Molecular Mechanisms Mediating Ceftazidime/Avibactam Resistance Amongst Carbapenem-Resistant Klebsiella pneumoniae Isolates from Cancer Patients.

Background: A growing body of evidence suggests that ceftazidime/avibactam (CZA) is a potential therapeutic option for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections; however, resistant strains are increasingly emerged worldwide. Herein, we deemed to investigate the susceptibility profile of CRKP isolates from cancer patients to CZA and to identify the underlying resistance mechanisms. Methods: Clinical samples were obtained from adult patients admitted to the Oncology Center of Mansoura University, Mansoura, Egypt. The antibiotic susceptibility pattern of K. pneumoniae isolates to different antibiotics was tested by the modified Kirby Bauer's disc diffusion method. Minimum inhibitory concentrations of CZA were assessed using broth microdilution method. Screening for carbapenemase-producing strains was achieved by the modified Hodge test. Multiplex polymerase chain reactions (PCRs) were conducted for uncovering of carbapenemase-encoding genes (blaKPC, blaVIM, blaIMP, blaNDM-1 , and blaOXA-48 ), and outer membrane porin genes (ompK35 and ompK36). Results: A total of 12 CZA-resistant isolates were identified out of 47 CRKP isolates (25.5%). The MIC50 and MIC90 of CZA against CRKP were 1 and 64 µg/mL, respectively. Risk factors for CZA resistance included chronic kidney disease, mechanical ventilation, longer length of hospital stay, and ICU admission. The multivariate logistic regression demonstrated that longer length of hospital stay (P=0.03) was the only independent predictor for acquisition of CZA-resistant isolates. The leading mechanism for CZA resistance was sustained by blaKPC (50%), meanwhile 16.7% and 8.3% of the CZA-resistant isolates harbored blaOXA-48 and blaOXA-48 /blaNDM-1 , respectively. The MBL-encoding genes blaNDM-1 and blaIMP were detected in 16.7% and 8.3% of the isolates, respectively. Absence of both ompK35 and ompK36 was observed in 58.3% of the CZA-resistant isolates. Conclusion: CZA has displayed superior in vitro activity against CRKP isolates in comparison to other antibiotics; however, thorough molecular characterization of resistant strains is highly recommended in future studies to detect and monitor the emergence of further tackling strains.

Suggested Modifications to the Management of Patients With Breast Cancer During the COVID-19 Pandemic: Web-Based Survey Study.

BACKGROUND: Management of patients with cancer in the current era of the COVID-19 pandemic poses a significant challenge to health care systems. Breast cancer is the most common cancer internationally. Breast cancer is a disease that involves surgery, chemotherapy, hormonal therapy, targeted therapy, radiotherapy, and, more recently, immunotherapy in its management plan. The immune system requires months to recover from these medications, and this condition is even worse in patients with metastatic breast cancer who need ongoing treatment with these drugs. Some of these drugs, such as inhibitors of cyclin-dependent kinases 4 and 6, can cause rare but life-threating lung inflammation. Patients with breast cancer who have metastatic disease to the lungs can experience deterioration of disease symptoms with COVID-19 infection. Oncologists treating patients with breast cancer are facing a difficult situation regarding treatment choice. The impact that COVID-19 has had on breast cancer care is unknown, including how to provide the best care possible without compromising patient and community safety. OBJECTIVE: The aim of this study was to explore the views of oncologists regarding the management of patients with breast cancer during the COVID-19 pandemic. METHODS: A web-based SurveyMonkey questionnaire was submitted to licensed oncologists involved in breast cancer management in Saudi Arabia, Egypt, and United Arab Emirates. The survey focused on characteristics of the participants, infection risk among patients with cancer, and possible treatment modifications related to different types of breast cancer. RESULTS: The survey was completed by 82 participants. For early hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, 61 of the 82 participants (74%) supported using neoadjuvant hormonal therapy in selected patients, and 58% (48/82) preferred giving 6 over 8 cycles of adjuvant chemotherapy when indicated. Only 43% (35/82) preferred inhibitors of cyclin-dependent kinases 4 and 6 with hormonal therapy as the first-line treatment in all patients with metastatic HR-positive disease. A total of 55 of the 82 participants (67%) supported using adjuvant trastuzumab for 6 instead of 12 months in selected patients with HER2-positive breast cancer. For metastatic HER2-positive, HR-positive breast cancer, 80% of participants (66/82) supported the use of hormonal therapy with dual anti-HER2 blockade in selected patients. The preferred choice of first-line treatment in metastatic triple negative patients with BRCA mutation and programmed cell death 1 ligand 1 (PD-L1) <1% was poly(adenosine diphosphate-ribose) polymerase inhibitor according to 41% (34/82) of the participants, and atezolizumab with nab-paclitaxel was preferred for PD-L1 >1% according to 71% (58/82) of the participants. CONCLUSIONS: Several modifications in breast cancer management were supported by the survey participants. These modifications need to be discussed on a local basis, taking into account the local infrastructure and available resources.

