Targeted therapies in small cell lung cancer: a review

Small cell lung cancer (SCLC) is an aggressive form of lung cancer that is characterized by a rapid doubling time, early onset of dissemination and high sensitivity to chemotherapy. Despite the potential for cure in patients with limited disease with concurrent chemoradiation and an initial good response to chemotherapy in extensive disease, there is a high chance of disease relapse with an overall poor median survival for both stages. With increasing translational research and a better understanding of the molecular basis of cancer, a number of molecular targets have been identified in various preclinical studies. This review summarizes potentially viable targets and new agents that have been developed and employed in recent, ongoing and future clinical trials to attempt to improve clinical outcomes in this disease.     

Validation of the MDS research criteria for prodromal Parkinson's disease: Longitudinal assessment in a REM sleep behavior disorder (RBD) cohort

Background : Recently, the International Parkinson and Movement Disorder Society introduced the prodromal criteria for PD. Objectives Our study aimed to examine diagnostic accuracy of the criteria as well as the independence of prodromal markers to predict conversion to PD or dementia with Lewy bodies. Methods : This prospective cohort study was performed on 121 individuals with rapid eye movement sleep behavior disorder who were followed annually for 1 to 12 years. Using data from a comprehensive panel of prodromal markers, likelihood ratio and post‐test probability of the criteria were calculated at baseline and during each follow‐up visit. Results : Forty‐eight (39.7%) individuals with rapid eye movement sleep behavior disorder converted to PD/dementia with Lewy bodies. The prodromal criteria had 81.3% sensitivity and 67.9% specificity for conversion to PD/dementia with Lewy bodies at 4‐year follow‐up. One year before conversion, sensitivity was 100%. The criteria predicted dementia with Lewy bodies with even higher accuracy than PD without dementia at onset. Those who met the threshold of prodromal criteria at baseline had significantly more rapid conversion into a neurodegenerative state (4.8 vs. 9.1 years; P < 0.001). Pair‐wise combinations of different prodromal markers showed that markers were independent of one another. Conclusion : The prodromal criteria are a promising tool for predicting incidence of PD/dementia with Lewy bodies and conversion time in a rapid eye movement sleep behavior disorder cohort, with high sensitivity and high specificity with long follow‐up. Prodromal markers influence the overall likelihood ratio independently, allowing them to be reliably multiplied. Defining additional markers with high likelihood ratio, further studies with longitudinal assessment and testing thresholds in different target populations will improve the criteria. © 2017 International Parkinson and Movement Disorder Society     

Navigating Latinas with breast screen abnormalities to diagnosis

BACKGROUND.

Breast cancer is the leading cause of cancer‐related deaths in Latinas, chiefly because of later diagnosis. The time from screening to diagnosis is critical to optimizing cancer care, yet the efficacy of navigation in reducing it is insufficiently documented. Here, the authors evaluate a culturally sensitive patient navigation program to reduce the time to diagnosis and increase the proportions of women diagnosed within 30 days and 60 days.

METHODS.

The authors analyzed 425 Latinas who had Breast Imaging Reporting and Data System (BI‐RADS) radiologic abnormalities categorized as BI‐RADS‐3, BI‐RADS‐4, or BI‐RADS‐5 from July 2008 to January 2011. There were 217 women in the navigated group and 208 women in the control group. Women were navigated by locally trained navigators or were not navigated (data for this group were abstracted from charts). The Kaplan‐Meier method, Cox proportional hazards regression, and logistic regression were used to determine differences between groups.

RESULTS.

The time to diagnosis was shorter in the navigated group (mean, 32.5 days vs 44.6 days in the control group; hazard ratio, 1.32; P = .007). Stratified analysis revealed that navigation significantly shortened the time to diagnosis among women who had BI‐RADS‐3 radiologic abnormalities (mean, 21.3 days vs 63.0 days; hazard ratio, 2.42; P < .001) but not among those who had BI‐RADS‐4 or BI‐RADS‐5 radiologic abnormalities (mean, 37.6 days vs 36.9 days; hazard ratio, 0.98; P = .989). Timely diagnosis occurred more frequently among navigated Latinas (within 30 days: 67.3% vs 57.7%; P = .045; within 60 days: 86.2% vs 78.4%; P = .023). This was driven by the BI‐RADS‐3 strata (within 30 days: 83.6% vs 50%; P < .001; within 60 days: 94.5% vs 67.2%; P < .001). A lack of missed appointments was associated with timely diagnosis.

