Retinal functional and structural changes in patients with Parkinson's disease.

BACKGROUND: Visual dysfunction have been well reported as one of the non-motor symptoms in Parkinson's disease (PD). The aim of this study was to evaluate the functional and structural changes in the retina in patients with PD, and to correlate these changes with disease duration and motor dysfunction. METHODS: For this case-control study, we recruited patients fulfilling the diagnostic criteria for idiopathic PD according to British Brain Bank criteria, aged between 50 and 80 years. Age- and sex-matched healthy controls aged between 50 and 80 years were also recruited. Motor function for PD patients was assessed using Modified Hoehn and Yahr staging scale (H & Y staging) and Unified Parkinson's Disease Rating Scale (UPDRS). Optical Coherence Tomography (OCT) and full field electroretinogram (ff-ERG) were done to all participants. RESULTS: Data from 50 patients and 50 healthy controls were included in the analysis. Patients with idiopathic Parkinson's had significantly reduced peripapillary retinal nerve fiber layer (RNFL) thickness and macular ganglion cell complex (GCC) thickness compared to healthy controls (P-value < 0.05 in all parameters). They also had significantly delayed latency and reduced amplitude in both dark-adapted rods and the light-adapted cone for both a & b waves compared to healthy controls (P-value < 0.001 in all parameters). There were statistically significant negative correlations between disease duration, and left superior, right inferior and right & left average RNFL thickness [(r) coef. = -0.327, -0.301, -0.275, and -0.285 respectively]. UPDRS total score was negatively correlated with the amplitude of light-adapted of both RT and LT a & b wave and with dark-adapted RT b-wave latency [(r) coef. = -0.311, -0.395, -0.362, -0.419, and -0.342]. CONCLUSION: The retinal structure and function were significantly affected in patients with PD in comparison to healthy controls. There was a significant impact of disease duration on retinal thickness, and there was a significant negative correlation between the degree of motor dysfunction in patients with PD and retinal function.

A U.S. Food and Drug Administration-pooled Analysis of Frontline Combination Treatment Survival Benefits by Risk Groups in Metastatic Renal Cell Carcinoma.

BACKGROUND: While frontline immuno-oncology/tyrosine kinase inhibitor (IO/TKI) combination therapy has established a benefit in metastatic renal cell carcinoma (mRCC), this may differ by International Metastatic RCC Database Consortium (IMDC) risk grouping. Looking at individual trials, we noted an apparently smaller magnitude of benefit for favorable-risk disease. OBJECTIVE: We aimed to assess treatment benefit by risk groupings, especially in favorable-risk, augmenting patient numbers via a pooled analysis. DESIGN, SETTING, AND PARTICIPANTS: We pooled four frontline mRCC trials of IO/TKI combinations including 3,098 patients (839 favorable-risk) with approvals from 2019 to 2021. INTERVENTION: All trials used IO/TKI combinations as the treatment option and sunitinib as the control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed progression-free survival (PFS) and overall survival (OS) by IMDC groupings. To specifically address the favorable-risk group, we combined all others into an intermediate/poor-risk group. RESULTS AND LIMITATIONS: In this exploratory analysis adjusted for baseline covariates, IO/TKI combinations have yet to demonstrate an OS benefit in favorable-risk (hazard ratio [HR] 1.24; 95% confidence interval [CI]: 0.86, 1.78) despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64; 95% CI: 0.55, 0.75). In contrast, IO/TKI demonstrated a PFS benefit for both the favorable-risk (HR 0.63; 95% CI: 0.50, 0.79) and the intermediate/poor-risk (HR 0.52; 95% CI: 0.45, 0.60) group. For objective response rate, a smaller difference was observed between the combination and sunitinib arms in favorable-risk (68.2% vs 49.9%) versus intermediate/poor-risk (59.9% vs 36.5%) groups, while the difference in complete response rate was larger for favorable-risk (15.3% vs 6.0%) versus intermediate/poor-risk (9.1% vs 3.4%) groups. CONCLUSIONS: The frontline IO/TKI combination therapy benefit was shown to be greater in the intermediate/poor-risk group than in the favorable-risk group. The OS benefit observed with IO/TKI for mRCC has yet to be demonstrated for favorable-risk patients; longer follow-up is needed. PATIENT SUMMARY: Patients with intermediate/poor-risk metastatic renal cell carcinoma derive an overall survival benefit from immuno-oncology/tyrosine kinase inhibitor combinations, while data for favorable-risk remain immature.

FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer.

On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52-0.74; P < 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.

FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease-Associated Tumors.

On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.

FDA Approval Summary: Tivozanib for Relapsed or Refractory Renal Cell Carcinoma.

On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75-1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.

Effect of heavy cigarette and water pipe smoking on antioxidants and lipids in Sudanese male smokers: a case-control study.

Background: Tobacco smoking is a source of many toxins such as free radicals, mutagenic substances as well as cause for developing cardiovascular diseases (CVD), particularly atherosclerosis. This study aims to assess the impact of smoking on antioxidants in Sudanese male smokers. Methods: Cases were 85 and 48 men who smoke cigarettes (CS) and water pipe (WPS) respectively and they were compared with matching 50 non-smoking controls. Blood samples were collected and following parameters: Glutathione peroxidase, Superoxide dismutase, Total cholesterol, Triglyceride, LDL, HDL, Paraoxinase, and Malondialdehyde were measured. Results: There were no significant differences in biochemical parameters between light CS and WPS compared to controls. In heavy smokers of both WPS and CS, the TC, TG, LDL, and MDA were higher than controls (p>0.05), GPx, SOD, HDL, and PON were lower in smokers than controls (p>0.05). In both groups of smokers; HDL, GPx, SOD, and PON were inversely correlated with duration of smoking (p>0.05), also, HDL was positively correlated with SOD and GPx (p>0.05). Moreover, GPx and SOD were correlated with each other in both groups of smokers (p>0.05). Conclusion: In Sudanese male smokers' biochemical profile disturbances suggest that heavy smoking was leading to developing CVD, particularly WPS.

U.S. FDA Drug Approvals for Gynecological Malignancies: A Decade in Review.

Over the last decade, there has been tremendous progress in the treatment of patients with gynecologic cancers with a changing therapy landscape. This summary provides an overview of U.S. Food and Drug Administration (FDA) approvals for gynecologic cancers from 2010 to 2020, totaling 17 new indications. For each of the approved indications, endpoints, trial design, results, and regulatory considerations are outlined. Among these 17 indications, six received accelerated approval (AA) and 11 received regular approval (RA). As of September 2021, of the six AA, three have subsequently demonstrated clinical benefit resulting in conversion to RA and the remaining three have ongoing clinical trials that have not yet reported results. Approval decisions for these 17 indications were supported by primary efficacy endpoints of progression-free survival (n = 10), objective response rate (n = 6), and overall survival (n = 1) and showed a favorable benefit-risk profile. Among the 17 indications, 15 received priority review and three applications participated in one or more novel Oncology Center of Excellence initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. Current FDA thinking on drug development opportunities and regulatory initiatives currently under way will be discussed.

U.S. FDA Drug Approvals for Breast Cancer: A Decade in Review.

Over the last decade, the treatment of patients with breast cancer has been greatly impacted by the approval of multiple drugs and indications. This summary describes 30 FDA approvals of treatments for breast cancer from 2010 to 2020. The trial design endpoints, results, and regulatory considerations are described for each approved indication. Of the 30 indications, 23 (76.6%) received regular and 7 (23.3%) received accelerated approval. Twenty-six approvals were granted in metastatic breast cancer (MBC) and four in early breast cancer. Approval decisions for the 26 MBC indications were initially supported by progression-free survival (PFS) in 21 (80.8%), overall survival (OS) or a combination of OS and PFS in two (7.7%), and objective response rate (ORR) in three (11.5%). The four approvals in early breast cancer utilized pathologic complete response (pCR) in one (25%) and invasive disease-free survival (iDFS) in three (75%) trials. Among the 30 indications, 22 received priority review, seven were granted Breakthrough Therapy Designation, and 10 applications participated in one or more pilot Oncology Center of Excellence regulatory review initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. FDA initiatives to advance breast cancer drug development are also described.

The beneficial effect of Adansonia digitata products success to modulate lipid profiles and inhibit LDL oxidation in-vitro: An associational study.

Background: There is a growing interest in medicinal plants in recent years due to their many therapeutic benefits and low side effects. Among the medicinal plants is the African Adansonia digitata (baobab) that has edible fruit. In the current study, the effect of A. digitata juice consumption on the lipid profile was investigated. In addition, inhibition of the oxidation of low-density lipoprotein cholesterol (LDL-C) in-vitro by A. digitata essential oil (EO) was also investigated. Methods: In this cohort study, a total of 70 subjects of A. digitata users (AD group, 42 male and 28 female) and 70 non A. digitata users (Non-AD group, 44 male and 26 female) were recruited to participate in this study. We evaluated lipid profile, HbA1c, liver/kidney functions, and phytosterol contents in fasting blood samples of all participants. Results: The present findings illustrated significantly lower levels of total cholesterol, triglycerides, and LDL in the AD group compared to Non-AD (p < 0.01). In addition, essential oil of A. digitata inhibited LDL oxidation in-vitro as shown by the significant decreases in the formation of malonaldehyde (MDA), protein carbonyl (PC), and lipid hydroperoxide (LHP) (P<0.05). No significant changes in fasting blood glucose, HbA1c, HDL, kidney function, and liver function enzymes between the two groups were detected (P>0.05). Conclusion: The juice of A. digitata has hypolipidemic and antioxidative effects and might be beneficial for the management of lipid levels in the body.

Effect of heavy cigarette and water pipe smoking on antioxidants and lipids in Sudanese male smokers: a case-control study

Background: Tobacco smoking is a source of many toxins such as free radicals, mutagenic substances as well as cause for developing cardiovascular diseases (CVD), particularly atherosclerosis. This study aims to assess the impact of smoking on antioxidants in Sudanese male smokers. Methods: Cases were 85 and 48 men who smoke cigarettes (CS) and water pipe (WPS) respectively and they were compared with matching 50 non-smoking controls. Blood samples were collected and following parameters: Glutathione peroxidase, Superoxide dismutase, Total cholesterol, Triglyceride, LDL, HDL, Paraoxinase, and Malondialdehyde were measured. Results: There were no significant differences in biochemical parameters between light CS and WPS compared to controls. In heavy smokers of both WPS and CS, the TC, TG, LDL, and MDA were higher than controls (p>0.05), GPx, SOD, HDL, and PON were lower in smokers than controls (p>0.05). In both groups of smokers, HDL, GPx, SOD, and PON were inversely correlated with duration of smoking (p>0.05), also, HDL was positively correlated with SOD and GPx (p>0.05). Moreover, GPx and SOD were correlated with each other in both groups of smokers (p>0.05). Conclusion: In Sudanese male smokers' biochemical profile disturbances suggest that heavy smoking was leading to developing CVD, particularly WPS

Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials.

BACKGROUND: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer. METHODS: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 µg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment. FINDINGS: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups). INTERPRETATION: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient. FUNDING: None.

Subgroup Analyses in Oncology Trials: Regulatory Considerations and Case Examples.

Subgroup analyses are assessments of treatment effects based on certain patient characteristics out of the total study population and are important for interpretation of pivotal oncology trials. However, appropriate use of subgroup analyses results for regulatory decision-making and product labeling is challenging. Typically, drugs approved by the FDA are indicated for use in the total patient population studied; however, there are examples of restriction to a subgroup of patients despite positive study results in the entire study population and also extension of an indication to the entire study population despite positive results appearing primarily in one or more subgroups. In this article, we summarize key issues related to subgroup analyses in the benefit-risk assessment of cancer drugs and provide case examples to illustrate approaches that the FDA Oncology Center of Excellence has taken when considering the appropriate patient population for cancer drug approval. In general, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven and have adequate sample size to demonstrate evidence of a treatment effect. In addition to statistical efficacy considerations, the decision on what subgroups to include in labeling relies on the pathophysiology of the disease, mechanistic justification, safety data, and external information available. The oncology drug review takes the totality of the data into consideration during the decision-making process to ensure the indication granted and product labeling appropriately reflect the scientific evidence to support patient population for whom the drug is safe and effective.

FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma.

On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single-arm, multicenter Study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% [95% confidence interval (CI), 35.1-53.2], with complete responses in 12%. Median response duration was 7.6 months (95% CI, 6.3-not estimable). Grade 3-4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA-Mutated Metastatic Castrate-Resistant Prostate Cancer.

The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%-57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3-4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. IMPLICATIONS FOR PRACTICE: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.

Frequency and severity of ketoacidosis at diagnosis among childhood type 1 diabetes in Khartoum state, Sudan.

BACKGROUND: Diabetic ketoacidosis (DKA) is a potentially life threatening acute complication of Type I diabetes mellitus (T1DM). This study aimed to determine the frequency and clinical characteristics of pediatric DKA at diagnosis of new-onset T1DM in Khartoum during 2000-2017 period. METHODS: The study was retrospective and involved review of medical files of children (<15 years) with T1DM in the city hospitals and diabetes centers. RESULTS: The overall frequency of DKA among T1DM children at onset of disease diagnosis was 17.6% (173/982). The episodes of DKA increased from 26% in first 6- year period (2000-2005) to 46.3% in the last 6-year period (2011-2012; p<0.001). No significant difference in the frequency of DKA was observed according to gender (p=0.9) and age (p=0.24). Compared to other age groups, the severity of DKA (pH<7.1) was higher in pre-school children (p<0.01). Approximately, 5% of patients were complicated with cerebral edema with a mortality rate of 1.7%. CONCLUSION: The DKA frequency at diagnosis of childhood T1DM in Khartoum was lower than previous reports. In addition, the severity of DKA was high among pre-school age children with a relatively high mortality rate when compared to the global rate.

Regulatory Considerations for Contribution of Effect of Drugs Used in Combination Regimens: Renal Cell Cancer Case Studies.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer.

The FDA has approved three androgen receptor inhibitors-enzalutamide, apalutamide, and darolutamide-for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

FDA Approval Summary: Ado-Trastuzumab Emtansine for the Adjuvant Treatment of HER2-positive Early Breast Cancer.

On May 3, 2019, the FDA granted regular approval to ado-trastuzumab emtansine (KADCYLA), for the adjuvant treatment of patients with HER2-positive early-breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment. Approval was based on data from the KATHERINE trial, which randomized patients to receive ado-trastuzumab emtansine or trastuzumab. At 3 years, the event-free rate for invasive disease-free survival in the ado-trastuzumab emtansine arm was 88.3% [95% confidence interval (CI), 85.8-90.7] compared with 77.0% (95% CI, 73.8-80.7) in the trastuzumab arm, (HR, 0.50; 95% CI, 0.39-0.64; P < 0.0001). Results from secondary endpoints, subgroup analyses, and sensitivity analyses generally supported the primary efficacy endpoint results. Common adverse reactions (>25% and higher incidence in ado-trastuzumab emtansine arm) with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. Ado-trastuzumab emtansine is the first drug approved for the treatment of patients with residual disease after neoadjuvant treatment and surgery. This article summarizes the FDA review and the data supporting the approval of ado-trastuzumab emtansine as a component of treatment for patients with HER2-positive EBC with residual disease.

FDA Approval Summary: Atezolizumab Plus Paclitaxel Protein-bound for the Treatment of Patients with Advanced or Metastatic TNBC Whose Tumors Express PD-L1.

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 [PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area], as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1-positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1-positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm [HR = 0.60; 95% confidence interval (CI), 0.48-0.77]. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1-expressing population to predict clinical benefit.

Eligibility and Radiologic Assessment for Adjuvant Clinical Trials in Kidney Cancer.

PURPOSE: To harmonize the eligibility criteria and radiologic disease assessment definitions in clinical trials of adjuvant therapy for renal cell carcinoma (RCC). METHOD: On November 28, 2017, US-based experts in RCC clinical trials, including medical oncologists, urologic oncologists, regulators, biostatisticians, radiologists, and patient advocates, convened at a public workshop to discuss eligibility for trial entry and radiologic criteria for assessing disease recurrence in adjuvant trials in RCC. Multiple virtual meetings were conducted to address the issues identified at the workshop. RESULTS: The key workshop conclusions for adjuvant RCC therapy clinical trials were as follows. First, patients with non-clear cell RCC could be routinely included, preferably in an independent cohort. Second, patients with T3-4, N+M0, and microscopic R1 RCC tumors may gain the greatest advantages from adjuvant therapy. Third, trials of agents not excreted by the kidney should not exclude patients with severe renal insufficiency. Fourth, therapy can begin 4 to 16 weeks after the surgical procedure. Fifth, patients undergoing radical or partial nephrectomy should be equally eligible. Sixth, patients with microscopically positive soft tissue or vascular margins without gross residual or radiologic disease may be included in trials. Seventh, all suspicious regional lymph nodes should be fully resected. Eighth, computed tomography should be performed within 4 weeks before trial enrollment; for patients with renal insufficiency who cannot undergo computed tomography with contrast, noncontrast chest computed tomography and magnetic resonance imaging of the abdomen and pelvis with gadolinium should be performed. Ninth, when feasible, biopsy should be undertaken to identify any malignant disease. Tenth, when biopsy is not feasible, a uniform approach should be used to evaluate indeterminate radiologic findings to identify what constitutes no evidence of disease at trial entry and what constitutes radiologic evidence of disease. Eleventh, a uniform approach for establishing the date of recurrence should be included in any trial design. Twelfth, patient perspectives on the use of placebo, conditions for unblinding, and research biopsies should be considered carefully during the conduct of an adjuvant trial. CONCLUSIONS AND RELEVANCE: The discussions suggested that a uniform approach to eligibility criteria and radiologic disease assessment will lead to more consistently interpretable trial results in the adjuvant RCC therapy setting.