Repurposing metformin as anticancer drug: Randomized controlled trial in advanced prostate cancer (MANSMED).

BACKGROUND: The proposal of metformin as an anticancer drug has been explored in many types of cancers. Metformin may act synergistically with standard prostate cancer therapies. However, there is still a debate about the effect of metformin on hormone sensitive prostate cancer (HSPC). PATIENTS AND METHODS: randomized controlled trial. Eligible patients were high risk locally advanced or metastatic HSPC. Patients were randomly assigned to receive either metformin plus standard of care or standard of care alone. The primary endpoint was castration-resistant prostate cancer-free survival (CRPC-FS). The secondary endpoints were overall survival, PSA level and adverse events. RESULTS: A total number of 124 patients underwent randomization where 62 patients were allocated in each arm. Over a median follow up of 22 months, the CRPC-FS was significantly improved with metformin (29 months, 95% CI 25-33 vs. 20 months 95% CI 16-24; P = 0.01). After subgroup analysis, the addition of metformin improved the CRPC-FS in patients with high risk localized disease (median not reached vs. 25 months, 95% CI 18-31; P = 0.02) and in patients with metastatic low tumor volume disease (median not reached vs. 15 months, 95% CI 5-25; P = 0.009). No significant difference in overall survival or PSA response in both treatment arms (P = 0.1 and 0.5, respectively). Metformin was not associated with significant adverse events apart from grade II diarrhea. CONCLUSION: Metformin is a safe and low-cost drug. Combining with androgen deprivation therapy improves the outcome in locally advanced or metastatic prostate cancer. Patients with low volume metastatic prostate cancer seem to drive more benefit.

Prognostic Value of TLE1 Gene Expression in Patients with T-cell Acute Lymphoblastic Leukemia.

BACKGROUND: Transducin-like enhancer of split 1 (TLE1( is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. The aim of this study was to evaluate the prognostic role of TLE1 gene expression in patients with T-cell acute lymphoblastic leukemia (T-ALL). METHOD: This study was conducted on 97 newly diagnosed T-ALL patients admitted to the Mansoura University oncology center (59 males and 38 females) with median age (33 years) in addition to 102 apparently healthy individuals served as a control group. TLE1 gene expression was measured in both patients and control groups by real time - PCR. The calculation of relative gene expression was done using the ΔΔCt method. RESULTS: TEL1 gene expression was significantly down regulated in T-ALL cases (median 2.83) as compared to controls (median 84.65) (p < 0.001). The low TEL1 gene expression was significantly associated with CNS infiltration, non-remission and higher relapse rate (p < 0.001, 0.001 and 0.023 respectively). Likewise, Low TEL1 gene expression was significantly associated with shorter OS and DFS (P= 0.012 and 0.011 respectively). Furthermore, Low TEL1 gene expression was considered as risk predictor of relapse with OR 3.636(CI.1.422-9.295) (P =0.007); and OR 0.803(CI. 0.609-0.96) (P=0.021) and independent predictor of T-ALL patient's outcome with OR 0.619 (CI. 0.44-0.872) (P=0.006). CONCLUSION: TLE1 gene expression was significantly down regulated in T-ALL cases as compared with controls. Low TLE1 expression is independent predictor of the T-ALL patient's outcome.
.