Microanatomical Nerve Architecture of 6 Mammalian Species: Is Trans-Species Translational Anatomic Extrapolation Valid?

Background and Objectives Various animal models have historically been used to study iatrogenic nerve injury during performance of conduction nerve blocks. Our aims were to compare the microstructures of nerves in commonly used species to those of humans and to explore the validity of the extrapolating these findings to humans. Methods High-resolution, light-microscopic images were obtained from cross sections of sciatic nerves at their bifurcation from fresh rat, rabbit, pig, sheep, dog, and human cadavers. Various microanatomical characteristics were measured and compared between the species. P

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Drug shortages in a pediatric stem cell transplantation ward: Challenges and implications. A 5-year bilan

Journal of Oncology Pharmacy Practice, Ahead of Print.


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Oral bisphosphonate use and lung cancer incidence among postmenopausal women

Abstract

Background

Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI.

Patients and methods

The association between oral bisphosphonate use and lung cancer risk was examined in 151,432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates.

Results

After a mean follow-up of 13.3 years, 2,511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio (HR), 0.91; 95% confidence intervals (CI), 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (HR = 0.57, 95% CI, 0.39-0.84; P < 0.01).

Conclusion

In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.

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Oral bisphosphonate use and lung cancer incidence among postmenopausal women

Abstract

Background

Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI.

Patients and methods

The association between oral bisphosphonate use and lung cancer risk was examined in 151,432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates.

Results

After a mean follow-up of 13.3 years, 2,511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio (HR), 0.91; 95% confidence intervals (CI), 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (HR = 0.57, 95% CI, 0.39-0.84; P < 0.01).

Conclusion

In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.

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Cancers, Vol. 10, Pages 97: Nanopulse Stimulation (NPS) Induces Tumor Ablation and Immunity in Orthotopic 4T1 Mouse Breast Cancer: A Review

Cancers, Vol. 10, Pages 97: Nanopulse Stimulation (NPS) Induces Tumor Ablation and Immunity in Orthotopic 4T1 Mouse Breast Cancer: A Review

Cancers doi: 10.3390/cancers10040097

Authors: Stephen Beebe Brittany Lassiter Siqi Guo

Nanopulse Stimulation (NPS) eliminates mouse and rat tumor types in several different animal models. NPS induces protective, vaccine-like effects after ablation of orthotopic rat N1-S1 hepatocellular carcinoma. Here we review some general concepts of NPS in the context of studies with mouse metastatic 4T1 mammary cancer showing that the postablation, vaccine-like effect is initiated by dynamic, multilayered immune mechanisms. NPS eliminates primary 4T1 tumors by inducing immunogenic, caspase-independent programmed cell death (PCD). With lower electric fields, like those peripheral to the primary treatment zone, NPS can activate dendritic cells (DCs). The activation of DCs by dead/dying cells leads to increases in memory effector and central memory T-lymphocytes in the blood and spleen. NPS also eliminates immunosuppressive cells in the tumor microenvironment and blood. Finally, NPS treatment of 4T1 breast cancer exhibits an abscopal effect and largely prevents spontaneous metastases to distant organs. NPS with fast rise–fall times and pulse durations near the plasma membrane charging time constant, which exhibits transient, high-frequency components (1/time = Hz), induce responses from mitochondria, endoplasmic reticulum, and nucleus. Such effects may be responsible for release of danger-associated molecular patterns, including ATP, calreticulin, and high mobility group box 1 (HMBG1) from 4T1-Luc cells to induce immunogenic cell death (ICD). This likely leads to immunity and the vaccine-like response. In this way, NPS acts as a unique onco-immunotherapy providing distinct therapeutic advantages showing possible clinical utility for breast cancers as well as for other malignancies.

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The impact of palliative care training for oncologists and integrative palliative service in a public-funded hospital cluster—a retrospective cohort study

Abstract

Purpose

Oncological care of advanced cancer patients was provided by multiple departments in Hong Kong. One of these departments, the clinical oncology department (COD), introduced systematic palliative care training for its oncologists since 2002. The COD was recognized as a European Society for Medical Oncology (ESMO) Designated Centre of Integrated Oncology and Palliative Care since 2009. This retrospective cohort study aims to review the impact of integrative training and service on palliative care coverage and outcome.

Methods

Clinical information, palliative service provision, and end-of-life outcomes of patients who passed away from lung, colorectal, liver, stomach, or breast cancer in the Hong Kong West public hospital network during July 2015 to December 2015 were collected.

Results

A total of 307 patients were analyzed. Around half (49.2%) were attended primarily by COD, and 68.9% received palliative service. There are significantly fewer patients referred to palliative care from other departments (p < 0.001), with only 19.9% of this patient group receiving palliative referral. COD patients had longer palliative coverage before death (median 65 days versus 24 days, p < 0.001), higher chance of receiving end-of-life care at hospice units (36.4 versus 21.2%, p = 0.003), lower ICU admission (0.66 versus 5.1%, p = 0.02), and higher percentage of receiving strong opioid in the last 30 days of life (51.0 versus 28.9%, p < 0.001) compared to other departments. In multivariable analysis, COD being the primary care team (odds ratio 12.2, p < 0.001) was associated with higher palliative care coverage.

Conclusion

The study results suggested that systematic palliative care training of oncologists and integrative palliative service model was associated with higher palliative service coverage and improved palliative care outcomes.

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Patient-clinician communication among patients with stage I lung cancer

Abstract

Purpose

Limited data exist about patient-centered communication (PCC) and patient-centered outcomes among patients who undergo surgery or stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC). We aimed to examine the relationship between PCC and decision-making processes among NSCLC patients, using baseline data from a prospective, multicenter study.

Methods

Patients with stage 1 NSCLC completed a survey prior to treatment initiation. The survey assessed sociodemographic characteristics, treatment decision variables, and patient psychosocial outcomes: health-related quality of life (HRQOL), treatment self-efficacy, decisional conflict, and PCC.

Results

Fifty-two percent (n = 85) of 165 individuals planned to receive SBRT. There were no baseline differences detected on patient psychosocial outcomes between those who planned to receive SBRT or surgery. All participants reported high HRQOL (M = 72.5, SD = 21.3) out of 100, where higher scores indicate better functioning; high self-efficacy (M = 1.5, SD = 0.5) out of 6, where lower numbers indicate higher self-efficacy; minimal decisional conflict (M = 15.2, SD = 12.7) out of 100, where higher scores indicate higher decisional conflict; and high levels of patient-centered communication (M = 2.4, SD = 0.8) out of 7 where higher scores indicate worse communication. Linear regression analyses adjusting for sociodemographic and clinical variables showed that higher quality PCC was associated with higher self-efficacy (β = 0.17, p = 0.03) and lower decisional conflict (β = 0.42, p < 0.001).

Conclusions

Higher quality PCC was associated with higher self-efficacy and lower decisional conflict. Self-efficacy and decisional conflict may influence subsequent health outcomes. Therefore, our findings may inform future research and clinical programs that focus on communication strategies to improve these outcomes.

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Demographic, clinical, lifestyle-related, and social-cognitive correlates of physical activity in head and neck cancer survivors

Abstract

Purpose

The purpose of the study is to identify demographic, clinical, lifestyle-related, and social-cognitive correlates of physical activity (PA) intention and behavior in head and neck cancer (HNC) survivors using the theory of planned behavior (TPB).

Methods

Data from two cross-sectional studies on correlates of PA in HNC survivors were pooled. Both studies used self-reports to assess PA and social-cognitive correlates. Potential correlates were collected via self-report or medical records. Univariable and multivariable multilevel linear mixed-effects models were built to identify correlates of PA intention and PA behavior (Z scores). Structural equation model analyses were conducted to study the full TPB model in one analysis, taking into account relevant covariates.

Results

In total, 416 HNC survivors were surveyed. Their mean (SD) age was 66.6 (9.4) years; 64% were men, and 78% were diagnosed with laryngeal cancer. The structural equation model showed that PA intention was significantly higher in HNC survivors with a history of exercising, who had a more positive attitude, subjective norm, and perceived behavioral control. Patients with higher PA intention, higher PBC, a lower age, and without unintentional weight loss or comorbidities had higher PA behavior. The model explained 22.9% of the variance in PA intention and 16.1% of the variance in PA behavior.

Conclusions

Despite significant pathways of the TPB model, the large proportion variance in PA intention and behavior remaining unexplained suggests the need for better PA behavior (change) models to guide the development of PA promotion programs, particularly for the elderly. Such programs should be tailored to comorbidities and nutritional status.

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Extended nursing for the recovery of urinary functions and quality of life after robot-assisted laparoscopic radical prostatectomy: a randomized controlled trial

Abstract

Purpose

The purpose of this work is to explore the effects of continuing nursing care intervention on postoperative urinary control and quality of life among patients with prostate cancer.

