Cardiovascular disease risk assessment and multidisciplinary care in prostate cancer treatment with ADT: recommendations from the APMA PCCV expert network.

PURPOSE: Androgen deprivation therapy (ADT) is the mainstay approach for prostate cancer (PCa) management. However, the most commonly used ADT modality, gonadotropin-releasing hormone (GnRH) agonists, has been associated with an increased risk of cardiovascular disease (CVD). METHODS: The PCa Cardiovascular (PCCV) Expert Network, consisting of multinational urologists, cardiologists and oncologists with expertise in managing PCa, convened to discuss challenges to routine cardiovascular risk assessment in PCa management, as well as how to mitigate such risks in the current treatment landscape. RESULTS: The experts identified several barriers, including lack of awareness, time constraints, challenges in implementing risk assessment tools and difficulties in establishing multidisciplinary teams that include cardiologists. The experts subsequently provided practical recommendations to improve cardio-oncology care for patients with PCa receiving ADT, such as simplifying cardiovascular risk assessment, individualising treatment based on CVD risk categories, establishing multidisciplinary teams and referral networks and fostering active patient engagement. A streamlined cardiovascular risk-stratification tool and a referral/management guide were developed for seamless integration into urologists' practices and presented herein. The PCCV Expert Network agreed that currently available evidence indicates that GnRH antagonists are associated with a lower risk of CVD than that of GnRH agonists and that GnRH antagonists are preferred for patients with PCa and a high CVD risk. CONCLUSION: In summary, this article provides insights and guidance to improve management for patients with PCa undergoing ADT.

Hematuria: Is it useful in predicting renal or ureteral stones in patient presenting to emergency department with flank pain?

Objectives: The objective of the study was to evaluate hematuria as a diagnostic test for renal and ureteral stones compared with a noncontrast-enhanced computed tomography (CT) scan (gold standard test) in emergency room patients with acute flank pain. Patients and Methods: In total, 604 patients treated in our emergency department from 2006 to 2011, with a history of flank pain and suspected urolithiasis were included in a retrospective review. All patients were evaluated with a noncontrast-enhanced CT scan and urine analysis. Using the noncontrast CT scan as the gold standard for the evaluation of the presence, number, size, and site (renal or ureteral [upper, middle, and lower]) of the stones, we calculated the sensitivity, specificity, and positive and negative predictive values of hematuria for diagnosing both renal and ureteral stones. Results: Urolithiasis was diagnosed in 388 patients (64%) and 216 patients (36%) had no stones on a noncontrast-enhanced CT scan. The sensitivity, specificity, positive predictive value, and negative predictive value for microhematuria were 77%, 33%, 67%, and 45%, respectively. Microhematuria was more common in patients with ureteral stones only (139 patients) and had a sensitivity of 85% compared to patients with renal stones only (32 patients), with a sensitivity of 55% (P < 0.001). There were no significant differences in the specificity or positive or negative predictive values. Conclusion: Although microhematuria is more sensitive to ureteral stones, the absence of microhematuria does not exclude the possibility of urolithiasis and a noncontrast-enhanced CT scan should be the gold standard diagnostic tool.

Prostate-specific Antigen Density as a Proxy for Predicting Prostate Cancer Severity: Is There Any Difference between Systematic and Targeted Biopsy?

