Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. METHODS: From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. RESULTS: The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. CONCLUSIONS: Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is safe and improves outcome. Dose escalation in 12.5 mg steps may be recommended for properly educated patients.

Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6.

An important barrier for axon regeneration and recovery after traumatic spinal cord injury (SCI) is attributed to the scar that is formed at the lesion site. Here, we investigated the effect of mouse mast cell protease (mMCP) 6, a mast cell (MC)-specific tryptase, on scarring and functional recovery after a spinal cord hemisection injury. Functional recovery was significantly impaired in both MC-deficient and mMCP6-knockout (mMCP6(-/-)) mice after SCI compared with wild-type control mice. This decrease in locomotor performance was associated with an increased lesion size and excessive scarring at the injury site. Axon growth-inhibitory chondroitin sulfate proteoglycans and the extracellular matrix components fibronectin, laminin, and collagen IV were significantly up-regulated in MC-deficient and mMCP6(-/-) mice, with an increase in scar volume between 23 and 32%. A degradation assay revealed that mMCP6 directly cleaves fibronectin and collagen IV in vitro In addition, gene expression levels of the scar components fibronectin, aggrecan, and collagen IV were increased up to 6.8-fold in mMCP6(-/-) mice in the subacute phase after injury. These data indicate that endogenous mMCP6 has scar-suppressing properties after SCI via indirect cleavage of axon growth-inhibitory scar components and alteration of the gene expression profile of these factors.-Vangansewinkel, T., Geurts, N., Quanten, K., Nelissen, S., Lemmens, S., Geboes, L., Dooley, D., Vidal, P. M., Pejler, G., Hendrix, S. Mast cells promote scar remodeling and functional recovery after spinal cord injury via mouse mast cell protease 6.

Continuous intra-arterial nimodipine infusion in patients with severe refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a feasibility study and outcome results.

BACKGROUND: Severe cerebral vasospasm is a major cause of death and disability in patients with aneurysmal subarachnoid hemorrhage. No causative treatment is yet available and hypertensive hypervolemic therapy (HHT) is often insufficient to avoid delayed cerebral ischemia and neurological deficits. We compared patients receiving continuous intra-arterial infusion of the calcium-antagonist nimodipine with a historical group treated with HHT and oral nimodipine alone. METHODS: Between 0.5 and 1.2 mg/h of nimodipine were continuously administered by intra-arterial infusion via microcatheters either into the internal carotid or vertebral artery or both, depending on the areas of vasospasm. The effect was controlled via multimodal neuromonitoring and transcranial Doppler sonography. Outcome was determined by means of the Glasgow Outcome Scale at discharge and 6 months after the hemorrhage and compared to a historical control group. RESULTS: Twenty-one patients received 28 intra-arterial nimodipine infusions. Six months after discharge, the occurrence of cerebral infarctions was significantly lower (42.6 %) in the nimodipine group than in the control group (75.0 %). This result was reflected by a significantly higher proportion (76.0 %) of patients with good outcome in the nimodipine-treated group, when compared to 10.0 % good outcome in the control group. Median GOS was 4 in the nimodipine group and 2 in the control group (p = 0.001). CONCLUSIONS: Continuous intra-arterial nimodipine infusion is an effective treatment for patients with severe cerebral vasospasm who fail to respond to HHT and oral nimodipine alone. Key to the effective administration of continuous intra-arterial nimodipine is multimodal neuromonitoring and the individual adaptation of dosage and time of infusion for each patient.

Technological advances in perioperative monitoring: Current concepts and clinical perspectives.

Minimal mandatory monitoring in the perioperative period recommended by Association of Anesthetists of Great Britain and Ireland and American Society of Anesthesiologists are universally acknowledged and has become an integral part of the anesthesia practice. The technologies in perioperative monitoring have advanced, and the availability and clinical applications have multiplied exponentially. Newer monitoring techniques include depth of anesthesia monitoring, goal-directed fluid therapy, transesophageal echocardiography, advanced neurological monitoring, improved alarm system and technological advancement in objective pain assessment. Various factors that need to be considered with the use of improved monitoring techniques are their validation data, patient outcome, safety profile, cost-effectiveness, awareness of the possible adverse events, knowledge of technical principle and ability of the convenient routine handling. In this review, we will discuss the new monitoring techniques in anesthesia, their advantages, deficiencies, limitations, their comparison to the conventional methods and their effect on patient outcome, if any.