Methods

This was a single-center, parallel, and randomized controlled trial that was carried out at the Department of Urology, the First Affiliated Hospital of Anhui Medical University, China. The participants underwent robot-assisted laparoscopic radical prostatectomy (RARP) between October 2014 and April 2016. The patients were randomized to the experimental and control groups (n=37/group). Patients in the control group received routine nursing care, while patients in the experimental group received continuing nursing care. During the 6-month follow-up, each patient was invited at the hospital discharge and at 1, 3, and 6 months to fill the ICI-Q-SF and SF-36 questionnaires.

Results

The scores of urinary incontinence were improved in the intervention group compared with controls at 3 and 6 months after discharge (both P < 0.01). The scores of quality of life in the experimental group were significantly higher than control group at 1, 3, and 6 months (all P < 0.01). Adverse events were mild or moderate in intensity and were resolved in all patients. All adverse events were related to RARP.

Conclusions

Continuing nursing care intervention had significant beneficial effects on urinary functions and quality of life in patients with prostate cancer after RARP. This approach warrants to be promoted in the clinical setting.

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Breast cancer survivors: return to work and wage loss in selected hospitals in Malaysia

Abstract

Purpose

This study aimed, firstly, to assess the determinants of return to work (RTW), secondly, to explore the amount of annual wage loss, and finally, to discover the determinants of wage loss among breast cancer (BC) survivors.

Methods

A cross-sectional study design was used in this research. The data was collected via interview using a validated questionnaire. Logistic regression models were developed to discover the significant determinants of RTW and of wage loss among BC survivors.

Results

A total of 256 BC survivors were included in this study. The analysis showed that there was a 21% loss of or reduction in mean income within 1 year after diagnosis. The significant predictors of RTW are being a government employee, having reduced wages or wage loss, and if the case had been diagnosed 1 year or more ago. Being a private sector employee and having a late stage of cancer was a barrier to RTW. The main risk factors for reduced wages or wage loss were belonging to the age group of 40–59 years, being of Chinese or Indian ethnicity, having low educational status, and not returning to work. However, belonging to the higher monthly income group (earning > RM 2000) is a protective factor against the risk of reduced wages or wage loss.

Conclusions

Non-RTW and wage loss after diagnosis of BC may result in the survivors experiencing a significant financial burden. Assessment of these patients is becoming more crucial because more women participate in the workforce in Malaysia nowadays and because BC is managed using multiple treatment modalities with their consequences could lead to long absences from work.

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Evaluation of quality of life in caregivers who are providing home care to cancer patients

Abstract

Purpose

The author aimed to evaluate the quality of life and the factors affecting the caregivers of cancer patients receiving home care.

Methods

This cross-sectional descriptive study was performed in 48 cancer patients who were served from home care unit and 48 caregivers between 01 and 28 February 2014. Patients' functional status was evaluated with Katz Index for Activities of Daily Living and the Lawton Scale for Instrumental Activities of Daily Living. The levels of quality of life of caregivers of patients with cancer were determined with Caregiver Quality of Life Index-Cancer (CQOLC).

Results

The mean age of forty-eight patients was 69.79 ± 16.09 years; 62.5% of them were female. The mean duration of home care was 5.99 ± 5.26 years; 25% of patients were fully dependent on the bed. 83.3% of caregivers were female, mean age of caregivers was 50.75 ± 14.89 years, and 77.1% of them were family members. The mean CQOLC score was 74.43 ± 24.45. The highest score was detected in the financial distress and the lowest score was detected in the positive adaptation. The quality of life is increasing as the length of care is reduced and income status increased.

Conclusion

The quality of life of caregivers is very low. Each characteristic of the caregiver will affect the care he/she gives. From this point of view, it is important to consider the characteristics of caregivers in improving the care given to cancer patients. In this respect, there is a need to support caregivers both materially and spiritually.

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The impact of remission status on patients’ experiences with acute myeloid leukemia (AML): an exploratory analysis of longitudinal patient-reported outcomes data

Abstract

Purpose

Shared decision-making in acute myeloid leukemia (AML) requires understanding patients' longitudinal experiences of illness, but little is known about the impact of remission status on patient-reported outcomes (PROs). We aimed to explore the association between remission status and PROs 6–12 months following induction chemotherapy.

Methods

Forty-two patients completed three validated instruments characterizing symptom burden (Patient Care Monitor v2.0), distress (NCCN Distress Thermometer), and QOL (FACT-Leu), as part of a longitudinal observational study. We used regression models to explore the relationship between remission status and PROs, and explore differences by initial disease type (de novo versus secondary/relapsed AML).

Results

Those with secondary or relapsed AML at study onset had marked impairments in all measures compared to de novo AML patients. After 6 months, their mean distress score was 4.8 (> 4.0 warrants intervention), they reported a mean of 14.1 moderate/severe symptoms and had a mean QOL score of 113.6, compared to 1.0, 1.7, and 155.2, respectively, for those with de novo AML (p < .0001). Similarly, patients in relapse had a mean distress score of 5.3, a mean of 12.8 moderate/severe symptoms, and a mean QOL score of 113.4, compared to 1.8, 5.7, and 143.8, respectively, among those in remission (p < .005). These patterns persisted after adjusting for baseline differences (p < .0001).

Conclusion

Remission is associated with markedly better patient well-being in AML. Patients with secondary or relapsed AML face more severe symptom burden, distress, and QOL issues after induction. Interventions are needed to improve AML patients' experiences of illness.

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Efficacy and safety of reinfusion of concentrated ascitic fluid for malignant ascites: a concept-proof study

Abstract

Purpose

Malignant ascites is one of the symptoms causing discomfort in advanced cancer patients. Cell-free and concentrated ascites reinfusion therapy (CART) is one treatment modality, but controlled trials are limited. The primary aim of this study was to explore the efficacy and safety of CART, as well as their predictors, to obtain data for planning a further controlled trial.

Methods

This was a single center retrospective cohort study in patients with refractory malignant ascites. Consecutive adult patients who underwent CART were enrolled. The primary endpoints were the time to next paracentesis and seven patient-reported symptoms (e.g., abdominal pain and distension). The secondary endpoints were adverse events, laboratory findings, and physical findings.

Results

A total of 104 CART procedures for 51 patients were analyzed. The median time to next paracentesis was 27 days (95% CI, 21–35). Intensities of all seven symptoms were significantly improved after CART (p < 0.0001 for all symptoms). Grade 3 hypotension occurred during one procedure, and mild fever occurred in 5%. Total protein, albumin, and estimated glomerular filtration rate were significantly increased. Hemorrhagic ascites, ascites white blood cell count, serum total protein, and lymphocyte percentages were the independent predictors of the time to next paracentesis.

Conclusion

The effects of reinfusion of concentrated ascitic fluid may be maintained for 1 month, being potentially longer than that of total paracentesis alone. This study had no comparison groups and examined the short-term effect. A randomized controlled study to compare the long-term effects of total paracentesis alone vs. CART is necessary.

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Levofloxacin for febrile neutropenia prophylaxis in acute myeloid leukemia patients associated with reduction in hospital admissions

Abstract

Purpose

The purpose of this study is to evaluate the efficacy and safety of prophylactic oral levofloxacin in acute myeloid leukemia (AML) patients after receiving consolidation chemotherapy to prevent febrile neutropenia.

Methods

We conducted a retrospective chart review of 50 AML patients who were prescribed levofloxacin and 50 AML patients who were not prescribed levofloxacin post-consolidation chemotherapy between June 2006 and August 2013 at a tertiary academic medical center. The primary outcome of this study was to evaluate the effectiveness of levofloxacin in preventing hospital readmission due to febrile neutropenia. Secondary outcomes evaluated the safety of this therapy, including the rate of Clostridium difficile-associated diarrhea (CDAD) within 30 days from discharge of receiving consolidation chemotherapy and rate of fluoroquinolone resistance in positive bacterial cultures.

Results

Hospital readmission due to febrile neutropenia after the first consolidation cycle occurred in 42% of patients prescribed levofloxacin, as compared to 72% that were not prescribed levofloxacin (p = 0.002). This was also significantly reduced when levofloxacin was prescribed after all consolidation cycles (51.4 vs. 67%, p = 0.023). CDAD did not occur in any patient prescribed levofloxacin after the first cycle, compared to one case in those not prescribed levofloxacin. Evaluation of the impact on fluoroquinolone resistance was limited due to a paucity of fluoroquinolone susceptibilities reported.

Conclusions

Prescribing oral levofloxacin post-consolidation chemotherapy in AML patients is associated with a reduction in febrile neutropenia. Further research is required to identify the impact on fluoroquinolone resistance and risk of CDAD.

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Tunneled pleural catheter use for pleural palliation does not increase infection rate in patients with treatment-related immunosuppression

Abstract

Purpose

Concerns for infections resulting from antineoplastic therapy-associated immunosuppression may deter referral for symptom palliation with a tunneled pleural catheter (TPC) in patients with malignant/para-malignant pleural effusions (MPE/PMPE). While rates of TPC-related infections range from 1 to 21%, those in patients receiving antineoplastic therapy with correlation to immune status has not been established. We aimed to assess TPC-related infection rates in patients on antineoplastic therapy, determine relation to immune system competency, and assess impact on the patient.

