The Evolving Landscape of Immunotherapy-Based Combinations for Frontline Treatment of Advanced Renal Cell Carcinoma

Insights into the biology of advanced renal cell carcinoma (aRCC) and the development of agents targeting the vascular endothelial growth factor (VEGF) pathway have positively impacted the outcomes for patients with aRCC. With the recent approval of the dual immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab, by the U.S. Food and Drug Administration (USFDA), and the European Medicines Agency (EMA), the era of VEGF monotherapy for untreated aRCC appears to be coming to an end for patients with access to the combination therapy. The frontline treatment options for renal cell carcinoma are evolving rapidly and will lead to the approval of other combination immunotherapies—especially those with VEGF inhibitors. Here we review the clinical data for dual immune checkpoint inhibition with nivolumab plus ipilimumab as well as the emerging data for ICI plus VEGF inhibitor combinations and discuss the challenges these will pose for the clinical practitioner

Paediatric femur fractures and long leg splinting

BackgroundSpica casting is frequently used for treating the paediatric femur fractures encounter injuries. However, patients may find Spica casting expensive and burdensome. Long leg splint is the other alternate possible treatment.MethodsThe children between the age of 6 months to 5 years having a femoral shaft fracture were treated with a long leg splint extended over the waist and it resembles with patient undergoing treatment with a Spica cast.ResultsAt the time of healing, the alignment with respect to coronal angulation is considerably better in Spica cast group as compared to splint group

Interleukin-2 in Renal Cell Carcinoma: A Has-Been or a Still-Viable Option?

Modulation of the immune response plays an important role in the natural history of renal cell carcinoma.  Spontaneous regression of metastases has been well documented in a small percentage of patients after they undergo de-bulking nephrectomy without any additional systemic intervention.  The only logical explanation for these observations is “resetting” of the balance between tumor and the host immune system that, having been overwhelmed by the tumor burden, is able to function better after tumor de-bulking.  Attempts to modulate the activity of the immune system “on demand” have included the use of vaccines, cytokines/lymphokines, adoptive cell transfer, monoclonal antibodies and most recently manipulation of immune checkpoint inhibitors.  Here we review the data for infusional interleukin-2 in the management of advanced renal cell carcinoma and its role in current clinical practice

Evaluation of Morphological Characteristics and Fatty Acid Compositions of Some Local Varieties of Oil Flax

Oil flax (Linum usitatissimum L.) is a valuable agricultural crop with potential uses in industries including oil production, nutrition, and medicine. It has a good reputation in Afghanistan as an oil crop. The objective of the current research was to compare the most significant morphological parameters and fatty acid compositions of some local oilflax. The study used a randomized complete block design and was conducted on the research and experimental farm of Parwan University\u27s (REFPU) Faculty of Agriculture in Parwan, Afghanistan, during the 2022 growing season. In this experiment, four seed samples from various regions of Afghanistan [Parwan (V1), Badakhshan (V2), Baghlan (V3), and Kunduz (V4)] were used. The results showed no significant difference between the local varieties on all growth parameters except for the number of seeds per capsule (NSC) and the weight of a thousand seeds (WTS). The maximum NSC was significantly observed in the V1 (10.8), followed by the V3 (7.13) and the V4 (7.33), and the lowest was recorded in the V2 (6.7). The heaviest WTS were significantly produced by V1 (9 gr) compared to V2 (4.67 gr), V3 (5.67 gr), and V4 (4.67 gr). Also, there was not a noticeable difference in the concentration of linoleic acid (LA) and linolenic acid (LLA) between the varieties. Each of the studied local varieties can be used because of their similar performance

Heavy metals mitigation and growth promoting effect of endophytic Agrococcus terreus (MW 979614) in maize plants under zinc and nickel contaminated soil

IntroductionHeavy metals such as iron, copper, manganese, cobalt, silver, zinc, nickel, and arsenic have accumulated in soils for a long time due to the dumping of industrial waste and sewage. Various techniques have been adapted to overcome metal toxicity in agricultural land but utilizing a biological application using potential microorganisms in heavy metals contaminated soil may be a successful approach to decontaminate heavy metals soil. Therefore, the current study aimed to isolate endophytic bacteria from a medicinal plant (Viburnum grandiflorum) and to investigate the growth-promoting and heavy metal detoxification potential of the isolated endophytic bacteria Agrococus tereus (GenBank accession number MW 979614) under nickel and zinc contamination.MethodsZinc sulfate and nickel sulfate solutions were prepared at the rate of 100 mg/kg and 50 mg/kg in sterilized distilled water. The experiment was conducted using a completely random design (CRD) with three replicates for each treatment.Results and DiscussionInoculation of seeds with A. tereus significantly increased the plant growth, nutrient uptake, and defense system. Treatment T4 (inoculated seeds), T5 (inoculated seeds + Zn100 mg/kg), and T6 (inoculated seeds + Ni 100 mg/kg) were effective, but T5 (inoculated seeds + Zn100 mg/kg) was the most pronounced and increased shoot length, root length, leaf width, plant height, fresh weight, moisture content, and proline by 49%, 38%, 89%, 31%, 113%, and 146%, respectively. Moreover the antioxidant enzymes peroxidase and super oxidase dismutase were accelerated by 211 and 68% in contaminated soil when plants were inoculated by A. tereus respectively. Similarly the inoculation of A. tereus also enhanced maize plants’ absorption of Cu, Mn, Ni, Na, Cr, Fe, Ca, Mg, and K significantly. Results of the findings concluded that 100 mg/kg of Zn and Ni were toxic to maize growth, but seed inoculation with A. tereus helped the plants significantly in reducing zinc and nickel stress. The A. tereus strain may be employed as a potential strain for the detoxification of heavy metal

No association of miscarriage and BRCA carrier status in Pakistani breast/ovarian cancer patients with a history of parental consanguinity

Q2Q1Carta al editor211-21

High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients

Background: Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient’s family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan. Methods: Five hundred and twenty-three breast cancer patients including 237 diagnosed ≤ 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics. Results: Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37% vs. 10%, P < 0.0001). 1% of TNBC patients were observed to have BRCA2 mutations. Subgroup analyses revealed a larger proportion of BRCA1 mutations in TNBC than non-TNBC among patients 1) diagnosed at early-age with no family history of breast/ovarian cancer (14% vs. 5%, P = 0.03), 2) diagnosed at early-age irrespective of family history (28% vs. 11%, P = 0.0003), 3) had a family history of breast cancer (49% vs. 12%, P < 0.0001), and 4) those with family history of breast and ovarian cancer (81% vs. 28%, P = 0.0005). TNBC patients harboring BRCA1 mutations were diagnosed at a later age than non-carriers (median age at diagnosis: 30 years (range 22–53) vs. 28 years (range 18–67), P = 0.002). The association between TNBC status and presence of BRCA1 mutations was independent of the simultaneous consideration of family phenotype, tumor histology and grade in a multiple logistic regression model (Ratio of the probability of carrying BRCA1/2 mutations for TNBC vs. non-TNBC 4.23; 95% CI 2.50–7.14; P < 0.0001). Conclusion: Genetic BRCA1 testing should be considered for Pakistani women diagnosed with TNBC

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

Abstract Introduction Nivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort. Methods Patients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review. Results Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively. Conclusions Whereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy

皮膚移植(第二回囘報告)

Deleterious BRCA1/2 germline mutations in Pakistani patients with TNBC. (DOCX 24 kb

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM

BACKGROUND: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). PATIENTS AND METHODS: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin RESULTS: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. CONCLUSIONS: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients