically significant relationship between the 2D radiotherapy technique compared with 3DCRT and development of lymphedema (55 vs. 16.6, respectively; p < 0.001). Patients who were treated with conventional radiotherapy had significantly higher rates of lymphedema (42.2%) compared with hypofractionated radiotherapy (8.5%) (p < 0.001). There was a non-significant relationship between mean radiotherapy dose to axillary levels or axillary vessels and development of lymphedema. Conclusion: Breast cancer radiotherapy with the 2D technique and conventional fractionation protocol might increase the risk of BCRL. No correlation was observed between radiotherapy dose to each axillary LN level, axillary vessels and BCRL.

Using Intervention Mapping to Develop a Theory-Based Intervention to Promote Colorectal Cancer Screening in Egypt.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates are increasing in Egypt. Because no national screening guidelines exist, developing an effective evidence-based screening intervention could lower rates by early detection of pre-cancerous and cancerous lesions and polyps. This paper describes the development of a CRC screening intervention in Alexandria, Egypt using Intervention Mapping (IM). MATERIALS AND METHODS: Between September 2019 and March 2020, the successive steps of the IM process were completed. Beginning with the needs assessment, we conducted a literature review, held focus groups with residents of Alexandria, and conducted interviews with local gastroenterologists and oncologists. Program objectives and target audience were determined before designing the program components and implementation plan. Using the PRECEDE-PROCEED theoretical model, predisposing, reinforcing, and enabling screening barriers were assessed. Finally, we developed a Standard Operating Procedures manual detailing aspects of the intervention and evaluation to serve as a model for an expanded screening program. RESULTS: The needs assessment, e.g., literature review, seven focus groups (N=61 participants) and interviews (N=17 participants), indicated that barriers among residents included CRC knowledge deficits, fear/anxiety regarding testing, high cost, and lack of accessibility. Physicians believed CRC testing should only be performed for high risk individuals. Findings from each step of the process informed successive steps. Our final intervention consisted of training components for medical students (Health Champions) who would deliver the intervention to patients in primary care waiting rooms, providing short descriptions of CRC risks and screening, educational brochures, and distributing vouchers for no-cost guaiac fecal occult blood test kits. Health Champions would then follow up with the patients, providing results and referrals for no-cost colonoscopy testing for those with abnormal results. CONCLUSION: Utilizing the IM steps successfully led to development of a theory-based CRC screening intervention for Egypt. Next steps include the implementation of a feasibility pilot intervention.

Therapeutic strategies of recurrent glioblastoma and its molecular pathways 'Lock up the beast'.

Glioblastoma multiforme (GBM) has a poor prognosis-despite aggressive primary treatment composed of surgery, radiotherapy and chemotherapy, median survival is still around 15 months. It starts to grow again after a year of treatment and eventually nothing is effective at this stage. Recurrent GBM is one of the most disappointing fields for researchers in which their efforts have gained no benefit for patients. They were directed for a long time towards understanding the molecular basis that leads to the development of GBM. It is now known that GBM is a heterogeneous disease and resistance comes mainly from the regrowth of malignant cells after eradicating specific clones by targeted treatment. Epidermal growth factor receptor, platelet derived growth factor receptor, vascular endothelial growth factor receptor are known to be highly active in primary and recurrent GBM through different underlying pathways, despite this bevacizumab is the only Food and Drug Administration (FDA) approved drug for recurrent GBM. Immunotherapy is another important promising modality of treatment of GBM, after proper understanding of the microenvironment of the tumour and overcoming the reasons that historically stigmatise GBM as an 'immunologically cold tumour'. Radiotherapy can augment the effect of immunotherapy by different mechanisms. Also, dual immunotherapy which targets immune pathways at different stages and through different receptors further enhances immune stimulation against GBM. Delivery of pro-drugs to be activated at the tumour site and suicidal genes by gene therapy using different vectors shows promising results. Despite using neurotropic viral vectors specifically targeting glial cells (which are the cells of origin of GBM), no significant improvement of overall-survival has been seen as yet. Non-viral vectors 'polymeric and non-polymeric' show significant tumour shrinkage in pre-clinical trials and now at early-stage clinical trials. To this end, in this review, we aim to study the possible role of different molecular pathways that are involved in GBM's recurrence, we will also review the most relevant and recent clinical experience with targeted treatments and immunotherapies. We will discuss trials utilised tyrosine receptor kinase inhibitors, immunotherapy and gene therapy in recurrent GBM pointing to the causes of potential disappointing preliminary results of some of them. Additionally, we are suggesting a possible future treatment based on recent successful clinical data that could alter the outcome for GBM patients.

Optimal breast reconstruction type for patients treated with neoadjuvant chemotherapy, mastectomy followed by radiation therapy.

PURPOSE: To explore the optimal type of breast reconstruction and the time interval to postmastectomy radiotherapy (PMRT) associated with lower complications in breast cancer patients receiving neoadjuvant chemotherapy. METHODS: We reviewed the medical records of 300 patients who received neoadjuvant chemotherapy, mastectomy with breast reconstruction and PMRT at our institution from 2000 to 2017. Reconstruction types included autologous flaps (AR), single-stage-direct-to-implant and two-stages expander/implant (TE/I). The primary endpoint was the rate of reconstruction complications including infection, skin and fat necrosis. Subgroup analysis compared rates of capsular contracture, implant rupture, implant exposure and overall implant failure in single-stage-direct-to-implant to TE/I. The secondary endpoint was identifying the time interval between surgery with immediate implant-based reconstruction and PMRT associated with lower probability of implant failure. Logistic regression models, Kaplan-Meier estimates and Polynomial regression were used to assess endpoints. RESULTS: The median follow-up was 43.5 months. 29.3%, 28.3% and 42.4% of the cohort had AR, TE/I and single-stage-direct-to-implant D, respectively. The 5-year cumulative incidence rate of complications was 14.0%, 29.7% and 19.4% for AR, TE/I and single-stage-direct-to-implant, respectively (Log rank p = 0.02). Multivariate analysis showed significant association between TE/I and higher risk of infection (OR 8.1, p = 0.009) compared to AR, while single-stage-direct-to-implant and AR were comparable (OR 3.2, p = 0.2). On subgroup analysis, TE/I was significantly associated with higher rates of implant failure. The mean wait time to deliver PMRT after immediate reconstruction with no adjuvant chemotherapy was 8.4 and 10.7 weeks in single-stage-direct-to-implant and TE/I, respectively (p < 0.005). Delivering PMRT after 8 weeks of surgery yielded 10% probability of reconstruction failure in single-stage-direct-to-implant versus 40% in TE/I. CONCLUSION: In comparison to two stages reconstruction, single-stage-direct-to-implant following neoadjuvant chemotherapy has lower complications and offers timely delivery of PMRT.

The Impact of Chest Wall Boost on Reconstruction Complications and Local Control in Patients Treated for Breast Cancer.

PURPOSE: Giving an additional radiation dose to the incision or chest wall has been a practice, but it has never been studied in a randomized setting, and it might lead to inferior cosmetic outcomes. This study aims to evaluate whether delivery of a chest wall boost (CWB) to the mastectomy scar or chest wall is independently associated with reconstruction complications and to assess its disease control efficacy in the setting of breast reconstruction. METHODS AND MATERIALS: We conducted a retrospective chart review of 746 patients with breast cancer who underwent mastectomy, breast reconstruction, and PMRT; all underwent treatment at our institution during 1997 to 2016. Various reconstruction techniques were used among this cohort including autologous reconstruction, single-stage direct-to-implant reconstruction, and 2-stage tissue expander implant. Cohorts were divided by administration of CWB. The primary objective was comparing the rate of reconstruction complications including skin necrosis, fat necrosis and infection between groups. Subgroup analysis for patients with implant-based reconstruction was performed to evaluate the effect of CWB on implant-related complications such as capsular contracture, implant exposure, and implant failure. The secondary objective was comparison of the cumulative incidence of local failure between groups overall and within clinically high-risk subgroups. RESULTS: The median follow-up was 5.2 years. Most clinicopathologic features were well balanced between the 379 (51%) patients who received CWB and the 367 (49%) who did not. On multivariate analysis, CWB was significantly associated with infection, skin necrosis, and implant exposure. For implant reconstruction patients, CWB independently increased risks of implant failure. CWB administration was not associated with local tumor control benefits, even in high-risk subgroups. CONCLUSIONS: Our findings suggest that omission of chest wall boost in postmastectomy radiation improves breast reconstruction outcomes without compromising local tumor control.

Natural Agents-Mediated Targeting of Histone Deacetylases.