Methods

Patients with a MPE/PMPE undergoing TPC management associated with antineoplastic therapy, from 2008 to 2016, were reviewed and categorized into those with an immunocompromised versus immunocompetent immune status.

Results

Of the 150 patients, a TPC-related infection developed in 13 (9%): pleural space in 11 (7%) and superficial in 2 (1%). Ninety-three percent (139/150) were identified to be immunocompromised during their antineoplastic therapy. No difference in TPC-related infections was seen in patients with an immunocompromised (9%, 12/139) versus immunocompetent status (9%, 1/11); p = 0.614. The presence of a catheter-related infection did not negatively impact overall survival over a median follow-up of 144 days (interquartile range 41–341); p = 0.740.

Conclusions

These results suggest that antineoplastic therapy may not significantly increase the overall risk of TPC-related infections, as the rate remains low and comparable to rates in patients not undergoing antineoplastic therapy. Regardless of immune status, the presence of a catheter-related infection did not negatively impact overall survival. These results should reassure clinicians that the need to initiate antineoplastic therapy should not delay definitive pleural palliation with a TPC.

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Comparison of the MASCC and CISNE scores for identifying low-risk neutropenic fever patients: analysis of data from three emergency departments of cancer centers in three continents

Abstract

Purpose

Patients with febrile neutropenia are a heterogeneous group with a minority developing serious medical complications. Outpatient management of low-risk febrile neutropenia has been shown to be safe and cost-effective. Scoring systems, such as the Multinational Association for Supportive Care in Cancer (MASCC) score and Clinical Index of Stable Febrile Neutropenia (CISNE), have been developed and validated to identify low-risk patients. We aimed to compare the performance of these two scores in identifying low-risk febrile neutropenic patients.

Methods

We performed a pooled analysis of patients presenting with febrile neutropenia to three tertiary cancer emergency centers in the USA, UK, and South Korea in 2015. The primary outcome measures were the occurrence of serious complications. Admission to an intensive care unit (ICU) and 30-day mortality were secondary outcomes. The predictive performance of each score was analyzed.

Results

Five hundred seventy-one patients presented with febrile neutropenia. With MASCC risk index, 508 (89.1%) were classified as low-risk febrile neutropenia, compared to 60 (10.5%) with CISNE classification. Overall, the MASCC score had a greater discriminatory power in the detection of low-risk patients than the CISNE score (AUC 0.772, 95% CI 0.726–0.819 vs. 0.681, 95% CI 0.626–0.737, p = 0.0024).

Conclusion

Both MASCC and CISNE scores have reasonable discriminatory value in predicting patients with low-risk febrile neutropenia. Risk scores should be used in conjunction with clinical judgment for the identification of patients suitable for outpatient management of neutropenic fever. Developing more accurate scores, validated in prospective settings, will be useful in facilitating more patients being managed in an outpatient setting.

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Photodynamic therapy for periungual pyogenic granuloma-like during chemotherapy: our preliminary results

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Phase II study of palonosetron, aprepitant and dexamethasone to prevent nausea and vomiting induced by multiple-day emetogenic chemotherapy

Abstract

Purpose

This study aimed to determine the antiemetic efficacy and safety of palonosetron, aprepitant and dexamethasone in patients with testicular germ cell tumours (TGCTs) receiving 5-day cisplatin-based combination chemotherapy.

Methods

In this open-label, single-arm, single-centre study, the antiemetic therapy consisted of palonosetron 0.75 mg on day 1, aprepitant 125 mg on day 1 and 80 mg on days 2–7 and dexamethasone 6.6 mg on days 1–7. The primary endpoint was complete response (CR; no vomiting/retching or rescue medication) in the overall period (0–240 h), and secondary endpoints included complete protection (CP; defined as CR and no more than mild nausea) and total control (TC; defined as CR and no nausea). The incidence and severity of nausea were assessed on the basis of the Common Terminology Criteria for Adverse Events v4.0 and a subjective rating scale completed by patients.

Results

Twenty-five patients were enrolled and evaluated for safety, and 24 patients were evaluated for efficacy. CR was achieved in 62.5% of patients (95% confidence interval [CI] = 40.6–81.2, p = 0.043) in the overall period. CP and TC were achieved in 62.5% (95% CI = 40.6–81.2) and 25.0% of patients (95% CI = 9.8–46.7), respectively, in the overall period. The primary adverse drug reaction was hiccups (48.0%). The events were expected, and none was grade 3 or 4.

Conclusions

The examined combination antiemetic therapy was effective and well-tolerated in patients with TGCTs receiving 5-day cisplatin-based combination chemotherapy.

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Burden of oral mucositis in stem cell transplant patients—the patients’ perspective

Abstract

Purpose

Purpose of this study was to determine the impact of Oral Mucositis (OM) on health-related quality of life (HRQoL) and quality of life associated symptoms and functions in patients undergoing hematopoietic stem cell transplantation (HSCT).

Methods

Prospective, non-interventional single-center observational study at a German tertiary teaching hospital. Inpatient allogenic and autologous stem cell transplant patients ≥18-year-old with high-dose chemotherapy. OM was assessed with the WHO Oral Toxicity Scale, pain according to the Numeric Rating Scale (NRS) and the performance status using the ECOG Score. QOL was captured with the EORTC QLQ-C30 and the QLQ-OH15 questionnaires.

Results

Forty-five stem cell transplant patients (20 autologous, 25 allogenic) were enrolled between August 2016 and February 2017. Twenty-six (58%, 95% CI: 42% - 72%) patients developed OM (10 grade I, 4 grade II, 8 grade III, 4 grade IV). OM affected patients suffered more from pain, sore mouth and sensitive mouth. A lower physical functioning (34.5 vs 7.5, p = 0.003) and a lower oral health-related quality of life (24.3 vs 7.7, p = 0.006) was found in patients with OM development. There was found a positive correlation between the grade of OM and the NRS-value (r = 0.93, 95% CI: 0.89–0.96, p < 0.001).

Conclusion

OM is associated with health-related quality of life and quality of life associated functions and symptoms. More research should be performed to find ways to prevent OM and to stabilize patients' quality of life during HSCT.

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Fractures frequently occur in older cancer patients: the MD Anderson Cancer Center experience

Abstract

Purpose and Introduction

A growing number of cancer patients are older adults aged 65 years and older. Patients with cancer are at increased risk for developing osteoporosis, falls, and fractures. We sought to identify the incidence of fractures in older adults who underwent cancer care between January 2013 and December 2015.

Methods

A comprehensive geriatric assessment was performed, and bone densitometry was measured at baseline, with a 2-year follow-up.

Results

In this study, among 304 patients with gastrointestinal, urologic, breast, lung, and gynecologic cancers we evaluated, and who completed the bone density testing (n = 199), 80% had osteoporosis or low bone mass (osteopenia). There was a higher prevalence of osteoporosis in cancer patients (40 vs. 16%, p = 0.05) than in population studies. Vitamin D insufficiency (< 30 ng/ml) was identified in 49% of tested cases (n = 245). Risk factors for low bone mass or osteoporosis were advanced age (p = 0.05), malnutrition (p = 0.04), and frailty (p = 0.01). Over the following 2 years (median follow-up 18 months), there was an incidence of fractures of 110 per 1000 person-years, or 2.8 times higher than reported in individuals without cancer. Risk factors for fractures included advanced age (70–79 vs. 60–69 years, p = 0.05) and frailty (p = 0.03).

Conclusion

Most older cancer patients studied have osteoporosis or low bone mass, resulting in an almost 3-fold increase in fracture risk as compared to epidemiologic studies. Bone health issues are commonly seen in older cancer patients, we recommend universal bone density testing. The initiation of antiresorptive treatment when findings are of osteopenia or osteoporosis will reduce the risk of fractures.

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Antimicrobial therapy in palliative care: an overview

Abstract

In the advanced stages of illness, patients often face challenging decisions regarding their treatment and overall medical care. Terminal ill patients are commonly affected by infections. However, in palliative care, the use of antimicrobials can be an ethical dilemma. Deciding whether to treat, withhold, or withdraw the antimicrobial treatment for an infection can be difficult. Antimicrobial administration can lead to adverse outcomes but the two main benefits, longer survival and symptom relief, are the main reasons why physicians prescribe antimicrobial when treating terminally ill patients. For the patient who has an irreversible advanced heart or lung disease, or an advanced dementia, or a metastatic cancer, it is easier the decision of withholding mechanical ventilation, tube feeding, and dialysis than antibiotherapy. To characterize infections, agents, and their treatments in palliative care, we conducted a review of the literature. We also included some tips to help health professionals to guide their clinical approach.

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Physical activity among cancer survivors—what is their perception and experience?

Abstract

Purpose

Physical activity (PA) plays an important role relating to cancer. The aim of this study was to investigate the attitude to and experience with the subject of PA in cancer in a large group of tumour patients.

Methods

A standardised questionnaire was carried out and distributed to patients online and in printed form.

Results

Nine hundred five patients answered the questionnaire. Most tumour patients (60%) received information about PA after their cancer therapy. The Internet was often rated to be inadequate as a source of information. One in two tumour patients were recommended PA by a therapist. During the acute phase, the majority (57% of the 776) did not receive a sport-therapeutic exercise programme. Two thirds (68%) of the 898 patients indicated regularly engaging in PA at least 3 or 5 days per week. In most cases (30% of the 787), 2 to 4 h per week were dedicated to PA. In addition to a desire to increase well-being, enjoyment played a large role. Weakness and lack of willpower are among the most common barriers. Most tumour patients confirmed that PA improved their body awareness (58%) or gave them the feeling that they could do something to better cope with the disease (61%) or feel better (68%).

Conclusion

On the one hand, the information requirements of tumour patients with respect to PA have not been adequately taken into account by practitioners. On the other hand, there are still subjective inhibitions on the part of the patients, which keep them from engaging in PA.

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Incongruence in treatment decision making is associated with lower health-related quality of life among prostate cancer survivors: results from the PiCTure study

Abstract

Purpose

We investigated associations between treatment decision making (TDM) and global health-related-quality-of-life (gHRQoL) among prostate cancer (PCa) survivors.

Methods

Postal questionnaires were sent to 6559 PCa survivors 2–18 years post-diagnosis, identified through population-based cancer registries in Ireland. The Control Preference Scale was used to investigate respondents' 'actual' and 'preferred' role in TDM. The TDM experience was considered 'congruent' when actual and preferred roles matched and 'incongruent' otherwise. The EORTC QLQ-C30 was used to measure gHRQoL. Multivariate linear regression was employed to investigate associations between (i) actual role in TDM, (ii) congruence in TDM, and gHRQoL.

Results

The response rate was 54% (n = 3348). The percentages of men whose actual role in TDM was active, shared or passive were 36, 33 and 31%, respectively. Congruence between actual and preferred roles in TDM was 58%. Actual role in TDM was not associated with gHRQoL. In multivariate analysis, after adjusting for socio-demographic and clinical factors, survivors whose TDM experience was incongruent had significantly lower gHRQoL than those who had a congruent experience (− 2.25 95%CI − 4.09, − 0.42; p = 0.008). This effect was most pronounced among survivors who had more involvement in the TDM than they preferred (− 2.69 95%CI − 4.74, − 0.63; p = 0.010).

Conclusions

Less than 6 in 10 PCa survivors experienced congruence between their actual and preferred roles in TDM. Having an incongruent TDM experience was associated with lower gHRQoL among survivors. These findings suggest that involving patients in TDM to the degree to which they want to be involved may help improve PCa survivors' gHRQoL.

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Financial toxicity and symptom burden: what is the big deal?

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Cancers, Vol. 10, Pages 97: Nanopulse Stimulation (NPS) Induces Tumor Ablation and Immunity in Orthotopic 4T1 Mouse Breast Cancer: A Review

Cancers, Vol. 10, Pages 97: Nanopulse Stimulation (NPS) Induces Tumor Ablation and Immunity in Orthotopic 4T1 Mouse Breast Cancer: A Review

Cancers doi: 10.3390/cancers10040097

Authors: Stephen Beebe Brittany Lassiter Siqi Guo

Nanopulse Stimulation (NPS) eliminates mouse and rat tumor types in several different animal models. NPS induces protective, vaccine-like effects after ablation of orthotopic rat N1-S1 hepatocellular carcinoma. Here we review some general concepts of NPS in the context of studies with mouse metastatic 4T1 mammary cancer showing that the postablation, vaccine-like effect is initiated by dynamic, multilayered immune mechanisms. NPS eliminates primary 4T1 tumors by inducing immunogenic, caspase-independent programmed cell death (PCD). With lower electric fields, like those peripheral to the primary treatment zone, NPS can activate dendritic cells (DCs). The activation of DCs by dead/dying cells leads to increases in memory effector and central memory T-lymphocytes in the blood and spleen. NPS also eliminates immunosuppressive cells in the tumor microenvironment and blood. Finally, NPS treatment of 4T1 breast cancer exhibits an abscopal effect and largely prevents spontaneous metastases to distant organs. NPS with fast rise–fall times and pulse durations near the plasma membrane charging time constant, which exhibits transient, high-frequency components (1/time = Hz), induce responses from mitochondria, endoplasmic reticulum, and nucleus. Such effects may be responsible for release of danger-associated molecular patterns, including ATP, calreticulin, and high mobility group box 1 (HMBG1) from 4T1-Luc cells to induce immunogenic cell death (ICD). This likely leads to immunity and the vaccine-like response. In this way, NPS acts as a unique onco-immunotherapy providing distinct therapeutic advantages showing possible clinical utility for breast cancers as well as for other malignancies.

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Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies

Future Oncology, Ahead of Print.


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Clonal Hematopoiesis after Induction Chemotherapy for Acute Myeloid Leukemia

Successful intensive induction chemotherapy for acute myeloid leukemia (AML) results in at least a 2 to 4 log10 reduction in the 1 trillion malignant cells that are present at diagnosis, often with recovery of normal platelet and neutrophil levels within a month after treatment initiation — an…

https://ift.tt/2pOxsfH

Molecular Minimal Residual Disease in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of clonal hematopoietic stem-cell disorders with a variable response to therapy. Although the majority of patients with newly diagnosed AML have morphologic complete remission after they are treated with intensive induction chemotherapy, relapse…

https://ift.tt/2J3ak6b

Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies

Future Oncology, Ahead of Print.


https://ift.tt/2uwTs4r

Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies

Future Oncology, Ahead of Print.


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Clonal Hematopoiesis after Induction Chemotherapy for Acute Myeloid Leukemia

Successful intensive induction chemotherapy for acute myeloid leukemia (AML) results in at least a 2 to 4 log10 reduction in the 1 trillion malignant cells that are present at diagnosis, often with recovery of normal platelet and neutrophil levels within a month after treatment initiation — an…

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Molecular Minimal Residual Disease in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of clonal hematopoietic stem-cell disorders with a variable response to therapy. Although the majority of patients with newly diagnosed AML have morphologic complete remission after they are treated with intensive induction chemotherapy, relapse…

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Cost the Focus of Cancer Panel Report [News in Brief]

Recommendations to president center on increasing drug affordability, value, and innovation.

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Clonal Hematopoiesis after Induction Chemotherapy for Acute Myeloid Leukemia

Successful intensive induction chemotherapy for acute myeloid leukemia (AML) results in at least a 2 to 4 log10 reduction in the 1 trillion malignant cells that are present at diagnosis, often with recovery of normal platelet and neutrophil levels within a month after treatment initiation — an…

https://ift.tt/2pOxsfH

Molecular Minimal Residual Disease in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogeneous group of clonal hematopoietic stem-cell disorders with a variable response to therapy. Although the majority of patients with newly diagnosed AML have morphologic complete remission after they are treated with intensive induction chemotherapy, relapse…

https://ift.tt/2J3ak6b

Transketolase regulates the metabolic switch to control breast cancer cell metastasis via the alpha-ketoglutarate signaling pathway

Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (α-KG) enhanced the levels of tumor suppressors succinate dehydrogenase (SDH) and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF-1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of α-KG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of α-KG in TNBC cells. Together, our study has identified a novel TKT-mediated α-KG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy.

https://ift.tt/2E3UXXq

Transketolase regulates the metabolic switch to control breast cancer cell metastasis via the alpha-ketoglutarate signaling pathway

Although metabolic reprogramming is recognized as a hallmark of tumorigenesis and progression, little is known about metabolic enzymes and oncometabolites that regulate breast cancer metastasis, and very few metabolic molecules have been identified as potential therapeutic targets. In this study, the transketolase (TKT) expression correlated with tumor size in the 4T1/BALB/c syngeneic model. In addition, TKT expression was higher in lymph node metastases compared with primary tumor or normal tissues of patients, and high TKT levels were associated with poor survival. Depletion of TKT or addition of alpha-ketoglutarate (α-KG) enhanced the levels of tumor suppressors succinate dehydrogenase (SDH) and fumarate hydratase (FH), decreasing oncometabolites succinate and fumarate and further stabilizing HIF prolyl hydroxylase 2 (PHD2) and decreasing HIF-1α, ultimately suppressing breast cancer metastasis. Reduced TKT or addition of α-KG mediated a dynamic switch of glucose metabolism from glycolysis to oxidative phosphorylation. Various combinations of the TKT inhibitor oxythiamine, docetaxel, and doxorubicin enhanced cell death in triple-negative breast cancer (TNBC) cells. Furthermore, oxythiamine treatment led to increased levels of α-KG in TNBC cells. Together, our study has identified a novel TKT-mediated α-KG signaling pathway that regulates breast cancer oncogenesis and can be exploited as a modality for improving therapy.