CONCLUSIONS.

Patient‐centered navigation to assist Latina women with abnormal screening mammograms appeared to reduced the time to diagnosis and increase rates of timely diagnosis overall. However, in stratified analyses, only navigated Latinas with an initial BI‐RADS‐3 screen benefited, probably because of a reduction in missed diagnostic appointments. Cancer 2013. © 2012 American Cancer Society.     

Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways

MAP4K4 is a serine/threonine kinase of the STE20 family involved in the regulation of actin cytoskeleton dynamics and cell motility. It has been proposed as a target of angiogenesis and inhibitors show potential in cardioprotection. MAP4K4 also mediates cell invasion in vitro, is overexpressed in various types of cancer, and is associated with poor patient prognosis. Recently, MAP4K4 has been shown to be overexpressed in pancreatic cancer, but its role in tumour initiation, progression, and metastasis is unknown. Here, using the Kras^G12D Trp53^R172H Pdx1-Cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC), we show that deletion of Map4k4 drives tumour initiation and progression. Moreover, we report that the acceleration of tumour onset is also associated with an overactivation of ERK and AKT, two major downstream effectors of KRAS, in vitro and in vivo. In contrast to the accelerated tumour onset caused by loss of MAP4K4, we observed a reduction in metastatic burden with both the KPC model and in an intraperitoneal transplant assay indicating a major role of MAP4K4 in metastatic seeding. In summary, our study sheds light on the dichotomous role of MAP4K4 in the initiation of PDAC onset, progression, and metastatic dissemination. It also identifies MAP4K4 as a possible druggable target against pancreatic cancer spread, but with the caveat that targeting MAP4K4 might accelerate early tumorigenesis. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

T1-mapping for assessment of ischemia-induced acute kidney injury and prediction of chronic kidney disease in mice

Objectives

To investigate whether T1-mapping allows assessment of acute kidney injury (AKI) and prediction of chronic kidney disease (CKD) in mice.

Methods

AKI was induced in C57Bl/6N mice by clamping of the right renal pedicle for 35 min (moderate AKI, n?=?26) or 45 min (severe AKI, n?=?23). Sham animals served as controls (n?=?9). Renal histology was assessed in the acute (day 1?+?day 7; d1?+?d7) and chronic phase (d28) after AKI. Furthermore, longitudinal MRI-examinations (prior to until d28 after surgery) were performed using a 7-Tesla magnet. T1-maps were calculated from a fat-saturated echoplanar inversion recovery sequence, and mean and relative T1-relaxation times were determined.

Results

Renal histology showed severe tubular injury at d1?+?d7 in both AKI groups, whereas, at d28, only animals with prolonged 45-min ischemia showed persistent signs of AKI. Following both AKI severities T1-values significantly increased and peaked at d7. T1-times in the contralateral kidney without AKI remained stable. At d7 relative T1-values in the outer stripe of the outer medulla were significantly higher after severe than after moderate AKI (138?±?2 % vs. 121?±?3 %, p?=?0.001). T1-elevation persisted until d28 only after severe AKI. Already at d7 T1 in the outer stripe of the outer medulla correlated with kidney volume loss indicating CKD (r?=?0.83).

Conclusion

T1-mapping non-invasively detects AKI severity in mice and predicts further outcome.

Key Points

? Renal T1-relaxation times are increased after ischemia-induced acute kidney injury. ? Renal T1-values correlate with subsequent kidney volume loss. ? T1-mapping detects the severity of acute kidney injury and predicts further outcome.     

Influence of respiratory rate and end-expiratory pressure variation on cyclic alveolar recruitment in an experimental lung injury model

Introduction  

Cyclic alveolar recruitment/derecruitment (R/D) is an important mechanism of ventilator-associated lung injury. In experimental models this process can be measured with high temporal resolution by detection of respiratory-dependent oscillations of the paO₂ (ΔpaO₂). A previous study showed that end-expiratory collapse can be prevented by an increased respiratory rate in saline-lavaged rabbits. The current study compares the effects of increased positive end-expiratory pressure (PEEP) versus an individually titrated respiratory rate (RR_ind) on intra-tidal amplitude of Δ paO₂ and on average paO₂ in saline-lavaged pigs.     

Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial

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