Background: Prostate cancer screening with prostate-specific antigen (PSA) can result in unnecessary biopsies and overdiagnosis. Alternately, PSA density (PSAD) calculation may help support biopsy decisions; however, evidence of its usefulness is not concrete. Objective: To evaluate the predictive value of PSAD for clinically significant prostate cancer detection by systematic and MRI-targeted biopsies. Methods: This prospective study was conducted at two tertiary hospitals in Riyadh, Saudi Arabia, between December 2018 and November 2021. Patients suspected of prostate cancer were subjected to multi-parametric MRI, and for those with positive findings, systematic and targeted biopsies were performed. Clinically non-significant and significant prostate cancer cases were classified based on histopathology-defined ISUP grade or Gleason score. The PSAD was measured using the prostate volume determined by the MRI and categorized into ≤0.15, 0.16-0.20, and >0.20 ng/ml2 subgroups. Results: Systematic and targeted biopsies were carried out for 284 patients. The discriminant ability of PSAD is higher in MRI-targeted biopsy compared with systematic biopsy (AUC: 0.77 vs. 0.73). The highest sensitivity (97%) and specificity (87%) were detected at 0.07 ng/ml2 in targeted biopsy. More than half of the clinically significant cases were detected in the >0.2 ng/ml2 PSAD category (systematic: 52.4%; targeted: 51.1%). The CHAID methodology found that the probability of having clinically significant cancer (CSC) in patients with PSAD >0.15 ng/ml2 was more than threefold than that in patients with PSAD ≤0.15 ng/ml2 (64% vs. 20.2%). When considered by age, in PSAD ≤0.15 ng/ml2 subgroup, the percentage of CSC detection rate increased from 20.2% to 24.6% in patients aged ≥60 years. Conclusion: PSAD has good discriminant power for predicting clinically significant prostate cancer. A cutoff of 0.07 ng/ml2 should be adopted, but should be interpreted with caution and by considering other parameters such as age.

Are There Any Developments in the Attitudes and Practices of Oncologists Regarding Fertility Preservation in Saudi Arabia After 12 Years?

INTRODUCTION: The current practice of offering fertility preservation (FP) counseling and treatment has become one of the focal points in patient care throughout cancer treatment. The turning point was the approval of the Council of Senior Religious Scholars four years ago to freeze tissues from the ovarian membrane, the entire ovary, and the eggs for later use in reproduction to preserve the offspring. Thus, we aimed to assess any development in oncologists' knowledge, attitude, and referral practices regarding FP in Saudi Arabia. METHODS: This is a cross-sectional survey using a self-administered questionnaire. We assessed oncologists' opinions on the importance of FP, their perception of the patient's preferences, and factors to consider when discussing the subject. Then, we assessed the knowledge and referral practices, including the timing of referral before starting cancer treatment. RESULTS: Most oncologists showed good knowledge and positive attitudes toward FP; however, their referral practices could be better. Most were familiar with FP options. The most significant factors influencing the oncologist-patient FP discussion were the number of existing children, marital status, cost, and type of cancer (96.6%, 76.7%, 65.7%, and 58.9%, respectively). CONCLUSIONS: There is a significant improvement in the knowledge and attitude of oncologists toward FP. However, patients' counseling and referral to fertility services still need to be improved. There is a shortfall in the clinical practice guidelines for FP in cancer patients in Saudi Arabia. The implementation of clinical practice guidelines would enhance FP. However, patients' counseling and referral to fertility services still need to be improved. The lack of proper guidelines on FP is affecting oncologists' practice.

False-positive magnetic resonance imaging prostate cancer correlates and clinical implications.

Background: False-positive (FP) multiparametric magnetic resonance imaging (MPMRI) obscures and swift needless biopsies in men with a high prostate-specific antigen. Materials and Methods: This was a retrospective study, in which all patients who had been exposed to consecutive MP-MRI of the prostate combined with transrectal ultrasound-guided-magnetic resonance imaging fusion-guided prostate biopsy between 2017 and 2020 were involved in the study. The FP was measured as the number of biopsies that did not encompass prostate cancer divided by the whole number of biopsies. Results: The percentage of FP cases was 51.1%, the highest percentage was found in Prostate Imaging-Reporting and Data System (PI-RADs) 3 (37.7%) and the lowest was detected in PI-RAD 5 (14.5%). Those with FP biopsies are younger, and their total prostate antigen (PSA) and PSA density (PSAD) are significantly lesser. The area under the curve PSAD, age, and total PSA are 0.76, 0.74, and 0.69, respectively. An optimum PSAD value of 0.135 was chosen as a cutoff because it showed the highest sum of sensitivity and specificity, 68% and 69%, respectively. Conclusion: FP results of mpMRI were detected in more than half of our sample, more than one-third were presented in Pi-RAD3, improved imaging techniques to decrease FP rates are highly needed.

