Median Development Time Research Articles

Breast cancer drugs: FDA approval, development time, efficacy, clinical benefits, innovation, trials, endpoints, quality of life, value, and price

ObjectiveThis study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval.MethodsWe identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response’s relative risk (RR) alongside objective response rate (ORR) were meta-analyzed.ResultsThe median development time for breast cancer drugs was 7.8 years (95% CI 6.2–10.8). 26% of treatments were considered innovative (“first-in-indication”) with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA’s special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417–752) at 181 centers (IQR 142–223) across 19 countries (IQR 17–20). New drugs’ HR were 0.78 for OS (95% CI 0.74–0.82) and 0.59 for PFS (95% CI 0.54–0.64) with a RR for tumor response of 1.61 (95% CI 1.46–1.76). Median improvements of OS were 2.8 months (IQR 1.8–5.8) and PFS were 4.4 months (IQR 2.2–7.1). In single-arm trials, the average ORR was 31% (95% CI 10–53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a ‘high-value’ ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097–17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840–86,062).ConclusionsOver the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life.

Oral and cutaneous immune‐related adverse events in cancer patients: Prevalence and overall survival

AbstractObjectivesTo assess the prevalence of cutaneous and oral immune‐related adverse events (irAEs) in cancer patients, risk factors for its development, and overall survival (OS).Materials and MethodsThis retrospective observational study which included 748 medical records of cancer patients who received immune checkpoint inhibitors (ICIs). Demographic and clinicopathological characteristics were collected and analyzed.ResultsMost patients were male (59.4%), with stage IV cancer (65%) and received pembrolizumab (46.7%). Four hundred fourteen (55.34%) patients developed cutaneous lesions, 84 (11.2%) developed oral mucosal lesions, and 70 (9.3%) developed xerostomia. The median time for irAEs development was 11 weeks for cutaneous and oral mucosal lesions, and 21.5 weeks for xerostomia. Patients who received PD‐1 + CTLA‐4 had a higher risk for developing cutaneous irAEs (p = 0.001), while those who underwent ICI and concurrent chemotherapy had a higher risk (p = 0.008) for developing oral mucosal lesions. Patients who presented oral and cutaneous irAEs had better OS than those who did not present (p = 0.0001).ConclusionCutaneous effects affected more than half of the patients, while oral effects and xerostomia were found in around 11% and 9% of patients, respectively. Concurrent chemotherapy and PD‐1 + CTLA‐4 were more associated with oral and cutaneous irAEs, respectively. Patients who developed such irAEs had better overall survival.

Factors associated with acceleration of clinical development for infectious diseases: a cross-sectional analysis of 10-year EMA registration data

Clinical trials feature centrally in the development of drugs and vaccines to determine safety and efficacy. Clinical development can be slow and may have a duration of more than ten years. Global public health threats such as Ebola virus disease (EVD) and COVID-19 have demonstrated that it is possible to accelerate clinical trials while maintaining safety and efficacy. We investigated acceleration in clinical trials over the past decade and identified factors associated with acceleration for drugs targeting infectious diseases. A cross-sectional study was performed of all medicinal compounds targeting infectious diseases that received marketing authorisation by the European Medicines Agency (EMA) between 2012 and 2022. We calculated median clinical development time in years between the first phase 1 trial enrolment date and the authorisation date. Multivariable linear regression analysis was performed to identify factors associated with shorter development times. Eighty-one trajectories were included. The median clinical development time was 7.3 years (IQR 4.4-12.3). The fastest times belonged to drugs and vaccines targeting COVID-19 (1.3 years, IQR 0.8-1.6), EVD (5.5 years, IQR 5.1-5.8), and Hepatitis A-E (5.5 years, IQR 3.9-8.2). Factors associated with shorter development times were outbreak setting (-5.4 years [95% CI,-8.2 to-2.6]), accelerated assessment status (-4.0 years [95% CI,-7.6 to-0.5]), and drugs with combined compounds (-2.7 years [95% CI,-4.9 to-0.4]). Clinical development time for infectious disease-related drugs and vaccines was relatively short, and outbreak setting and accelerated EMA assessment were associated with shorter development times. Amsterdam Public Health research institute.

Breakthrough Therapy Cancer Drugs and Indications With FDA Approval: Development Time, Innovation, Trials, Clinical Benefit, Epidemiology, and Price.