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Hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging of prostate cancer in vivo predicts efficacy of targeting the Warburg effect

Purpose:  To evaluate the potential of hyperpolarized [1-¹³C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) of prostate cancer as a predictive biomarker for targeting the Warburg effect. Experimental Design:  Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts.  The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-¹³C]-pyruvate MRSI after systemic delivery of [1-¹³C] pyruvic acid.  Steady state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady state lactate concentrations were measured with proton (¹H) MRS.  Perfusion and oxygenation of xenografts was measured with electron paramagnetic resonance (EPR) imaging with OX063. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 µg/mouse/day for 5 days x 2 weekly cycles).  Lactate production, pyruvate uptake, extracellular acidification rates and oxygen consumption of the prostate cancer cell lines was analyzed in vitro.  LDH activity was assessed in tumor homogenates.Results: DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-¹³C]-pyruvate MRSI compared to PC3, and a corresponding greater sensitivity to LDH inhibition.  No difference was observed between PC3 and DU145 xenografts in steady state measures of pyruvate fermentation, oxygenation, or perfusion.  The two cell lines exhibited similar sensitivity to FX-11 in vitro.  LDH activity correlated to FX-11 sensitivity. Conclusions: Hyperpolarized [1-¹³C]-pyruvate MRSI of prostate cancer predicts efficacy of targeting the Warburg effect.

https://ift.tt/2IhBpkR

Clinical utility of cell-free DNA for the detection of ALK fusions and genomic mechanisms of ALK inhibitor resistance in non-small cell lung cancer

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase ALK gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without biopsy. Experimental Design: The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ,KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK positive patients had no history of targeted therapy (cohort 1) with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, 11 tissue insufficient). Follow-up of 3 of the 5 tissue negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 - 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR activating mutations, an ALK fusion was identified on progression (cohort 4) (4 STRN, 1 EML4; one both STRN and EML4), five harbored EGFR T790M. Conclusions: In this cohort of cfDNA detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a non-invasive means of detecting targetable alterations, and characterizing resistance mechanisms on progression.

https://ift.tt/2pPBYM1

Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low passage tumor cells derived from a patient with a treatmentresistant HPV-negative HNSCC. Experimental design: A tumor cell culture was established and subjected to whole exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two non-tumorigenic keratinocyte cell cultures for validation and to assess cancer-specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial. Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome and G2/M kinases WEE1 and CHK1. We also show the feasibility of ex-vivo drug profiling for patients enrolled in a clinical trial. Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology.

https://ift.tt/2GpOWGj

Combinatorial effects of VEGFR kinase inhibitor axitinib and oncolytic virotherapy in mouse and human glioblastoma stem-like cell models

Purpose: Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature. Experimental design: We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib in vitro and then tested anti-tumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing anti-angiogenic cytokine murine IL12 (G47-mIL12) in two orthotopic GSC-derived GBM models: patientderived recurrent MGG123 GSCs, forming vascular xenografts in immune-deficient mice, and mouse 005 GSCs, forming syngeneic tumors in immune-competent mice. Results: GSCs form endothelial-like tubes and were sensitive to axitinib. G47-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared to single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis and PDGFR/ERK pathway inhibition. In the mouse 005 model, anti-glioma activity, after single and combination therapy, was only observed in immune-competent mice and not T cell-deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy. Conclusions: Systemic TKI (axitinib) beneficially combines with G47-mIL12 to enhance anti-tumor efficacy in both immune-deficient and immune-competent orthotopic Saha et al 4 GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment.

https://ift.tt/2pPVeZO

CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy naive melanoma patients and expand significantly during anti-PD1 treatment.

Purpose: Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses however, occur in less than half of those treated and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate anti-tumor immune response. Experimental Design: We performed multi-parameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy. Results: Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells was associated with improved melanoma-specific survival in immunotherapy-naive melanoma patients. Local IL-15 expression levels strongly correlated with these tumor-resident T cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset and these cells significantly expanded early during anti-PD-1 immunotherapy. Conclusions: Tumor-resident CD8+ T cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade.

https://ift.tt/2GpOO9N

Hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging of prostate cancer in vivo predicts efficacy of targeting the Warburg effect

Purpose:  To evaluate the potential of hyperpolarized [1-¹³C]-pyruvate magnetic resonance spectroscopic imaging (MRSI) of prostate cancer as a predictive biomarker for targeting the Warburg effect. Experimental Design:  Two human prostate cancer cell lines (DU145 and PC3) were grown as xenografts.  The conversion of pyruvate to lactate in xenografts was measured with hyperpolarized [1-¹³C]-pyruvate MRSI after systemic delivery of [1-¹³C] pyruvic acid.  Steady state metabolomic analysis of xenograft tumors was performed with mass spectrometry and steady state lactate concentrations were measured with proton (¹H) MRS.  Perfusion and oxygenation of xenografts was measured with electron paramagnetic resonance (EPR) imaging with OX063. Tumor growth was assessed after lactate dehydrogenase (LDH) inhibition with FX-11 (42 µg/mouse/day for 5 days x 2 weekly cycles).  Lactate production, pyruvate uptake, extracellular acidification rates and oxygen consumption of the prostate cancer cell lines was analyzed in vitro.  LDH activity was assessed in tumor homogenates.Results: DU145 tumors demonstrated an enhanced conversion of pyruvate to lactate with hyperpolarized [1-¹³C]-pyruvate MRSI compared to PC3, and a corresponding greater sensitivity to LDH inhibition.  No difference was observed between PC3 and DU145 xenografts in steady state measures of pyruvate fermentation, oxygenation, or perfusion.  The two cell lines exhibited similar sensitivity to FX-11 in vitro.  LDH activity correlated to FX-11 sensitivity. Conclusions: Hyperpolarized [1-¹³C]-pyruvate MRSI of prostate cancer predicts efficacy of targeting the Warburg effect.

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Clinical utility of cell-free DNA for the detection of ALK fusions and genomic mechanisms of ALK inhibitor resistance in non-small cell lung cancer

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase ALK gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without biopsy. Experimental Design: The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ,KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK positive patients had no history of targeted therapy (cohort 1) with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, 11 tissue insufficient). Follow-up of 3 of the 5 tissue negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 - 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR activating mutations, an ALK fusion was identified on progression (cohort 4) (4 STRN, 1 EML4; one both STRN and EML4), five harbored EGFR T790M. Conclusions: In this cohort of cfDNA detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a non-invasive means of detecting targetable alterations, and characterizing resistance mechanisms on progression.

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Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low passage tumor cells derived from a patient with a treatmentresistant HPV-negative HNSCC. Experimental design: A tumor cell culture was established and subjected to whole exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two non-tumorigenic keratinocyte cell cultures for validation and to assess cancer-specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial. Results: Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome and G2/M kinases WEE1 and CHK1. We also show the feasibility of ex-vivo drug profiling for patients enrolled in a clinical trial. Conclusions: High-throughput phenotyping with siRNA and drug libraries using patient derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology.

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Combinatorial effects of VEGFR kinase inhibitor axitinib and oncolytic virotherapy in mouse and human glioblastoma stem-like cell models

Purpose: Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature. Experimental design: We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib in vitro and then tested anti-tumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing anti-angiogenic cytokine murine IL12 (G47-mIL12) in two orthotopic GSC-derived GBM models: patientderived recurrent MGG123 GSCs, forming vascular xenografts in immune-deficient mice, and mouse 005 GSCs, forming syngeneic tumors in immune-competent mice. Results: GSCs form endothelial-like tubes and were sensitive to axitinib. G47-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared to single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis and PDGFR/ERK pathway inhibition. In the mouse 005 model, anti-glioma activity, after single and combination therapy, was only observed in immune-competent mice and not T cell-deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy. Conclusions: Systemic TKI (axitinib) beneficially combines with G47-mIL12 to enhance anti-tumor efficacy in both immune-deficient and immune-competent orthotopic Saha et al 4 GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment.

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CD103+ tumor-resident CD8+ T cells are associated with improved survival in immunotherapy naive melanoma patients and expand significantly during anti-PD1 treatment.

Purpose: Therapeutic blockade of immune checkpoints has revolutionized cancer treatment. Durable responses however, occur in less than half of those treated and efforts to improve treatment efficacy are confounded by a lack of understanding of the characteristics of the cells that initiate anti-tumor immune response. Experimental Design: We performed multi-parameter flow cytometry and quantitative multiplex immunofluorescence staining on tumor specimens from immunotherapy-naïve melanoma patients and longitudinal biopsy specimen obtained from patients undergoing anti-PD-1 therapy. Results: Increased numbers of CD69+CD103+ tumor-resident CD8+ T cells was associated with improved melanoma-specific survival in immunotherapy-naive melanoma patients. Local IL-15 expression levels strongly correlated with these tumor-resident T cell numbers. The expression of several immune checkpoints including PD-1 and LAG3 was highly enriched in this subset and these cells significantly expanded early during anti-PD-1 immunotherapy. Conclusions: Tumor-resident CD8+ T cell numbers are more prognostic than total CD8+ T cells in metastatic melanoma. In addition, they are likely to initiate response to anti-PD-1 and anti-LAG-3 treatments. We propose that the immune profile of these cells prior to treatment could inform strategies for immune checkpoint blockade.