Nutritional Related Knowledge of Cancer Prevention among Primary Health Care Physicians.

OBJECTIVES: To explore the cancer prevention-related nutrition knowledge of primary health care physicians towards nutrition and its relation to the development of cancer. MATERIALS AND METHODS: a cross-sectional study was conducted among family physicians in Riyadh, between November 2019 and April 2020. The participants in the current study were surveyed using a self-administered questionnaire. The questionnaire included socio-economic data and data related to the association between nutrition and cancer. RESULTS: The mean correct knowledge score for physicians is good but less than expected (26.5+5.8) 73.6%. Multiple regression revealed that age, position, and nationality to be significantly associated with knowledge of cancer prevention (P<0.05) among physicians. CONCLUSIONS: Primary care physicians have good knowledge about the relation between nutrition and cancer but not sufficient, they should have continuous nutrition educational training programs to ensure safe and sound nutritional advice to patients and for the public about the relation of nutrition and cancer.

Effectiveness of magnetic resonance imaging-targeted biopsy for detection of prostate cancer in comparison with systematic biopsy in our countries with low prevalence of prostate cancer: our first experience after 3 years.

BACKGROUND: Some men are subjected to multiple repeated biopsies because of ongoing suspicion of prostate cancer, which might subject them to complications. The aim of the study was to determine the diagnostic accuracy of magnetic resonance imaging (MRI)/target fusion-guided biopsy in comparison with systematic biopsy in our low prevalence prostate cancer population, in terms of validity measure, case detection rate, and detection of clinically significant cancer. METHODS: This is a retrospective cohort study. All consecutive patients who met the inclusion criteria (all men with persistent high prostate-specific antigen levels >4 ng/ml and/or subnormal finding in direct rectal examination, with suspicious regions identified on prebiopsy MRI) were subjected to transrectal MRI/ultrasound fusion-guided biopsy. RESULTS: A total of 165 cases met the inclusion criteria and were included in the study. The cancer detection rate (CDR) of target biopsy was significantly higher than that of standard biopsy (27.9% vs 14%, respectively), and 25 cases (52%) were missed by standard strategy and correctly classified by multiparametric MRI with targeted biopsy (MRI-TB). On the other hand, only 2 cases (4.3%) were misclassified by MRI-TB, and one of them was clinically significant. There was an exact agreement between the 2 strategies in 15 (31%) cases. Targeted biopsy diagnosed 41.5% more high-risk cancers vs systematic biopsy (41.6% vs 6.2%, P < .001). The difference between sensitivity, specificity, and negative predictive value of MRI-TG varies between 80% and 98%. CONCLUSION: The CDR of prostate cancer in general and clinically significant cancer, in specific, is significantly higher with MRI-TG modality than with systematic modality. Yet, MRI-TG biopsy still misses some men with clinically significant prostate cancer. Hence, the addition of a 12-core biopsy is required to evade missing cases of clinically significant and insignificant cancer.

Factors influencing urology physicians in Saudi Arabia for choosing their subspecialty program.

AIM: The aim of the study was to identify factors that influence urology physicians for choosing subspecialty and to know the most competitive urology subspecialty among residents. METHODOLOGY: An online questionnaire was sent to all Saudi Urology residents, registrars, and fellows all over Saudi Arabia, during February 2019-June 2019. The survey included demographic data, level and location of training, a subspecialty of interest, as well as 15 influencing factors that could affect physicians' choice in the form of Likert scale, ranging from strongly disagree = 0 to strongly agree = 4. RESULTS: Of the 193 urology Saudi physicians, 85 replied (44.1%). Their mean age was 29 + 3.2 years. The majority of them were male (98.8%). There were 66 (77.6%) residents, 12 (14.1%) were fellows, and 7 (8.2%) were registrars. Four factors were found to be significantly different across positions, i.e., personal interest in the subspecialty, patient's prognosis, potential to join a private hospital, and family/friend advice. Among residents, the highest score means of the impact factors were the patient's prognosis, potential to join a private hospital and family/friend advice. The most prominent factors that influence urology physicians to select their subspecialty were personal interest in the specialty (88.2%), followed by the patient prognosis and lifestyle (84.7%, 78.8%). About 28.2% of the participants have a desire of endourology, followed by infertility and pediatric urology (23.5% and 20%, respectively). CONCLUSION: The most influencing factors among urology physicians for choosing their subspecialty are the patient's prognosis and personal interest. Female medical graduates should be encouraged to join a urology residency.

Vitamin D status and its correlates in Saudi male population.

BACKGROUND: Vitamin-D deficiency is a universal health problem caused primarily by inadequate exposure to sunlight. This study aimed to assess the vitamin D status and investigate the factors affecting vitamin D distribution among Saudi males. METHODS: A cross-sectional study was conducted at the King Saud University Medical City from December 2015 to August 2016. Saudi males attending the outpatient primary health care clinics were invited to participate in the study. Data were collected on the current and past health status along with biochemical investigations for total 25-hydroxyvitamin D (25OHD), blood sugar, and cholesterol. RESULTS: Majority of the participants (76.1%) had vitamin D deficiency. Blood sugar level, age, and cholesterol level were the most significant factors associated with vitamin D status. The highest percentage of deficiency was observed in the youngest age group (30-40 years). With increasing age, the percentage of deficiency decreased significantly. Those with normal blood sugar and cholesterol level had higher serum vitamin D levels compared to those with diabetes and hypercholesterolemia. CONCLUSIONS: Vitamin D deficiency is still endemic in Saudi Arabia, particularly among younger males and those with diabetes and hypercholesterolemia. Vitamin D screening, supplementations, and vitamin D-fortified foods should be provided especially for these groups.

Prostate cancer screening in a low prevalence population. Is it worth it?

OBJECTIVES: To embrace a national screening program for prostate cancer, putting into consideration the cost, and the attitude of the general population towards such screening. METHODS: Men aged greater than 45 and less than 70 years were invited to participate in the current prospective study conducted at  King Saud University Medical City, Riyadh, Saudi Arabia between December 2014 and July 2015. Those with confirmed high prostate-specific antigen (PSA) (≥4 ng/ml) were referred to the urology clinic, then subjected to magnetic resonance imaging. RESULTS:   The total cohort screened were 2898, we  found 118 cases with high PSA (≥4 ng/ml). Fifty-two cases (60.4%) were confirmed high PSA. All of them were subjected to MRI and biopsy. The confirmed prostate cancer were 7 cases (0.24%). The age of confirmed prostate cancer cases ranged from 49 years to 68 years, Gleason score for 4 cases was low grade (3+3), while it was 3+4 for 2 cases, and only one case had advanced cancer (3+5). Approximately 12% of cases with high PSA did not show up for confirmation of their results for further examination. CONCLUSIONS:   The present study recommends against mass screening among Saudi population; however, men before 50 years of age should start PSA blood testing until before 70 years after discussing the benefits and harms of such screening through shared decision making.

Comparison of escalating, constant, and reduction energy output in ESWL for renal stones: multi-arm prospective randomized study.

This study was designed to find out the optimized energy delivery strategy in Shock Wave Lithotripsy (SWL) that yield to the best stone-free rate (SFR). In this clinical trial, 150 consecutive patients were randomized into three groups: (a) Dose escalation, 1500 SW at 18 kV, followed by 1500 SW at 20 kV then 1500 SW at 22 kV. (b) Constant dose, 4500 SW at 20 kV. All patients undergo plain X-ray film of the urinary tract at day 1, 14, and 90 to assess stone-free rate (SFR) which was defined as no stones or painless fragments less than 4 mm. (c) Dose reduction, 1500 SW at 22 kV, followed by 1500 SW at 20 kV and then 1500 SW at 18 kV. The three treatment groups were comparable in terms of age, sex, stone size and distribution of the kidneys, and the need for Double J stent use. On day 90, the SFR achieved was 82, 90, and 84 % in the escalating, constant, and reduction energy groups, respectively. However, this rate was not statistically significant (x 2 = 1.38, p level = 0.28). At a slow rate of 60 shocks, there was no difference in stone-free rate between different voltages at 1, 14, and 90 days. Our randomized clinical trial showed no statistically significant difference in SFR between the three groups while using the slow SWL rate. Our trial is the first randomized trial comparing the three strategies. As such, a dose adjustment strategy while delivering SWL in slow rate was not recommended.