The breakthrough therapy designation (BTD) facilitates the development of drugs with a large preliminary benefit in treating serious or life-threatening diseases. This study analyzes the FDA approval, trials, benefits, unmet needs, and pricing of breakthrough and nonbreakthrough therapy cancer drugs and indications. We analyzed 355 cancer indications with FDA approval (2012-2022). Breakthrough and nonbreakthrough indications were compared regarding their FDA approval, innovativeness, clinical trials, epidemiology, and price. Data were extracted from FDA labels, the Global Burden of Disease study, and the Centers for Medicare & Medicaid Services. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) of tumor response were meta-analyzed across randomized controlled trials. Objective response rates (ORRs) were meta-analyzed for single-arm trials. We identified 137 breakthrough and 218 nonbreakthrough cancer indications. The median clinical development time was 3.2 years shorter for breakthrough drugs than for nonbreakthrough drugs (5.6 vs 8.8 years; P=.002). The BTD was more frequently granted to biomarker-directed indications (46% vs 34%; P=.025) supported by smaller trials (median, 149 vs 326 patients; P<.001) of single-arm (53% vs 27%; P<.001) and phase I or II design (61% vs 31%; P<.001). Breakthrough indications offered a greater OS (HR, 0.69 vs 0.74; P=.031) and tumor response (RR, 1.48 vs 1.32; P=.006; ORR, 52% vs 40%; P=.004), but not a PFS benefit (HR, 0.53 vs 0.58; P=.212). Median improvements in OS (4.8 vs 3.2 months; P=.002) and PFS (5.4 vs 3.3 months; P=.005) but not duration of response (8.7 vs 4.7 months; P=.245) were higher for breakthrough than for nonbreakthrough indications. The BTD was more frequently granted to first-in-class drugs (42% vs 28%; P=.001) and first-in-indication treatments (43% vs 29%; P<.001). There were no differences in treatment and epidemiologic characteristics between breakthrough and nonbreakthrough drugs. Breakthrough drugs were more expensive than nonbreakthrough drugs (mean monthly price, $38,971 vs $22,591; P=.0592). The BTD expedites patient access to effective and innovative, but also expensive, new cancer drugs and indications.

Risk Factors for Developing Low Estimated Glomerular Filtration Rate and Albuminuria in Living Kidney Donors

Rationale & ObjectiveChronic kidney disease is associated with significant morbidity and mortality in the general population, but little is known about the incidence and risk factors associated with developing low eGFR and moderate-severe albuminuria in living kidney donors following nephrectomy. Study DesignRetrospective, population-based cohort study. Setting& Participants: Kidney donors in Alberta, Canada. ExposureDonor nephrectomy between May 2001 and December 2017. Outcome2 estimated glomerular filtration rate (eGFR) measurements <45 mL/min/1.73 m2 or 2 measurements of moderate or severe albuminuria from one-year post-donation onwards that were at least 90 days apart. Analytical ApproachAssociations between potential risk factors and the primary outcome were assessed using Cox proportional hazard regression analyses. ResultsOver a median follow-up period of 8.6 years (interquartile range [IQR]: 4.7-12.6 years), 47 of 590 donors (8.0%) developed sustained low eGFR or moderate-severe albuminuria, with an incidence rate of 9.2 per 1000 person-years (95% confidence interval: 6.6-11.8). The median time for development of this outcome beyond the first year after nephrectomy was 2.9 years (IQR: 1.4-8.0 years). Within the first four years of follow-up, a 5 mL/min/1.73 m2 lower pre-donation eGFR increased the hazard of developing post-donation low eGFR or moderate-severe albuminuria by 26% (aHR, 1.26; 95% CI, 1.10-1.44). Furthermore, donors were at higher risk of developing low eGFR or albuminuria if they had evidence of pre-donation hypertension (aHR, 2.52; 95% CI, 1.28-4.96) or post-donation diabetes (aHR, 4.72; 95% CI, 1.54-14.50). LimitationsWe lacked data on certain donor characteristics that may impact long-term kidney function such as race, smoking history, and transplant-related characteristics. ConclusionsA proportion of kidney donors, at an incidence rate of 9.2 per 1,000 person-years, will develop low eGFR or albuminuria after donation. Donors with lower pre-donation eGFR, pre-donation hypertension, and post-donation diabetes are at increased risk of developing this outcome.

Clinical benefit, development, innovation, trials, epidemiology, and price for cancer drugs and indications with multiple special FDA designations.

This study analyzes the development, US Food and Drug Administration (FDA) approval, benefits, innovation, trials, epidemiology, and price of cancer drugs with multiple special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. In total, 355 FDA-approved cancer drug indications with 841 special designations were identified (2012-2022). Trial, epidemiology, and price data were collected from FDA labels, the Global Burden of Disease study, and Medicare and Medicaid. The association between efficacy outcomes and indications' number of special designations were compared in meta-analyses. Median development times were 7.3, 7.8, and 5.4 months (P = .027) for drugs with 0 to 1, 2 to 3, and 4 to 5 special designations, respectively. Multiple special designations were associated with higher biotechnological and clinical innovation. Median patient enrollment in trials were 615, 471, 398, 168, 104, and 120 (P < .001) for indications with 0 to 5 special designations. Drugs for rare diseases supported by open-label phase 1/2 trials of single-arm design were granted more special designations. Hazard ratios for overall survival (0.80 vs 0.73 vs 0.73 vs 0.69 vs 0.56 vs 0.52; P = .003) and progression-free survival (0.70 vs 0.61 vs 0.59 vs 0.44 vs 0.37 vs 0.67; P < .001) substantially declined while tumor response increased with more special designations. Mean monthly prices increased for drugs with 0 to 4 but not 5 special designations ($21 596 vs $14 753 vs $32 410 vs $41 240 vs $38 703 vs $19 184). Multiple special designations are associated with faster clinical development and greater benefits for patients with unmet needs but also with nonrobust trial evidence and a tendency toward higher drug prices.

Susceptibility of pro-Vitamin A biofortified maize genotypes to Sitophilus zeamais (Mots) in Ghana

Pro-Vitamin A Biofortified maize is one of the crops with the cheapest and most sustainable option for preventing Vitamin A deficiency in humans in Ghana. It is also a key energy component of feed for layer chicken, forming about 60-70% of the total feed. Sitophilus zeamais is one of the most serious primary internal feeding pests of maize and other grains in sub-Saharan Africa. It causes both quantitative and qualitative grain losses. Two no - choice laboratory experiments in 112 days cumulative feeding of S. zeamais and 60 days susceptibility of six pro-Vitamin A Biofortified Maize (PVABM) genotypes to the insect were conducted. The experimental designs were Completely Randomized Design in four replications. Percentage grain damage and weight loss were significantly lower (P&lt;0.05) in Aburokokoo than the other genotypes. Significantly more S. zeamais emerged from Accession GH2354 which also had significant (P&lt;0.05) higher percentage grain damage than other genotypes. In the 60-day susceptibility experiment, grain hardness had significant (P&lt;0.05) negative correlation with F1 progeny, index of susceptibility and protein content but positive significant correlation with median development period. Large number of S. zeamais F1 progeny, high susceptibility index, high protein, low total carbohydrate content, short median development time with low grain hardness value were observed on accession GH2354. Aburokokoo had significantly (P&lt;0.05) small number of F1 progeny, low index of susceptibility, low protein and high total carbohydrate, long development period and intermediate value of grain hardness. The ascending order of grain hardness among the maize genotypes was GH2354&lt;Obatanpa &lt;Aburokokoo&lt;Abontem&lt;Honampa&lt;Ahoodzin. There was no relationship between grain length, width and thickness and grain susceptibility. A cluster dendrogram obtained from the maize genotypes with regard to resistance parameters to S. zeamais showed that accession GH2354 and Obatanpa-QPM were susceptible, Ahoodzin, Honampa and Abontem were moderately resistant, with Aburokokoo resistant to the maize weevil infestation. Key words: Biofortified maize, stored produce, insect pest, Vitamin A deficiency, grain damage

Screening date cultivars for resistance against the saw-toothed grain beetle, Oryzaephilus surinamensis L. (Coleoptera: Silvanidae)

The saw-toothed grain beetle, Oryzaephilus surinamensis L. (Coleoptera: Silvanidae) is an important insect pest of stored dates. This study aims to assess the susceptibility of ten date cultivars to the infestation by O. surinamensis. The tested cultivars were Rushodia, Segae, Shaishee, Nabtat Ali, Sari, Khalas, Ruzeiz, Sukkari, Ajwa Al Madina, and Deglet Noor. The response of the beetle to the ten cultivars was studied using a ten-arm olfactometer choice test. The nature of injury incurred by the beetle on the cultivars and the number of individuals produced per gram of consumed dates were determined. Additionally, the F1 progeny produced on each cultivar and the median developmental time were identified and used to calculate the susceptibility index (SI) for each cultivar. The cultivars Rushodia, Segae, and Shaishee were highly susceptible to the infestation by the saw-toothed beetle according to their high SI of 12.05, 12.02, and 11.11, respectively. However, the cultivar Deglet Noor was resistant to the infestation showing the smallest SI of 4.15. The ten cultivars were classified as highly susceptible, susceptible, moderately resistant, and resistant to attack by the saw-toothed grain beetle. The degree of susceptibility or resistance of the tested cultivars to the beetle also coincided with the beetle's mode of damage as well as the total number of progeny developed upon feeding on each date cultivar. The findings of the study can be used in the management strategies of O. surinamensis in stored dates.

Incidence and risk factors for incisional hernia after open abdominal aortic aneurysm repair

IntroductionIncisional hernia (IH) is common after open abdominal aortic aneurysm (AAA) repair. Recent studies reported incidence rates higher than previously stated. The aim of this study was to quantify the IH incidence after open AAA surgery. The secondary outcome was to identify the risk factors associated with the development of an IH. MethodsRetrospective observational study of all consecutive patients who underwent an open repair of AAA, from January 2010 to June 2018, at our institution. Patients were free of abdominal wall hernias at the moment of inclusion in the study. Data were extracted from electronic records: baseline characteristics, surgical factors, and postoperative events. Computed tomography (CT) scans performed during follow-up were analyzed. ResultsA total of 157 patients were analysed. The IH incidence after open repair of AAA was 46.5% (73 patients). The median time for IH development was 24.43 months (IQR: 10.40–45.27), while the median follow-up time was 37.20 months (IQR: 20.53–64.12). The risk factors linked to IH were: active (HR: 4.535; 95% CI: 1.369–15.022) or previous smoking habit (HR: 4.652; 95% CI: 1.430–15.131), chronic kidney disease (HR: 2.007; 95% CI: 1.162–3.467) and previous abdominal surgery (HR: 1.653; 95% CI: 1.014–2.695). ConclusionThe incisional hernia after open abdominal aortic aneurysm repair affected a high proportion of the intervened patients. Previous abdominal surgery, chronic kidney disease, and smoking habit were independent factors for the development of an incisional hernia.

Association between Adverse Events and Prognosis in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab: A Multicenter Retrospective Study.

Simple SummaryThis study aimed to evaluate the correlation between adverse events (AEs) and overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (atezo/beva). Liver injuries were significantly correlated with shorter survival. In a logistic regression analysis, fatigue ≥ grade 2, liver injury ≥ grade 3, and modified albumin–bilirubin grade 2b were identified as independent factors for discontinuation due to AEs. We concluded that the development of liver injury was a negative factor for OS and that we should be vigilant in monitoring AE during atezo/beva treatments.This study aimed to evaluate the correlation between adverse events (AEs) and overall survival (OS) in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab (atezo/beva). This was a multicenter study in which 130 patients were enrolled. Hypertension and skin disorders had a significant correlation with longer survival (median survival time (MST): not reached vs. 14.3 months and not reached vs. 14.8 months, p = 0.001 and p = 0.047, respectively). In contrast, liver injuries were significantly correlated with shorter survival (MST: 14.7 months vs. not reached, p = 0.036), and the median development time was 21 days. In a logistic regression analysis, fatigue ≥ grade 2, liver injury ≥ grade 3, and modified albumin–bilirubin grade 2b were identified as independent factors for discontinuation due to AEs. The OS in the no discontinuation due to AE group was significantly longer than that in the discontinuation due to AEs group (MST not reached vs. 11.2 months, p = 0.001). We concluded that the development of liver injury was a negative factor for OS and that we should be vigilant in monitoring AE during atezo/beva treatments.

Clinicopathological Characteristics Predicting Further Recurrence and Survival Following Resection of In-Transit Melanoma Metastases

BackgroundIn-transit metastases (ITMs) affect approximately 4% of patients with cutaneous melanoma. This study sought to identify clinical and pathological characteristics that predict further recurrence and survival following resection of ITMs.Patients and MethodsPatients (n = 573) who underwent surgical resection of their first presentation of ITM following previous surgical treatment of an American Joint Committee on Cancer (AJCC) stage I–II melanoma between 1969 and 2017 were identified from an institutional database. Clinicopathological predictors of patterns of recurrence and survival following ITM resection were sought.ResultsThe median time of ITM development was 2.4 years after primary melanoma resection. ITMs were most frequently located on the lower limb (51.0%). The most common melanoma subtype associated with ITM development was nodular melanoma (44.1%). After surgical resection of a first ITM, 65.4% of patients experienced recurrent disease. Most recurrences were locoregional (44.7%), with distant metastasis occurring in 23.9% of patients. Lower limb ITMs were more frequently associated with subsequent ITMs [odds ratio (OR) 2.41, p = 0.0002], and the lowest risk of distant metastasis (p < 0.0001) compared with other primary sites. Primary melanomas and ITM on head and neck, as well as the presence of ulceration, were associated with worse survival.ConclusionsRecurrence after surgical resection of a first ITM was common. Patterns of recurrence differed according to anatomical site; further ITM recurrences were more likely for lower limb ITMs, which were also associated with longer distant recurrence-free survival. Distant metastasis was more common for ITM on the head and neck, with worse survival.

KARAKTERISTIK DIMENSI BERAS LOKAL PROPINSI SUMATERA UTARA DAN KAJIAN KERENTANANNYA TERHADAP Sitophilus oryzae (Coleoptera: Curculionidae)

The rice weevil, Sitophilus oryzae L. (Coleoptera: Curculionidae) is a major pest and causes damage to rice in storage. This study aimed to study the dimensional characters and determine the susceptibility of rice from germplasm paddy local in Dairi Regency, North Sumatra Province, against S. oryzae during storage. The types of local rice are Sibatubara, Siramos, Sijarum, Siangkat, Si100 hari, Sibosur, Sirukun, Sicantik, and Sigabe. Evaluation susceptibility of rice used the method without choice. The results showed that local rice in Dairi Regency, North Sumatra Province, was grouped into rice long–very long and medium-sized and had different levels of susceptibility against S. oryzae. Rice of Sibatubara, Sijarum, Siramos, and Sicantik was classified as susceptible, while rice Sijarum, Si100 hari, Sirukun, and Siangkat classified as moderate-susceptible. Rice Sigabe were classified moderate against S. oryzae during storage. The susceptibility of rice was influenced by the large number of F1 and short median development time. The damage of higher causes rice classified as susceptible and moderate-susceptible. Dimensions of rice are a source susceptibility rice against S. oryzae.

Rhyzopertha dominica Fabricius (Coleoptera: Bostrichidae): Growth and Developement on Six Different Varieties of Maize (Zea mays L.)

The research aimed to evaluate the Rhyzoperta dominica growth and development on six maize varieties. The No-choice method was adopted to evaluate the R. dominica life cylce from February to September 2018. Based on the result, the R. dominica growth and development were appropriate to be examined by the number of eggs, larvae, pupae, and F1 progenies and the percentage of weight loss rather than using the development time, the stage of development time, the median development time, the growth index of larvae, the potential of biotic, and susceptibility index. The development and the median development time were positively correlated with number of eggs, larvae, pupae, and F1 progenies. The R. dominica growth and development were faster on maize ‘ROK’ variety than other maize varieties. The highest number of eggs, larvae, pupae, and F1 progenies and the percentage of weight loss were detected on ‘ROK’ variety. On the other hand, the lowest growth and the longest development were observed on ‘Anoman’ variety. The variation of the R. dominica growth and development was due to the variation of the physical and biochemical characteristics of maize varieties.

Risk of second primary malignancies among patients with nasopharyngeal cancer in the United States: A population-based study.

e18056 Background: Nasopharyngeal cancers (NPCs) have an estimated incidence of 0.5 to 2 cases per 100,000 in the United States. Treatment of NPC with combination chemoradiotherapy has resulted in an 18% increase in 5-year overall survival in the US. It is essential to focus on the developments of second primary malignancies (SPMs) with improved survival. We aim to analyze the risk of SPMs among NPC survivors in this study. Methods: We estimated the incidence of SPMs among two-month survivors of NPC using the Surveillance, Epidemiology, and End Results (SEER)-18 registries between 2006 to 2018. The risk of SPMs was calculated using standardized incidence ratios (SIRs). Results: We included 7,560 patients with NPC in this study. The median age of diagnosis was 56 yrs (range 0 to 85 yrs). The median follow-up duration was 33 months (range 0 to 155 months). The median time for SPM development from initial diagnosis was 41 months (range 2 to 140 months). A total of 367 (5%) patients developed 398 SPMs at the last follow-up, of which 89% were solid organ malignancies, and 11% were hematologic neoplasms. The SPM risk for cohort was significantly elevated (SIR = 1.88, 95% confidence interval [CI] = 1.7 to 2.07) compared with the general population. The SIR was slightly higher in males (SIR = 1.90, 95% CI = 1.69 to 2.13) compared to females (SIR = 1.81, 95% CI = 1.48 to 2.20). The SIR according to age groups were as follows: age &lt; 65 years (SIR = 2.03, 95% CI = 1.79 to 2.29), age &gt; 65 years (SIR = 1.65, 95% CI = 1.38 to 1.94). Sites with highest risk included the nose, nasal cavity, and middle ear (SIR = 22.98, 95% CI = 9.92 to 45.27), nasopharynx (SIR = 17.28, 95% CI = 8.93 to 30.19), oral cavity and pharynx (SIR = 10.07, 95% CI = 7.81 to 12.79), esophagus (SIR = 3.97, 95% CI = 1.9 to 7.29), lung and bronchus (SIR = 3.53, 95% CI = 2.86 to 4.32), and liver (SIR = 3.05, 95% CI = 1.86 to 4.71) (Table). The risk of malignancies of the esophagus and lung were higher within the first year of diagnosis of NPC. The risk of malignancies of the nasopharynx, oral and nasal cavity, and liver was higher after one year of latency and remained statistically significantly elevated throughout the follow-up period. Conclusions: Our study reveals that patients with NPC are at higher risk of SPMs than the general population, most notably in the oral and nasal cavity, nasopharynx, esophagus, and lungs. These patients may benefit from cancer-specific screening during follow-up.[Table: see text]

Effect of clinical and histologic features on time to malignancy in 224 cases of oral leukoplakia treated by surgery

ObjectivesOur main purpose and research question were to analyze and quantify whether there were significant differences in the time to develop cancer among patients with oral leukoplakia (OL), comparing the more susceptible cases to those with the least susceptibility to malignancy.Materials and methodsWe followed 224 cases of OL after surgical or CO2 laser treatment for a mean time of 6.4 years. A Bayesian mixture cure model based on the Weibull distribution was used to model the relationship between our variables and cancer risk. In this model type, the population is considered a mixture of individuals who are susceptible or non-susceptible to developing cancer. The statistical model estimates the probability of cure (incidence model) and then infers the time to malignancy. The model was adjusted using the R-package INLA using default priors.ResultsHistology type (moderate or severe dysplasia) and tongue location showed hazard ratios (HR) of 3.19 (95% CI [1.05–8.59]) and 4.78 (95% CI [1.6–16.61]), respectively. Both variables increased the risk of malignant transformation, thus identifying a susceptible subpopulation with reduced time required to develop cancer, as with non-homogeneous leukoplakias. The median time for cancer development was 4 years and 5 months, with a minimum of 9 months after the diagnosis of OL and a maximum of 15 years and 2 months.ConclusionsSusceptible patients with non-homogeneous leukoplakia, dysplasia, or leukoplakia in the tongue develop cancer earlier than those with homogeneous OL and those without dysplasia.Clinical relevanceThe novel contribution of this research is that, until now, the time it took for oral leukoplakias to develop cancer based on whether they were homogeneous or non-homogeneous, and if they have or not epithelial dysplasia, had not been comparatively described and quantified. As a final result, the time to malignant transformation in non-homogeneous and dysplastic leukoplakias is significantly shorter.

Sub-classification of borderline changes into diffuse or focal and its impact on long-term renal transplant outcomes

BackgroundBorderline changes (BL) with stable renal function is a controversial category in renal transplantation, given its contradictory outcomes. The aim of this study was to compare the clinical outcomes of BL in patients with stable renal function classified as focal and diffuse according to the extent of tubulitis. MethodsPatients with no history of rejection with a surveillance graft biopsy at 3 or 12 months showing BL (n = 40), acute cellular rejection (n = 20) or normal biopsies (n = 20), were included in this study. Biopsies with BL were divided into diffuse BL (BLD) and focal BL (BLF) according to the extent of tubulitis. Because of the low frequency of subclinical ACR (ACRND) (n = 12), biopsies with ACR and graft dysfunction (ACRD) (n = 8) were also included. A composite outcome that included the presence of rejection in subsequent biopsies, graft loss, patient death, decrease in GFR ≥30% or presence of de novo DSA (dnDSA) during the first year of follow-up was evaluated. ResultsThe primary composite outcome occurred in five patients of each of the Normal, BLF and ACRND, eight patients with BLD and six patients with ACRD (p = 0.105). A trend towards more rejection episodes was observed in the ACRND and ACRD. Also, a shorter time to rejection in the BLD, ACRND and ACRD groups compared to BLF and Normal groups (p = 0.039) was observed. During the first year of follow-up, no patient in the ACRND group developed dnDSA, compared to 15–25% in the other groups. The median time of dnDSA development in the BLF group was 45 months, and in the BLD group was 10 months (p = 0.020). ConclusionClassifying BL biopsies with stable renal function into focal and diffuse categories, is a simple and feasible strategy that helps to differentiate between BLD with a phenotype that shows a trend towards worse outcomes, and BLF that behaves more similar to normal biopsies.

Stewart-Treves Syndrome in the Lower Limb after Arthroplasty- A Case Report.

Stewart-Treves Syndrome is a rare and fatal condition where cutaneous angiosarcoma—a high-grade malignant tumor originating in the vascular and lymphatic endothelium—classically develops in the upper limbs post-mastectomy, with radiation therapy and axillary lymph node dissection. There are very few reports of the syndrome developing in the lower limbs, without any preceding malignancy or radiation therapy. The median development time is 11 years. Angiosarcoma originates in the vascular and lymphatic vessels, and the diagnosis is based on histopathology and immunohistochemistry findings. We report an unusual presentation of the Stewart–Treves Syndrome in an elderly female involving the lower limb with preexisting chronic lymphedema, where the tumor developed 15 months after total knee arthroplasty.

Serum Potassium Disorders Predict Subsequent Kidney Injury: A Retrospective Observational Cohort Study of Hospitalized Patients

Introduction: Electrolyte disorders are common findings in kidney diseases and might represent a useful biomarker preceding kidney injury. Serum potassium [K⁺] imbalance is still poorly investigated for association with acute kidney injury (AKI), and most evidence came from intensive care units. The aim of our study was to comprehensively investigate this association in a large, unselected cohort of hospitalized patients. Methods: We performed a retrospective observational cohort study on the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 1, 2010 and December 31, 2014, with inclusion of adult patients with at least 2 [K⁺] and 3 serum creatinine measurements who did not develop AKI during an initial 10-day window. The outcome of interest was in-hospital AKI. The exposures of interest were [K⁺] fluctuations and hypo (HoK) and hyperkalemia (HerK). [K⁺] variability was evaluated using the coefficient of variation. Cox proportional hazards regression models were used to obtain hazard ratios and 95% confidence intervals of the association between the exposures of interest and development of AKI. Results: About 21,830 hospital admissions from 18,836 patients were included in our study. During a median follow-up of 5 (interquartile range [IQR] 7) days, AKI was observed in 555 hospital admissions (2.9%); median time for AKI development was 5 (IQR 7) days. Higher [K⁺] variability was independently associated with increased risk of AKI with a statistically significant linear trend across groups (p value = 0.012). A significantly higher incidence of AKI was documented in patients with HerK compared with normokalemia. No statistically significant difference was observed between HoK and HerK (p value = 0.92). Conclusion: [K⁺] abnormalities including fluctuations even within the normal range are associated with development of AKI.

Clinical and Subclinical Cardiotoxicity after Hematopoietic Stem Cell Transplantation

Introduction:Cardiovascular disease is the leading cause of death, in Uruguay it corresponds to 30%. To the known risk factors, the use of QT and RT are added. The improvement in response and overall survival of hematologic patients allow a longer time to develop cardiovascular complications. Cardiotoxicity has been extensively studied in the context of breast cancer and the use of anthracyclines; however, there are very few data on hematopoietic stem cell transplantation (HSCT).Objective:Assess subclinical myocardial damage by measuring biomarkers and echocardiography and identify patients at high risk of developing cardiotoxicity after HSCT.Methods:This is a prospective, single-center study between April 2017 and November 2020. Population: adult patients admitted in the British Hospital Transplant Unit, Montevideo Uruguay to receive either an autologous or allogeneic HSCT. Measurement: cardiac biomarkers (pro-BNP, Troponin T, Troponin I and CPK) at admission, D1, D14 and D30. Echocardiograms were performed on admission and at D30 by the same team of 3 echocardiographers with the same machine. It was repeated at D100 if some alteration was seen.Results:We included 158 transplants: 148 autologous and 10 allogeneic. The characteristics of the population and results are shown in Table 1. 126 raised some biomarker during the first 100 days (79.7%). Pro-BNP is the biomarker that most frequently rises after admission until day 100: 125/158 (79.1%). The kinetics of the biomarkers are shown in Figure 1. Regarding echocardiograms, there were no patients with a cardiotoxicity criterion defined by: a decrease in LVEF of more than 10% to a value less than 53%. Regarding myocardial deformability, there was a reduction in strain between the initial echocardiogram and D30 in 76 patients of 116 patients with both determinations (65.5%). A reduction of 15% or more was evidenced in 18 (11.3%). Of them, 13 (72.2%) had elevated biomarkers in the first 100 days. Of the patients who did not have strain changes, 78.6% had elevated biomarkers. No statistically significant relationship was found between strain reduction and the presence or absence of elevated biomarkers in the first 100 days.With a median follow-up of 23.3 months (0.89-48.62), 11 (7%) developed clinical cardiotoxicity: hypertension 6, arrhythmia 4, pulmonary embolism 1, sudden death 1. We have strain data of 6/11 patients, and there was no reduction of 15%. Of the 11, 90.9% raised some biomarker during the 100 days. Median development time of cardiotoxicity: 10.3 months (0.03-36.6). 133 had one year follow up so, the incidence of clinical cardiotoxicity at 1 year is 4.5%.There were no differences in elevated biomarkers in the first 100 days and use of Melphalan (p = 0.096) however, there was a difference with BEAM versus other plans, p = 0.035. The reduction in strain at day 30 was not influenced by Melphalan or BEAM.Patients with subclinical myocardial damage were older than those without it: mean age: 56.7 +/- 11.2 versus 44.1 +/- 13.1, p = 0.0001. There was no statistically significant difference between patients who had elevated biomarkers in the first 100 days versus those who did not in relation to a history of diabetes, hypertension, dyslipidemia, heart disease or previous use of anthracyclines. Either in patients with a 15% reduction in strain versus those without.This is one of the first studies worldwide that comprehensively evaluates cardiovascular function during HSCT. Given the small number of observed cardiac complications, greater follow-up of this subpopulation with elements of subclinical cardiotoxicity is required to determine if they are indeed predictive parameters of cardiovascular complications in the future in the transplant setting.Conclusions:Subclinical cardiotoxicity is common in transplantation: Pro-BNP is the biomarker that most frequently rises after admission until day 100: 79.1%. Strain reduction of 15% or more occurs in 11,3%. Subclinical myocardial damage parameters were not associated with type of conditioning, previous use of anthracyclines, comorbidities and clinical cardiotoxicity at 1 year. Clinical cardiotoxicity post HSCT is low, 4,5% at 1 year. We must do a longer-term follow-up in order to evaluate whether the combination of pro-BNP associated with strain reduction can be predictive factors of clinical cardiotoxicity. [Display omitted] DisclosuresOliver: Roche: Other: conference support and fees ; Abbvie: Other: conference support and fees .

Incidence and risk factors for incisional hernia after open abdominal aortic aneurysm repair

IntroductionIncisional hernia (IH) is common after open abdominal aortic aneurysm (AAA) repair. Recent studies reported incidence rates higher than previously stated. The aim of this study was to quantify the IH incidence after open AAA surgery. The secondary outcome was to identify the risk factors associated with the development of an IH. MethodsRetrospective observational study of all consecutive patients who underwent an open repair of AAA, from January 2010 to June 2018, at our institution. Patients were free of abdominal wall hernias at the moment of inclusion in the study. Data were extracted from electronic records: baseline characteristics, surgical factors, and postoperative events. Computed tomography (CT) scans performed during follow-up were analyzed. ResultsA total of 157 patients were analysed. The IH incidence after open repair of AAA was 46.5% (73 patients). The median time for IH development was 24.43 months (IQR: 10.40–45.27), while the median follow-up time was 37.20 months (IQR: 20.53–64.12). The risk factors linked to IH were: active (HR: 4.535; 95% CI: 1.369–15.022) or previous smoking habit (HR: 4.652; 95% CI: 1.430–15.131), chronic kidney disease (HR: 2.007; 95% CI: 1.162–3.467) and previous abdominal surgery (HR: 1.653; 95% CI: 1.014–2.695). ConclusionThe incisional hernia after open abdominal aortic aneurysm repair affected a high proportion of the intervened patients. Previous abdominal surgery, chronic kidney disease, and smoking habit were independent factors for the development of an incisional hernia.