The Evolution of Anterior Transpetrosal Approach for the Treatment of Petroclival Meningiomas: A Single-Center 128-Case Experience.

BACKGROUND: The profound understanding of anterior transpetrosal approach (ATPA) is increasingly used to treat petroclival meningiomas (PCMs). We introduce the evolution of ATPA and the outcomes of PCMs treatment. METHODS: Between January 2013 and December 2019, 128 patients with PCMs underwent surgery. According to tumor extension, we classified the 128 patients into 5 types (I-V), introduced key technologies of ATPA into different types for the first time, and achieved a supreme surgical technology. Clinical data, radiological findings, surgical treatments, complications, and patient outcomes were retrospectively analyzed. RESULTS: A total of 22 (17.2%), 44 (34.4%), 25 (19.5%), 29 (22.7%), and 8 (6.3%) patients had type I, II, III, IV, and V disease, respectively. Tumors were gross totally removed (Simpson I and II) in 100 patients (78.1%), subtotally removed (Simpson III) in 20 patients (15.6%), and partially removed (Simpson IV) in 8 patients (6.3%). The progression or recurrence rates were 5% (5/100) for gross totally removed, 22.3% (6/20) for subtotally removed, and 62.5% (5/8; 1 died) for partially removed. According to the Karnofsky Performance Scale and Glasgow Outcome Scale, 108 patients had good recovery (84.4%, 108/128) and 115 were independent (89.8%, 115/128) at the end of follow-up. CONCLUSIONS: Because some key technologies were used in ATPA, the application of ATPA was extended, and greater tumor resection and nerve function protection could be achieved in the treatment of PCMs.

Improved outcome in early induction deaths in patients with acute promyelocytic leukemia after therapeutic and supportive interventions: a follow up study of seven-years' experience at a tertiary care center.

INTRODUCTION AND OBJECTIVES: Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia with characteristic morphology and clinical features. Early mortality rate of 30% has been reported in developed countries despite prompt initiation of treatment. We have previously reported an early induction mortality of approximately 62% in our cohort. Based on this mortality rate, we made changes in our treatment protocol. The objective of this follow-up study was to report the early induction mortality and overall survival of patients with APL after incorporating changes in chemotherapy and supportive care regimen. SUBJECTS AND METHODS: This was a prospective descriptive study conducted at Aga Khan University Karachi, Pakistan from October 2012 till October 2019. Data of patients included clinical features, morphological findings, cytogenetic and PCR studies, cytotoxic protocols, overall outcome and causes of early induction mortality. The changes in treatment protocol included prophylactic infusion of fresh frozen plasma, dexamethasone therapy and other changes in supportive care regimen. Results were recorded as frequencies and percentages. Statistical Package for the Social Sciences version 19.0 (SPSS Inc., Chicago, IL, USA) was used to analyze patient's data. Survival curves were calculated using the Kaplan-Meier method. RESULTS: During the study period, total of 447 patients presented with acute myeloid leukemia at our institution out of which 40 patients were diagnosed with acute promyelocytic leukemia (9%). Out of these 40 patients 24 were males and 16 were females. The median age was 37 years. Twenty-five patients were in low risk group whereas 15 were high-risk. Differentiation syndrome was seen in 14 patients. As a part of induction chemotherapy, 13 patients received only ATRA because they were not eligible for chemotherapy and 17 patients received a combination of ATRA and anthracycline. Among the remaining patients, four received ATRA, arsenic and anthracycline while two received ATRA and arsenic only. Four patients did not receive any treatment because of rapid deterioration of clinical condition and death. The overall survival was 65% and early induction mortality was 30%. CONCLUSION: The early induction mortality decreased to 30% from 62% in this study and the overall survival was 65%. With the introduction of prophylactic infusion of fresh frozen plasma, dexamethasone and appropriate supportive treatment during the induction chemotherapy, we were able to improve the induction mortality and overall survival of patients.

Cycle day 2 insulin-like growth factor-1 serum levels as a prognostic tool to predict controlled ovarian hyperstimulation outcomes in poor responders.

OBJECTIVE: To study whether patients exhibiting poor ovarian response have abnormal levels of serum insulin-like growth factor (IGF)-1 on cycle day 2 when compared with age-matched normal and high responders. DESIGN: Retrospective cohort. SETTING: University-based practice. PATIENT(S): All women between the ages of 21 and 42 years who underwent in vitro fertilization treatment cycle without estrogen pretreatment at our institution between 2013 and 2015. INTERVENTION(S): Patients were separated into three groups: poor responders (≤4 oocytes retrieved/cycle cancellation), normal responders (8-12 oocytes), and high responders (≥18 oocytes). Subanalysis focused on the next cycle for poor responders adjacent to the nonpretreated index cycle, in which estrogen pretreatment was implemented. MAIN OUTCOME MEASURE(S): Serum cycle day 2: IGF-1, insulin-like growth factor-binding protein (IGFBP)-3 levels, and IGF-1:IGFBP3 ratio, number of eggs retrieved, number of two pronuclei embryos, cumulative pregnancy rate, and live birth. RESULT(S): A total of 184 patients met the inclusion criteria. The poor responder group exhibited a more than twofold increase in the cycle day IGF-1 serum levels when compared with normal responders and a threefold increase when compared with the high responders. Cycle day 2 IGF-1 level >72 ng/mL in poor responders had 70% sensitivity and 78% specificity for a negative controlled ovarian hyperstimulation cycle outcome with an area under the curve of 0.83. Luteal estrogen pretreatment in the poor responder group was associated with a significant reduction in IGF-1 levels. Significantly, more retrieved and mature oocytes, as well as two pronuclei embryos, were achieved in the pretreated poor responder group when compared with the yield from their adjacent nonpretreated index cycles. Furthermore, cumulative rates were higher for intrauterine pregnancies, and lower for negative pregnancy outcome. CONCLUSION(S): Patients who respond poorly to controlled ovarian stimulation, despite normal cycle day 2 follicle-stimulating hormone levels, have significantly higher serum cycle day 2 IGF-1 levels when compared with age-matched normal and high responders. Cycle day 2 IGF-1 level >72 ng/mL in poor responders was predictive of a negative cycle outcome. Luteal estrogen pretreatment in the poor responder group was associated with a significant reduction in IGF-1 levels, improved response to stimulation, and higher cumulative rates for intrauterine pregnancies, and lower for negative pregnancy outcome.

Outcomes of women with gestational diabetes mellitus in Sweden.

OBJECTIVE: The number of women with gestational diabetes mellitus (GDM) during pregnancy is increasing around the world and in our region in the south Sweden 1.2% of all pregnant women received the GDM diagnosis in the 90s and now it is about 2.2%. The aim of this study was to compare women with GDM 1995-99 against women with GDM 2012-13 regarding eventual differences in demographics and pregnancy outcome. STUDY DESIGN: In our region in Sweden, all pregnant women are tested for GDM with a 2-h 75g oral glucose tolerance test and the 2-h cut off value for GDM is ≥10.0mmol/l in capillary plasma glucose. 1995-99 there were 131 women with GDM and their medical journals were compared against the 210 women with GDM during 2012-13. The same screening and diagnostic method was uses during the whole time period. RESULTS: In the 2012-13 GDM pregnancies there were more non-Scandinavian women, more women with insulin treatment during pregnancy and a higher frequency of cesarean deliveries compared to 1995. First weight of the women during GDM pregnancy 2012-13 was significantly higher than the weight of women with GDM 1995-99, 71kg (43-138; n=201) and 65kg (43-133; n=125) (p=0.008) respectively. However, there was no significant difference in weight of the mother at delivery. Birth weight of the child in GDM pregnancies 1995-99 was 3722.4g±578.2 (n=109; p=0.009), and in GDM pregnancies 2012-13 3555.6g±465.8 (n=162). CONCLUSION: Even though women with GDM 2012-13 weigh more when they start the pregnancy there is no difference in weight at delivery compared to women with GDM 1995-99. This is also reflected on the newborn, that 2012-13 had significantly lower birth weight but with the same gestational length as 1995-1999. We believe that this is due to a more active and intense treatment of women with GDM during pregnancy together with higher frequency of cesarean delivery. Prevention of large infants is crucial to avoid complications during delivery.

Can we Improve Outcome in High Risk Surgery?

Despite the small number of high-risk surgical patients in comparison to all surgical patients, they account for the largest proportion of overall perioperative mortality. Goal directed hemodynamic support may result in a lower incidence of complications and reduced length of hospital stay in these patients. Beyond the standard monitoring of circulation, such as blood pressure and heart rate, further parameters and procedures such as pulse pressure/stroke volume variation-, stroke volume/cardiac index-, and central venous oxygen saturation-guided resuscitation may improve the outcome of high-risk surgical patients. The aim of this review is to focus on the results of animal and clinical studies investigating the usefulness of these indices in the context of goal-directed perioperative support.