With increasing trends of prostate cancer in the Saudi Arabia and Arab World: Should we start screening programs?

Incidence rate for prostate cancer in the Arab World is significantly lower than United States and Europe, it ranges from 5.5% to 39.2%. However, the incidence and the number of deaths is expected to increase. In Saudi Arabia, the crude incidence rate and age standardized incidence rate of prostate cancer are reported to be steadily increasing in between 2001-2008. Only two screening trials were attempted in 2001 and 2009 which yielded an incidence rate of 1.17% and 2.5% respectively. Men in the Arab world are sharing a common characteristic of poor knowledge and poor attitude towards prostate cancer examination and screening practices. They are ill-informed about the PSA test's strengths and drawbacks because the doctors are not talking to them about the importance of counselling. Men should be encouraged to do PSA testing before the age of 50 and till the age of 70 years. This could be achieved by enhancing their attitude and enriching the knowledge of the physicians towards PSA testing, harms and benefits, through shared decision making, which would increase men's knowledge scores, reduced their decisional conflict and promote greater involvement in decision making.

Knowledge and attitude of the population toward cancer prostate Riyadh, Saudi Arabia.

AIMS: The aim of the following study is to assess the knowledge and attitude of men, in our region, regarding cancer prostate and its screening practices. SUBJECTS AND METHODS: The field work was conducted in Riyadh City, during the period February through July 2011. It was a population - based cross-sectional study comprising 400 men over 40 years. In addition to socio-demographic data, history of the present and past medical illness, history of prostatic diseases and examination, family history of cancer prostate; participants were inquired about their knowledge and attitude toward prostate cancer (PC) and screening behavior using through two different Likert scales. RESULTS: Only 10% of the respondents had practiced a regular PC examination checkup. Their knowledge about PC was poor and their attitude toward examination and screening was fair, where the mean of total correct knowledge score was 10.25 ± 2.5 (51.25%), while the mean of total attitude score was 18.3 ± 4.08 (65.3%). The respondents identified the physicians as the main sources of this information (62.4%), though they were not the main motives for a regular checkup. Knowledge represented the only significant predictor for participants' attitude. CONCLUSION: Beliefs and attitudes have a great impact, at every stage of the cancer continuum, this attitudes depends mainly on level of knowledge and quantity of information provided to patients and their families. Such attitudes should rely on a solid background of proper information and motivation from physicians to enhance and empower attitudes toward PC screening behavior.

Assessment of lower urinary tract symptoms in Saudi men using the International Prostate Symptoms Score.

BACKGROUND: Benign prostatic hyperplasia-related lower urinary tract symptoms (LUTS) are common among older men, the incidence and prevalence are increasing rapidly, and they are associated with diminished health-related quality-of-life (QOL). OBJECTIVE: The aim was to describe the prevalence of LUTS in Saudi population and its relation to some other parameters. SUBJECTS AND METHODS: Saudi men over the age of 40 were invited to participate in the study; in Riyadh city from August 2012 through March 2013. All participants were assessed for the serum level of prostate-specific antigen (PSA) and digital rectal examination. Participants were given a linguistically validated Arabic version of the International Prostate Symptom Score (IPSS). Demographic and other medical comorbidities were assessed. RESULTS: Based on the IPSS, a subdivision of men into three symptoms classes has been proposed, resulting in groups with mild (1265, 58.3%), moderate (505, 27.3%), and severe symptoms (81, 4.4%) and the prevalence of moderate to severe was 31.7%. There was a weak, but significant correlation between the total IPSS and age, total prostate volume, and PSA. Severity of symptoms is increasing with increased age. Multiple regression analysis reported that prostate volume and all individual items of IPSS except straining were significant predictors of QOL and patient satisfaction, where frequency and incomplete emptying had the heaviest impact on patient's QOL. CONCLUSION: LUTS were common among men in Saudi population over 40, the prevalence increases with age and most of them were unpleased because of their urinary symptoms, poor QOL was mainly determined by individual symptoms; mainly frequency and incomplete emptying.