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Survival is influenced by approaches to local treatment of Ewing sarcoma within an international randomised controlled trial: analysis of EICESS-92

Abstract

Background

Two national clinical trial groups, United Kingdom Children's Cancer and Leukaemia Group (CCLG) and the German Paediatric Oncology and Haematology Group (GPOH) together undertook a randomised trial, EICESS-92, which addressed chemotherapy options for Ewing's sarcoma. We sought the causes of unexpected survival differences between the study groups.

Methods

647 patients were randomised. Cox regression analyses were used to compare event-free survival (EFS) and overall survival (OS) between the two study groups.

Results

5-year EFS rates were 43% (95% CI 36–50%) and 57% (95% CI 52–62) in the CCLG and GPOH patients, respectively; corresponding 5-year OS rates were 52% (95% CI 45–59%) and 66% (95% CI 61–71). CCLG patients were less likely to have both surgery and radiotherapy (18 vs. 59%), and more likely to have a single local therapy modality compared to the GPOH patients (72 vs. 35%). Forty-five percent of GPOH patients had pre-operative radiotherapy compared to 3% of CCLG patients. In the CCLG group local recurrence (either with or without metastases) was the first event in 22% of patients compared with 7% in the GPOH group. After allowing for the effects of age, metastases, primary site, histology and local treatment modality, the risk of an EFS event was 44% greater in the CCLG cohort (95% CI 10–89%, p = 0.009), and the risk of dying was 30% greater, but not statistically significant (95% CI 3–74%, p = 0.08).

Conclusions

Unexpected differences in EFS and OS occurred between two patient cohorts recruited within an international randomised trial. Failure to select or deliver appropriate local treatment modalities for Ewing's sarcoma may compromise chances of cure.

Trial registration Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Clinical trial information can be found for the following: NCT0000251

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Survival is influenced by approaches to local treatment of Ewing sarcoma within an international randomised controlled trial: analysis of EICESS-92

Abstract

Background

Two national clinical trial groups, United Kingdom Children's Cancer and Leukaemia Group (CCLG) and the German Paediatric Oncology and Haematology Group (GPOH) together undertook a randomised trial, EICESS-92, which addressed chemotherapy options for Ewing's sarcoma. We sought the causes of unexpected survival differences between the study groups.

Methods

647 patients were randomised. Cox regression analyses were used to compare event-free survival (EFS) and overall survival (OS) between the two study groups.

Results

5-year EFS rates were 43% (95% CI 36–50%) and 57% (95% CI 52–62) in the CCLG and GPOH patients, respectively; corresponding 5-year OS rates were 52% (95% CI 45–59%) and 66% (95% CI 61–71). CCLG patients were less likely to have both surgery and radiotherapy (18 vs. 59%), and more likely to have a single local therapy modality compared to the GPOH patients (72 vs. 35%). Forty-five percent of GPOH patients had pre-operative radiotherapy compared to 3% of CCLG patients. In the CCLG group local recurrence (either with or without metastases) was the first event in 22% of patients compared with 7% in the GPOH group. After allowing for the effects of age, metastases, primary site, histology and local treatment modality, the risk of an EFS event was 44% greater in the CCLG cohort (95% CI 10–89%, p = 0.009), and the risk of dying was 30% greater, but not statistically significant (95% CI 3–74%, p = 0.08).

Conclusions

Unexpected differences in EFS and OS occurred between two patient cohorts recruited within an international randomised trial. Failure to select or deliver appropriate local treatment modalities for Ewing's sarcoma may compromise chances of cure.

Trial registration Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Clinical trial information can be found for the following: NCT0000251

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Radiotherapy quality assurance for the RTOG 0834/EORTC 26053-22054/NCIC CTG CEC.1/CATNON intergroup trial “concurrent and adjuvant temozolomide chemotherapy in newly diagnosed non-1p/19q deleted anaplastic glioma”: Individual case review analysis

The EORTC phase III 26053-22054/ RTOG 0834/NCIC CTG CEC.1/CATNON intergroup trial was designed to evaluate the impact on concurrent and adjuvant temozolomide chemotherapy in newly diagnosed non-1p/19q deleted anaplastic gliomas. The primary endpoint was overall survival.We report the results of retrospective individual case reviews (ICRs) for the first patient randomized per institution to detect the compliance with the study protocol.

http://bit.ly/2Ihb0n1

Influence of deformable image registration on 4D dose simulation for extracranial SBRT: A multi-registration framework study

To evaluate the influence of deformable image registration approaches on correspondence model-based 4D dose simulation in extracranial SBRT by means of open source deformable image registration (DIR) frameworks.

http://bit.ly/2GU4wew

External beam radiation therapy to hepatocellular carcinoma involving inferior vena cava and/or right atrium: A meta-analysis and systemic review

Hepatocellular carcinoma (HCC) involving inferior vena cava (IVC) and/or right atrium (RA) is a very rare but serious disease. The objective of this meta-analysis was to assess efficacy and safety of external beam radiotherapy (EBRT) for HCC involving IVC and/or RA.

http://bit.ly/2IgZUP3

Economic data for particle therapy: Dealing with different needs in a heterogeneous landscape

In the light of scarce resources to be allocated for cancer care and a steady stream of costly innovations in all modalities applied to treat cancer, particle therapy needs to demonstrate its cost-utility balance to allow its positioning in the context of competing modalities. In the continuous evolving particle therapy landscape, the timely availability of appropriate economic data is crucial.

http://bit.ly/2GUQg5a

The Impact of Postreperfusion Syndrome on Acute Kidney Injury in Living Donor Liver Transplantation: A Propensity Score Analysis

BACKGROUND: Postreperfusion syndrome (PRS) has been shown to be related to postoperative morbidity and graft failure in orthotopic liver transplantation. To date, little is known about the impact of PRS on the prevalence of postoperative acute kidney injury (AKI) and the postoperative outcomes after living donor liver transplantation (LDLT). The purpose of our study was to determine the impact of PRS on AKI and postoperative outcomes after LDLT surgery. METHODS: Between January 2008 and October 2015, we retrospectively collected and evaluated the records of 1865 patients who underwent LDLT surgery. We divided the patients into 2 groups according to the development of PRS: PRS group (n = 715) versus no PRS group (n = 1150). Risk factors for AKI and mortality were investigated by multivariable logistic and Cox proportional hazards regression model analysis. Propensity score (PS) analysis (PS matching and inverse probability of treatment weighting analysis) was designed to compare the outcomes between the 2 groups. RESULTS: The prevalence of PRS and the mortality rate were 38% and 7%, respectively. In unadjusted analyses, the PRS group showed more frequent development of AKI (P

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Anesthetics Influence Mortality in a Drosophila Model of Blunt Trauma With Traumatic Brain Injury

Background: Exposure to anesthetics is common in the majority of early survivors of life-threatening injuries. Whether and to what degree general anesthetics influence outcomes from major trauma is unknown. Potential confounding effects of general anesthetics on outcome measures are usually disregarded. We hypothesized that exposure to isoflurane or sevoflurane modulates the outcome from blunt trauma with traumatic brain injury (bTBI). Methods: We tested the hypothesis in a novel model of bTBI implemented in Drosophila melanogaster. Fruit flies of the standard laboratory strain w1118 were cultured under standard conditions. We titrated the severity of bTBI to a mortality index at 24 hours (MI24) of approximately 20% under control conditions. We administered standard doses of isoflurane and sevoflurane before, before and during, or after bTBI and measured the resulting MI24. We report the MI24 as mean ± standard deviation. Results: Isoflurane or sevoflurane administered for 2 hours before bTBI reduced the MI24 from 22.3 ± 2.6 to 10.4 ± 1.8 (P

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Database Quality and Access Issues Relevant to Research Using Anesthesia Information Management System Data

For this special article, we reviewed the computer code, used to extract the data, and the text of all 47 studies published between January 2006 and August 2017 using anesthesia information management system (AIMS) data from Thomas Jefferson University Hospital (TJUH). Data from this institution were used in the largest number (P = .0007) of papers describing the use of AIMS published in this time frame. The AIMS was replaced in April 2017, making this finite sample finite. The objective of the current article was to identify factors that made TJUH successful in publishing anesthesia informatics studies. We examined the structured query language used for each study to examine the extent to which databases outside of the AIMS were used. We examined data quality from the perspectives of completeness, correctness, concordance, plausibility, and currency. Our results were that most could not have been completed without external database sources (36/47, 76.6%; P = .0003 compared with 50%). The operating room management system was linked to the AIMS and was used significantly more frequently (26/36, 72%) than other external sources. Access to these external data sources was provided, allowing exploration of data quality. The TJUH AIMS used high-resolution timestamps (to the nearest 3 milliseconds) and created audit tables to track changes to clinical documentation. Automatic data were recorded at 1-minute intervals and were not editable; data cleaning occurred during analysis. Few paired events with an expected order were out of sequence. Although most data elements were of high quality, there were notable exceptions, such as frequent missing values for estimated blood loss, height, and weight. Some values were duplicated with different units, and others were stored in varying locations. Our conclusions are that linking the TJUH AIMS to the operating room management system was a critical step in enabling publication of multiple studies using AIMS data. Access to this and other external databases by analysts with a high degree of anesthesia domain knowledge was necessary to be able to assess the quality of the AIMS data and ensure that the data pulled for studies were appropriate. For anesthesia departments seeking to increase their academic productivity using their AIMS as a data source, our experiences may provide helpful guidance. Accepted for publication January 29, 2018. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Data from this study were presented, in part, at the 2017 Annual Meeting of the American Society of Anesthesiologists, October 21–25, 2017, Boston, MA. Reprints will not be available from the authors. Address correspondence to Richard H. Epstein, MD, Department of Anesthesiology, Perioperative Medicine & Pain Management, University of Miami, Miller School of Medicine, 1400 NW 12th Ave, Suite 3075, Miami, FL 33136. Address e-mail to repstein@med.miami.edu. © 2018 International Anesthesia Research Society