In the past few years, basic and clinical scientists have witnessed landmark achievements in many research projects, such as those conducted by the US National Institutes of Health Roadmap Epigenomics Mapping Consortium, the International Human Epigenome Consortium, The Cancer Genome Atlas Network and the International Cancer Genome Consortium, which have provided near-complete resolution of epigenetic landscape in different diseases. Furthermore, genome sequencing of tumors has provided compelling evidence related to frequent existence of mutations in readers, erasers and writers of epigenome in different cancers. Histone acetylation is an intricate mechanism modulated by two opposing sets of enzymes and deeply studied as a key biological phenomenon in 1964 by Vincent Allfrey and colleagues. The research group suggested that this protein modification contributed substantially in transcriptional regulation. Subsequently, histone deacetylases (HDACs), histone acetyltransferases and acetyl-Lys-binding proteins were identified as transcriptional mediators, which further deepened our comprehension regarding biochemical modifications. Overwhelmingly increasing high-impact research is improving our understanding of this molecularly controlled mechanism; moreover, quantification and identification of lysine acetylation by mass spectrometry has added new layers of information. We partition this multi-component review into how both activity and expression of HDAC are targeted using natural agents. We also set spotlight on how oncogenic fusion proteins tactfully utilize HDAC-associated nano-machinery to modulate expression of different genes and how HDAC inhibitors regulate TRAIL-induced apoptosis in cancer cells. HDAC inhibitors have been reported to upregulate expression of TRAIL receptors and protect TRAIL from proteasomal degradation. Deeper understanding of HDAC biology will be useful for stratification and selection of patients who are responders, non-responders and poor-responders for HDACi therapy, and for the rational design of combination studies using HDACi.

Journey of TRAIL from Bench to Bedside and its Potential Role in Immuno-Oncology.

Induction of apoptosis in cancer cells has increasingly been the focus of many therapeutic approaches in oncology field. Since its identification as a TNF family member, TRAIL (TNF-related apoptosis-inducing ligand) paved a new path in apoptosis inducing cancer therapies. Its selective ability to activate extrinsic and intrinsic cell death pathways in cancer cells only, independently from p53 mutations responsible for conventional therapeutics resistance, spotted TRAIL as a potent cancer apoptotic agent. Many recombinant preparations of TRAIL and death receptor targeting monoclonal antibodies have been developed and being tested pre-clinically and clinically both as a single agent and in combinations. Of note, the monoclonal antibodies were not the only type of antibodies developed to target TRAIL receptors. Recent technology has brought forth several single chain variable domains (scFv) designs fused recombinantly to TRAIL as well. Also, it is becoming progressively more understandable that field of nanotechnology has revolutionized cancer diagnosis and therapy. The recent breakthroughs in materials science and protein engineering have helped considerably in strategically loading drugs into nanoparticles or conjugating drugs to their surface. In this review we aim to comprehensively highlight the molecular knowledge of TRAIL in the context of its pathway, receptors and resistance factors. We also aim to review the clinical trials that have been done using TRAIL based therapies and to review various scFv designs, the arsenal of nano-carriers and molecules available to selectively target tumor cells with TRAIL.

Survivin a radiogenetic promoter for glioblastoma viral gene therapy independently from CArG motifs.

BACKGROUND: Radiogenetic therapy is a novel approach in the treatment of cancer, which employs genetic modification to alter the sensitivity of tumor cells to the effect of applied radiation. AIM: To select a potent radiation inducible promoter in the context of brain tumors and to investigate if CArG radio responsive motifs or other elements in the promoter nucleotide sequences can correlate to its response to radiation. METHODS: To select initial candidates for promoter inducible elements, the levels of mRNA expression of six different promoters were assessed using Quantitative RTPCR in D54 MG cells before and after radiation exposure. Recombinant Ad/reporter genes driven by five different promoters; CMV, VEGF, FLT-1, DR5 and survivin were constructed. Glioma cell lines were infected with different multiplicity of infection of the (promoter) Ad or CMV Ad. Cells were then exposed to a range of radiation (0-12 Gy) at single fraction. Fluorescent microscopy, Luc assay and X-gal staining was used to detect the level of expression of related genes. Different glioma cell lines and normal astrocytes were infected with Ad survivin and exposed to radiation. The promoters were analyzed for presence of CArG radio-responsive motifs and CCAAT box consensus using NCBI blast bioinformatics software. RESULTS: Radiotherapy increases the expression of gene expression by 1.25-2.5 fold in different promoters other than survivin after 2 h of radiation. RNA analysis was done and has shown an increase in copy number of tenfold for survivin. Most importantly cells treated with RT and Ad Luc driven by survivin promoter showed a fivefold increase in expression after 2 Gy of radiation in comparison to non-irradiated cells. Presence or absence of CArG motifs did not correlate with promoter response to radiation. Survivin with the best response to radiation had the lowest number of CCAAT box. CONCLUSION: Survivin is a selective potent radiation inducible promoter for glioblastoma viral gene therapy and this response to radiation could be independent of CArG motifs.