Nomogram Predicting Prostate Cancer-specific Mortality for Men with Biochemical Recurrence After Radical Prostatectomy.

BACKGROUND: The natural history of prostate-specific antigen (PSA)-defined biochemical recurrence (BCR) of prostate cancer (PCa) after definitive local therapy is highly variable. Validated prediction models for PCa-specific mortality (PCSM) in this population are needed for treatment decision-making and clinical trial design. OBJECTIVE: To develop and validate a nomogram to predict the probability of PCSM from the time of BCR among men with rising PSA levels after radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: Between 1987 and 2011, 2254 men treated by radical prostatectomy at one of five high-volume hospitals experienced BCR, defined as three successive PSA rises (final value >0.2 ng/ml), single PSA >0.4 ng/ml, or use of secondary therapy administered for detectable PSA >0.1 ng/ml. Clinical information and follow-up data were modeled using competing-risk regression analysis to predict PCSM from the time of BCR. INTERVENTION: Radical prostatectomy for localized prostate cancer and subsequent PCa BCR. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCSM. RESULTS AND LIMITATIONS: The 10-yr PCSM and mortality from competing causes was 19% (95% confidence interval [CI] 16-21%) and 17% (95% CI 14-19%), respectively. A nomogram predicting PCSM for all patients had an internally validated concordance index of 0.774. Inclusion of PSA doubling time (PSADT) in a nomogram based on standard parameters modestly improved predictive accuracy (concordance index 0.763 vs 0.754). Significant parameters in the models were preoperative PSA, pathological Gleason score, extraprostatic extension, seminal vesicle invasion, time to PCa BCR, PSA level at PCa BCR, and PSADT (all p<0.05). CONCLUSIONS: We constructed and validated a nomogram to predict the risk of PCSM at 10 yr among men with PCa BCR after radical prostatectomy. The nomogram may be used for patient counseling and the design of clinical trials for PCa. PATIENT SUMMARY: For men with biochemical recurrence of prostate cancer after radical prostatectomy, we have developed a model to predict the long-term risk of death from prostate cancer.

Priapism associated with pregabalin.

Priapism is a well-known cause of erectile dysfunction. There are a wide variety of causes, including hemoglobinopathy, neurological diseases, and drugs. We present a case report of an Asian man who presented with priapism that was continuous for 3 days after taking three doses of pregabalin for chronic back pain. Cavernous aspiration, phenylephrine injection, and a winter shunt all failed to achieve detumescence. The patient then presented to our institution on the 5(th) day of his initial presentation, and an El-Ghorab shunt was performed, after which detumescence and pain relief were achieved. We suggest that pregabalin might induce tumescence through acting on the α2δ1 subunit of voltage-gated calcium channels in the penile smooth muscle or by presynaptic inhibition of noradrenaline release. Further studies are warranted regarding the action of pregabalin and its effect on penile physiology.

Do margins matter? The influence of positive surgical margins on prostate cancer-specific mortality.

BACKGROUND: Positive surgical margins (PSMs) in radical prostatectomy (RP) specimens are a frequent indication for adjuvant radiotherapy and are used as a measure of surgical quality. However, the association between PSMs and prostate cancer-specific mortality (CSM) is poorly defined. OBJECTIVE: Analyze the association of PSMs with CSM, adjusting for fixed and time-dependent parameters. DESIGN, SETTING, AND PARTICIPANTS: Fine and Gray competing risk regression analysis was used to model the clinical data and follow-up information of 11,521 patients treated by RP between 1987 and 2005. Two extended models were used that adjusted for the use of postoperative radiotherapy, which was handled as a time-dependent covariate. Postoperative radiotherapy was modeled as a single parameter and also as early and late therapy, based on the prostate-specific antigen level at the start of treatment (≤0.5 vs >0.5 ng/ml). INTERVENTION: RP for clinically localized prostate cancer and selective use of secondary local and/or systemic therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome measure was prostate cancer-specific mortality. RESULTS AND LIMITATIONS: The 15-yr CSM rates for patients with PSMs and negative surgical margins were 10% and 6%, respectively (p<0.001). No significant association between PSM and CSM was observed in the conventional model with fixed covariates (hazard ratio [HR]: 1.04; 95% confidence interval [CI], 0.7-1.5; p=0.8) or in the two extended models that adjusted for postoperative radiotherapy (HR: 0.96; 95% CI, 0.7-1.4; p=0.9), or early and late postoperative radiotherapy (HR: 1.01; 95% CI, 0.7-1.4; p=0.9). CONCLUSIONS: PSMs alone are not associated with a significantly increased risk of CSM within 15 yr of RP. However, urologists should continue to strive to avoid PSMs, as they increase a man's risk of biochemical recurrence and need for secondary therapy and may be a source of considerable patient anxiety.

Enhanced anticancer efficacy of snake venom combined with silica nanoparticles in a murine model of human multiple myeloma: molecular targets for cell cycle arrest and apoptosis induction.

Multiple myeloma (MM) is a clonal disease of plasma cells that reside in the bone marrow (BM). MM is an incurable disease; thus, screening for novel anti-myeloma drugs remains critically important. We recently described a silica nanoparticle-based snake venom delivery model that targets cancer cells, but not normal cells. Using this model, we demonstrated a strong enhancement of the antitumor activity of snake venom extracted from Walterinnesia aegyptia (WEV) in two breast carcinoma cell lines when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we aimed to delineate the in vivo therapeutic efficacy of WEV+NP in an MM-bearing experimental nude mouse model. We found that treatment with WEV+NP or WEV alone significantly inhibited tumor growth compared to treatment with NP or vehicle. WEV+NP- and WEV-treated cancer cells exhibited marked elevations in oxidative stress and robust reductions in the levels of interleukin-6 (IL-6) and B cell-activating factor (BAFF). WEV+NP also decreased the surface expression of the chemokine receptors CXCR3, CXCR4 and CXCR6 to a greater extent than WEV alone, and WEV+NP subsequently reduced migration in response to the cognate ligands CXCL10, CXCL12 and CXCL16. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (EGF-1)- and IL-6-mediated MM cell proliferation, altered the cell cycle and enhanced the induction of apoptosis of MM cells. In addition, the results of treatment with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the expression of cyclin D1, Bcl-2 and the phosphorylation of AKT; increased the expression of cyclin B1; altered the mitochondrial membrane potential; increased the activity of caspase-3, -8 and -9; and sensitized MM cells to growth arrest and apoptosis. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom to fight cancer cells.

Therapeutic efficacy and molecular mechanisms of snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles in the treatment of breast cancer- and prostate cancer-bearing experimental mouse models.