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Dexamethasone as an Adjuvant for Caudal Blockade in Pediatric Surgical Patients: A Systematic Review and Meta-analysis

BACKGROUND: Caudal block is commonly used to provide postoperative analgesia after pediatric surgery in the lower abdomen. Typically administered as a single-shot technique, 1 limitation of this block is the short duration of analgesia. To overcome this, dexamethasone has been used as an adjuvant to prolong block duration. However, there are concerns about steroid-related morbidity and the optimal route of dexamethasone administration (eg, caudal or intravenous) is unknown. METHODS: We conducted a systematic review and random-effects meta-analysis of randomized controlled trials recruiting pediatric surgical patients receiving a caudal block for surgical anesthesia or postoperative analgesia. Included studies compared dexamethasone (caudal, intravenous, or both) to control. Duration of analgesia was the primary outcome. Database sources were Medline, Embase, the Cochrane Library, and Google Scholar searched up to August 18, 2017, without language restriction. Screening of studies, data extraction, and risk of bias assessment were performed independently and in duplicate by 2 authors. Risk of bias was assessed using Cochrane methodology and the strength of evidence was scored using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. RESULTS: The initial search retrieved 93 articles. Fourteen randomized controlled trials that comprised 1315 pediatric patients met the inclusion criteria. All but 1 study involved lower abdominal operations (orchidopexy, inguinal hernia repair, and hypospadias repair). The caudal and intravenous dose of dexamethasone ranged from 0.1 to 0.2 mg/kg and 0.5 to 1.5 mg/kg, respectively, and all studies were pooled in the main analysis. Dexamethasone prolonged the duration of analgesia by both the caudal route (5.43 hours, 95% confidence interval [CI], 3.52–7.35; P

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Time for a Fresh Approach to Examining Factors Associated With Red Blood Cell Transfusion Outcome

No abstract available

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Repeated Morphine Prolongs Postoperative Pain in Male Rats

BACKGROUND: Opioids are effective postoperative analgesics. Disturbingly, we have previously reported that opioids such as morphine can worsen inflammatory pain and peripheral and central neuropathic pain. These deleterious effects are mediated by immune mediators that promote neuronal hyperexcitability in the spinal dorsal horn. Herein, we tested whether perioperative morphine could similarly prolong postoperative pain in male rats. METHODS: Rats were treated with morphine for 7 days, beginning immediately after laparotomy, while the morphine was tapered in a second group. Expression of genes for inflammatory mediators was quantified in the spinal dorsal horn. In the final experiment, morphine was administered before laparotomy for 7 days. RESULTS: We found that morphine treatment after laparotomy extended postoperative pain by more than 3 weeks (time × treatment: P

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A Dedicated Acute Pain Service Is Associated With Reduced Postoperative Opioid Requirements in Patients Undergoing Cytoreductive Surgery With Hyperthermic Intraperitoneal Chemotherapy

BACKGROUND: The Acute Pain Service (APS) was initially introduced to optimize multimodal postoperative pain control. The aim of this study was to evaluate the association between the implementation of an APS and postoperative pain management and outcomes for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: In this propensity-matched retrospective cohort study, we performed a before-after study without a concurrent control group. Outcomes were compared among patients undergoing CRS-HIPEC when APS was implemented versus historical controls (non-APS). The primary objective was to determine if there was a decrease in median total opioid consumption during postoperative days 0–3 among patients managed by the APS. Secondary outcomes included opioid consumption on each postoperative day (0–6), time to ambulation, time to solid intake, and hospital length of stay. RESULTS: After exclusion, there were a total of 122 patients, of which 51 and 71 were in the APS and non-APS cohort, respectively. Between propensity-matched groups, the median (quartiles) total opioid consumption during postoperative days 0–3 was 27.5 mg intravenous morphine equivalents (MEQs) (7.6–106.3 mg MEQs) versus 144.0 mg MEQs (68.9–238.3 mg MEQs), respectively. The median difference was 80.8 mg MEQs (95% confidence interval, 46.1– 124.0; P 50%, as well as shorter time to ambulation and time to solid intake. Implementation of an APS may improve outcomes in CRS-HIPEC patients. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Accepted for publication February 2, 2018. E. T. Said and J. F. Sztain contributed equally to this manuscript. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. This work has been presented, in part, as an oral presentation at the Enhanced Recovery After Surgery US Conference, November 10, 2017, Dallas, TX. Reprints will not be available from the authors. Address correspondence to Engy T. Said, MD, Department of Anesthesiology, University of California, 200 W Arbor Dr, MC 8770, San Diego, CA 92103. Address e-mail to esaid@ucsd.edu. © 2018 International Anesthesia Research Society

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Evidence Basis for Regional Anesthesia in Ambulatory Anterior Cruciate Ligament Reconstruction: Part I—Femoral Nerve Block

The optimal management of pain after ambulatory anterior cruciate ligament reconstruction (ACLR) is unclear. Femoral nerve block (FNB) is purported to enhance postoperative analgesia, but its effectiveness in the setting of modern multimodal analgesia is unclear. This systematic review examines the effect of adding FNB to multimodal analgesia on analgesic outcomes after ACLR, whether or not the analgesic regimen used included local instillation analgesia (LIA). We retrieved randomized controlled trials evaluating the effects of adding FNB to multimodal analgesia on analgesic outcomes after ACLR, compared to multimodal analgesia alone (control). We designated postoperative opioid consumption at 24 hours as our primary outcome. Secondary outcomes included postoperative opioid consumption at 24–48 hours, rest, and dynamic pain severity between 0 and 48 hours, time to analgesic request, postanesthesia care unit and hospital stay durations, patient satisfaction, postoperative nausea and vomiting, functional outcomes, and long-term (>1 month) quadriceps strength. Eight randomized controlled trials (716 patients) were identified. Five trials compared FNB administration to control, and another 3 compared the combination of FNB and LIA to LIA alone. Compared to control, adding FNB resulted in modest reductions in 24-hour opioid consumption in 2 of 3 trials, and improvements in rest pain at 1 hour in 1 trial and up to 24 hours in another. In contrast, the combination of FNB and LIA, compared to LIA alone, did not reduce opioid consumption in any of the trials, but it did improve pain scores at 20 minutes only in 1 trial. The effect of FNB on long-term quadriceps strength or function after ACLR was not evaluated in the reviewed trials. Contemporary evidence suggests that the benefits of adding FNB to multimodal analgesia for ACLR are modest and conflicting, but there is no incremental analgesic benefit if the multimodal analgesic regimen included LIA. Our findings do not support the routine use of FNB for analgesia in patients having ACLR. Accepted for publication January 10, 2018. Funding: Departmental. Both F. W. Abdallah and R. Brull are supported by the Merit Award Program, Department of Anesthesia, University of Toronto. R. Brull receives research support from the Evelyn Bateman Cara Operations Endowed Chair in Ambulatory Anesthesia and Women's Health, Women's College Hospital, Toronto. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Faraj W. Abdallah, MD, Department of Anesthesia, St Michael's Hospital, 30 Bond St, Toronto, ON M5B 1W8, Canada. Address e-mail to abdallahf@smh.ca. © 2018 International Anesthesia Research Society

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Determination of Geolocations for Anesthesia Specialty Coverage and Standby Call Allowing Return to the Hospital Within a Specified Amount of Time

BACKGROUND: For emergent procedures, in-house teams are required for immediate patient care. However, for many procedures, there is time to bring in a call team from home without increasing patient morbidity. Anesthesia providers taking subspecialty or backup call from home are required to return to the hospital within a designated number of minutes. Driving times to the hospital during the hours of call need to be considered when deciding where to live or to visit during such calls. Distance alone is an insufficient criterion because of variable traffic congestion and differences in highway access. We desired to develop a simple, inexpensive method to determine postal codes surrounding hospitals allowing a timely return during the hours of standby call. METHODS: Pessimistic travel times and driving distances were calculated using the Google distance matrix application programming interface for all N= 136 postal codes within 60 great circle ("straight line") miles of the University of Miami Hospital (Miami, FL) during all 108 weekly standby call hours. A postal code was acceptable if the estimated longest driving time to return to the hospital was ≤60 minutes (the anesthesia department's service commitment to start an urgent case during standby call). Linear regression (with intercept = 0) minimizing the mean absolute percentage difference between the distances (great circle and driving) and the pessimistic driving times to return to the hospital was performed among all 136 postal codes. Implementation software written in Python is provided. RESULTS: Postal codes allowing return to the studied hospital within the specified interval were identified. The linear regression showed that driving distances correlated poorly with the longest driving time to return to the hospital among the 108 weekly call hours (mean absolute percentage error = 25.1% ± 1.7% standard error [SE]; N = 136 postal codes). Great circle distances also correlated poorly (mean absolute percentage error = 28.3% ± 1.9% SE; N = 136). Generalizability of the method was determined by successful application to a different hospital in a rural state (University of Iowa Hospital). CONCLUSIONS: The described method allows identification of postal codes surrounding a hospital in which personnel taking standby call could be located and be able to return to the hospital during call hours on every day of the week within any specified amount of time. For areas at the perimeter of the acceptability, online distance mapping applications can be used to check driving times during the hours of standby call. Accepted for publication January 9, 2018. Funding: None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Richard H. Epstein, MD, Department of Anesthesiology, Perioperative Medicine & Pain Management, University of Miami, Miller School of Medicine, 1400 NW 12th Ave, Suite 3075, Miami, FL 33136. Address e-mail to repstein@med.miami.edu. © 2018 International Anesthesia Research Society

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Intravenous Acetaminophen Does Not Reduce Inpatient Opioid Prescription or Opioid-Related Adverse Events Among Patients Undergoing Spine Surgery

BACKGROUND: Having entered the US market relatively recently, the perioperative role of intravenous acetaminophen (ivAPAP) remains to be established for several surgeries. Using national data, we therefore assessed current utilization and whether it reduces inpatient opioid prescription and opioid-related side effects in a procedure with relatively high opioid utilization. METHODS: Patients undergoing a lumbar/lumbosacral spinal fusion (n = 117,269; 2011–2014) were retrospectively identified in a nationwide database and categorized by the amount and timing of ivAPAP administration (1 or >1 dose on postoperative day [POD] 0, 1, or 1+). Multivariable models measured associations between ivAPAP utilization categories and opioid prescription and perioperative complications; odds ratios (or % change) and 95% confidence intervals are reported. RESULTS: Overall, ivAPAP was used in 18.9% (n = 22,208) of cases of which 1 dose on POD 0 was the most common (73.6%; n = 16,335). After covariate adjustment, use of ivAPAP on POD 0 and 1 was associated with minimal changes in opioid prescription, length and cost of hospitalization particularly favoring >1 ivAPAP dose with a modestly (-5.2%, confidence interval, -7.2% to -3.1%; P

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Clonidine Effect on Pain After Cesarean Delivery: A Randomized Controlled Trial of Different Routes of Administration

BACKGROUND: Intrathecal clonidine prolongs spinal anesthesia. We evaluated the effects of the addition of intrathecal or intravenous clonidine (75 µg) to standard cesarean delivery spinal anesthesia on postoperative pain and neonatal outcomes. METHODS: In a randomized, placebo-controlled, double-blind trial, 64 women scheduled for elective cesarean delivery under spinal anesthesia were randomly allocated and compared among 3 groups: intrathecal clonidine 75 µg, intravenous clonidine 75 µg, and placebo. The primary outcome was acute postoperative pain. A sample size of 26 individuals per group (N = 78) was planned. RESULTS: From April 2015 to April 2016, 64 women were analyzed (14 excluded). No differences in postoperative pain scores were found (Numerical Verbal Scale for pain at movement at 24 hours of postcesarean delivery: 4.53 ± 3.0 vs 4.45 ± 2.73 vs 3.93 ± 3.07 for control, intrathecal, and intravenous, respectively, P = .771). Intrathecal and intravenous clonidine led to more sedation, in comparison to the control group, during the intraoperative period (Richmond Agitation and Sedation Scale: −0.3 ± 0.47 vs −1 ± 0.53 vs −0.73 ± 0.45 for control, intrathecal, and intravenous, respectively, overall P

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Changes in International Normalized Ratios After Plasma Transfusion of Varying Doses in Unique Clinical Environments

BACKGROUND: Plasma transfusion is commonly performed for the correction of abnormal coagulation screening tests. The goal of this investigation was to assess the relationship between the dose of plasma administered and changes in coagulation test results in a large and diverse cohort of patients with varying levels of coagulation abnormalities and comorbid disease and in a variety of clinical settings. METHODS: In this single-center historical cohort study, all plasma transfusion episodes in adult patients with abnormal coagulation screening tests were extracted between 2011 and 2015. The primary outcome was the proportion of patients attaining normal posttransfusion international normalized ratio (INR ≤1.1) with secondary outcomes including the proportion of patients attaining partial normalization of INR (INR ≤1.5) or at least 50% normalization in pretransfusion values with respect to an INR of 1.1. RESULTS: In total, 6779 unique patients received plasma with a median (quartiles) pretransfusion INR of 1.9 (1.6–2.5) and a median transfusion volume of 2 (2–3) units. The majority (85%) of transfusions occurred perioperatively, with 20% of transfusions administered prophylactically before a procedure. The median decrease in INR was 0.4 (0.2–0.8). Complete INR normalization was obtained in 12%. Reductions in INR were modest with pretransfusion INR values

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Adding Cetuximab to Definitive Chemoradiation for Esophageal Cancer

To the Editor In a recent issue of JAMA Oncology, Suntharalingam et al reported that the addition of cetuximab to concurrent chemoradiation therapy (CRT) with paclitaxel and cisplatin failed to improve the survival of patients undergoing nonoperative treatment of esophageal cancer. They concluded that RTOG 0436 had negative results and suggested focusing future trials on patients with actionable molecular targets. Surprisingly, Suntharalingam et al also stated that because of the toxic effects observed in both experimental and control treatment arms, they were inclined to recommend a systemic therapy that uses a platinum-taxane combination rather than fluorouracil.

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Patterns in Health Care Access and Affordability Among Cancer Survivors

This population-based study analyzes cancer survivors' ability to access and afford health care during implementation of the US Affordable Care Act using data from the 2010 to 2016 National Health Interview Survey.

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Adding Cetuximab to Definitive Chemoradiation for Esophageal Cancer—Reply

In Reply We read with interest the Letters to the Editor from Liu and Yue as well as Adenis and Lordick, and we appreciate the opportunity to provide a response. We agree with Liu and Yue that this phase 3 trial was not designed or powered to assess the primary end point within the histology subsets. The Statistical Considerations section of the article describes the rationale for stratifying patients based on histologic type. In addition, it describes the required clinical complete response rate that would have to be achieved in order to continue to accrue patients with a specific histologic type. The Results section provides the outcome for patients with adenocarcinoma. The failure to meet the required end point of a 12% improvement in clinical complete response rate led to the mandated cessation of accruing patients with adenocarcinoma histologic type. The subsequent decision to discontinue accruing patients with squamous cell carcinoma histologic type and close the trial early came as a result of the publication of the United Kingdom SCOPE1 trial in January 2013, which failed to document a benefit of the addition of cetuximab to chemoradiation therapy in a similar cohort. Again, this is described in the Results section of the article. We did not perform toxicity, survival, or local failure analyses between treatment arms within histology subsets because these were not considered part of the primary end point of the trial and, therefore, not appropriate for this article. We note that the results of the phase 2 multi-institutional trial mentioned by the authors describe a clinical complete response rate of 64%, which is consistent with the findings of the control arm of RTOG 0436, and does not provide level 1 evidence to support a benefit associated with the addition of cetuximab. We look forward to the publication of the results of their phase 3 trial (NCT02858206).

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Genetic Alterations and Response to EGFR Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer

This cohort study examines the association of concomitant genetics alterations with response to treatment with epidermal growth factor receptor tyrosine kinase inhibitors among patients with EGFR-mutant advanced non–small cell lung cancer.

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Rituximab Maintenance Therapy After Induction Chemoimmunotherapy for Follicular Lymphoma

This synopsis summarizes the prospective randomized clinical trials that examined the use of rituximab maintenance therapy in treatment-naive patients with follicular lymphoma after first-line induction chemoimmunotherapy.

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Adding Cetuximab to Definitive Chemoradiation for Esophageal Cancer

To the Editor We read with interest the article by Suntharalingam et al demonstrating that the addition of cetuximab to concurrent chemoradiation therapy did not improve overall survival in the nonoperative treatment of patients with esophageal cancer. Although the study stratified patients according to tumor histologic type, it was not powered to assess with certainty the benefit of cetuximab therapy in each of the 2 main histological variants of this disease.

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CSF Biomarkers of CNS Injury and Neurocognitive Outcomes in Children With Acute Lymphoblastic Leukemia

This cohort study evaluates the association of cerebrospinal fluid biomarkers of brain injury with short- and long-term outcomes and genetic polymorphisms in children receiving chemotherapy for acute lymphoblastic leukemia.

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Assessment of Tumor Sequencing to Screen for Lynch Syndrome in Colorectal Cancer

This genetic sequencing study explores whether up-front tumor sequencing can replace the prevailing paradigm for universal tumor screening for Lynch syndrome, which includes a sequence of several screening tests.

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