A phase 2 study of radiosurgery and temozolomide for patients with 1 to 4 brain metastases.

PURPOSE: To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1 to 4 brain metastases treated with radiosurgery without whole-brain radiation therapy (WBRT). METHODS AND MATERIALS: Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase 2 trial of radiosurgery (15-24 Gy) and adjuvant temozolomide. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy. RESULTS: Twenty-five patients were enrolled between 2002 and 2005; 3 were not evaluable for determining DBF. Of the remaining 22 patients, tumor types included non-small cell lung cancer (n = 8), melanoma (n = 7), and other (n = 7). Extracranial disease was present in 10 (45%) patients. The median number of tumors at the time of radiosurgery was 3 (range, 1-6). The median overall survival was 31 weeks. The median radiographic follow-up for patients who did not develop DBF was 33 weeks. Six patients developed DBF. The 1-year actuarial risk of DBF was 37%. CONCLUSIONS: In this study, there was a relatively low risk of distant brain failure observed in the nonmelanoma subgroup receiving temozolamide. However, patient selection factors rather than chemotherapy treatment efficacy are more likely the reason for the relatively low risk of distant brain failure observed in this study. Future trial design should account for these risk factors.

An adenovirus encoding proapoptotic Bax synergistically radiosensitizes malignant glioma.

PURPOSE: We explore the utility of the adenovirus-mediated delivery of proapoptotic Bax for enhancing the cytotoxicity of radiotherapy (RT) in RT-refractory glioma cells. MATERIALS AND METHODS: Cell lines D54 MG and U87 MG (p53 wild-type), and U251 MG and U373 MG (p53 mutant), and patient-derived astrocytes were evaluated. Cells were irradiated and infected with an inducible adenovirus encoding Bax. Cell proliferation, colony formation assay, quantification of early apoptotic alteration in the plasma membrane by fluorescence-activated cell sorter using annexin V, and nuclear staining with H33258 were used to evaluate apoptosis. The capacity of the combined treatment to induce regression of subcutaneous D54 MG tumors was tested in nude mice. A dose of 5 Gy was administered every other day, four times, for a total dose of 20 Gy. One day after each irradiation, tumors were injected with 1 x 10(9) plaque-forming units (PFU). RESULTS: Apoptotic death was enhanced by the combination of Ad/Bax and RT. In D54 MG, levels of apoptosis after RT alone, Ad/Bax alone, or the combination were, respectively, 12.3%, 32.1%, and 78.5%. In contrast, treatment of astrocytes did not significantly induce apoptosis. A colony-formation assay showed a 2-log inhibition with respect to controls after combined treatment, irrespective of the endogenous levels of p53. The other apoptosis assays also showed the defining characteristics of apoptosis in the combination group. Remarkably, combined treatment induced regression of tumors in mice. CONCLUSIONS: Ad/Bax synergistically radiosensitizes glioma, with a seemingly favorable therapeutic index.

Adenovirus-mediated transfer of BAX driven by the vascular endothelial growth factor promoter induces apoptosis in lung cancer cells.

Apoptosis induction is a promising approach for cancer gene therapy. Bax is a death-promoting member of the Bcl2 family of genes that are intimately involved in apoptosis. Overexpression of BAX protein can accelerate cell death by homodimers that promote apoptosis in a variety of cancer cell lines. The cytotoxic effect of BAX was evaluated in vitro by a recombinant adenovirus system expressing the human BAX gene under control of human vascular endothelial growth factor (VEGF) promoter element (AdVEGFBAX). Overexpression of BAX in human lung carcinoma cells resulted in apoptosis induction, caspase activation, and cell growth suppression, none of which were observed in BEAS-2B normal human bronchial epithelial cells that do not overexpress VEGF under normoxic conditions. To examine the hypoxia responsiveness of the VEGF promoter, lung cancer cells were transiently exposed to hypoxia; this treatment increased enhanced green fluorescent protein (EGFP) expression after AdVEGFEGFP infection in both normal and cancer cell lines, and enhanced apoptosis and decreased the number of surviving cancer cells compared with the Ad/BAX plus Ad/Cre binary adenoviral system. These results suggest a possible therapeutic application of cancer-specific expression of the pro-apoptotic Bax gene driven by the VEGF promoter.