The treatment of drug-resistant cancer is a clinical challenge, and thus screening for novel anticancer drugs is critically important. We recently demonstrated a strong enhancement of the antitumor activity of snake (Walterinnesia aegyptia) venom (WEV) in vitro in breast carcinoma, prostate cancer, and multiple myeloma cell lines but not in normal cells when the venom was combined with silica nanoparticles (WEV+NP). In the present study, we investigated the in vivo therapeutic efficacy of WEV+NP in breast cancer- and prostate cancer-bearing experimental mouse models. Xenograft breast and prostate tumor mice models were randomized into 4 groups for each cancer model (10 mice per group) and were treated with vehicle (control), NP, WEV, or WEV+NP daily for 28 days post tumor inoculation. The tumor volumes were monitored throughout the experiment. On Day 28 post tumor inoculation, breast and prostate tumor cells were collected and either directly cultured for flow cytometry analysis or lysed for Western blot and ELISA analysis. Treatment with WEV+NP or WEV alone significantly reduced both breast and prostate tumor volumes compared to treatment with NP or vehicle alone. Compared to treatment with WEV alone, treatment of breast and prostate cancer cells with WEV+NP induced marked elevations in the levels of reactive oxygen species (ROS), hydroperoxides, and nitric oxide; robust reductions in the levels of the chemokines CXCL9, CXCL10, CXCL12, CXCL13, and CXCL16 and decreased surface expression of their cognate chemokine receptors CXCR3, CXCR4, CXCR5, and CXCR6; and subsequent reductions in the chemokine-dependent migration of both breast and prostate cancer cells. Furthermore, we found that WEV+NP strongly inhibited insulin-like growth factor 1 (IGF-1)- and epidermal growth factor (EGF)-mediated proliferation of breast and prostate cancer cells, respectively, and enhanced the induction of apoptosis by increasing the activity of caspase-3,-8, and -9 in both breast and prostate cancer cells. In addition, treatment of breast and prostate cancer cells with WEV+NP or WEV alone revealed that the combination of WEV with NP robustly decreased the phosphorylation of AKT, ERK, and IκBα; decreased the expression of cyclin D1, surviving, and the antiapoptotic Bcl-2 family members Bcl-2, Bcl-XL, and Mcl-1; markedly increased the expression of cyclin B1 and the proapoptotic Bcl-2 family members Bak, Bax, and Bim; altered the mitochondrial membrane potential; and subsequently sensitized tumor cells to growth arrest. Our data reveal the therapeutic potential of the nanoparticle-sustained delivery of snake venom against different cancer cell types.

Maternal supplementation of diabetic mice with thymoquinone protects their offspring from abnormal obesity and diabetes by modulating their lipid profile and free radical production and restoring lymphocyte proliferation via PI3K/AKT signaling.

BACKGROUND: Epidemiological studies have shown that the offspring of mothers who experience diabetes mellitus during pregnancy are seven times more likely to develop health complications than the offspring of mothers who do not suffer from diabetes during pregnancy. The present study was designed to investigate whether supplementation of streptozotocin (STZ)-induced diabetic pregnant mice with thymoquinone (TQ) during pregnancy and lactation improves the risk of developing diabetic complications acquired by their offspring. METHODS: Three groups of pregnant female mice were used: non-diabetic control dams (CD), diabetic dams (DD), and diabetic dams supplemented with TQ (DD + TQ) during pregnancy and lactation (n = 10 female mice in each group). RESULTS: Our data demonstrated a marked decrease in the number of neonates born to DD, and these neonates showed a marked increase in their mean body weight (macrosomic pups) compared to those born to CD and DD + TQ. The induction of diabetes during pregnancy and lactation resulted in macrosomic pups with several postpartum complications, such as a marked increase in their levels of blood glucose, free radicals, plasma pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α), and lipids, and a tendency toward abnormal obesity compared to the offspring of CD. By contrast, macrosomic offspring born to DD exhibited a marked reduction in plasma cytokine levels (IL-2, -4 and -7), an obvious reduction in the number of circulating lymphocytes, decreased proliferation of superantigen (SEB)-stimulated lymphocytes and aberrant AKT phosphorylation. Interestingly, the supplementation of DD with TQ during pregnancy and lactation had an obvious and significant effect on the number and mean body weight of neonates. Furthermore, TQ significantly restored the levels of blood glucose, insulin, free radicals, plasma cytokines, and lipids as well as lymphocyte proliferation in the offspring. CONCLUSIONS: Our data suggest that the nutritional supplementation of DD with the natural antioxidant TQ during pregnancy and lactation protects their offspring from developing diabetic complications and preserves an efficient lymphocyte immune response later in life.