Impact of reflux esophagitis on the esophageal function before and after laparoscopic fundoplication

Abstract

Background

High-resolution manometry (HRM), which is breakthrough testing equipment to evaluate esophageal motor function, was developed in Europe and United State and has garnered attention. Moreover, multichannel intraluminal impedance pH (MII-pH) testing has allowed us to grasp all liquid/gas reflux including not only acid but also non-acid reflux. We examined the impact of the presence of reflux esophagitis (RE) on esophageal motor function before and after laparoscopic fundoplication.

Materials and methods

The subjects included 100 patients (male: 63 patients, mean age: 54.1 ± 15.8) among 145 patients who underwent laparoscopic fundoplication for GERD associated diseases during a 4-year period from October 2012 to September 2016, excluding 6 patients who underwent further surgery, 32 patients on whom HRM was not performed, 3 patients who had technical errors during testing, and 4 patients for whom the status of RE was unknown. Regarding HRM, Mano Scan from Given Imaging Ltd. was used, and for the analysis, Mano View version 3.0 from the same company was used, after which data was calculated based on the Chicago Classification advocated by Pandolfino et al. Moreover, for the MII-pH testing, Sleuth manufactured by Sandhill Scientific. Inc. was used and automatic analysis was conducted by a computer. Postoperative assessments were conducted 3 months following surgery for all. Data was described in the median value and inter-quartile range, with a statistically significant difference defined as p < 0.05 by Chi square, Mann–Whitney, and Wilcoxon tests.

Results

RE+ group (Los Angeles classification A:B:C:D = 7:9:16:12 patients) included 44 patients (44%), of older age compared to the RE− group (62 vs. 50 years, p = 0.012) and a higher Body Mass Index value (24.0 vs. 22.5, p = 0.045); however, no differences were observed in terms of gender and duration of symptoms. In the preoperative findings on MII-pH, the RE+ group demonstrated significantly longer acid reflux time (4.7 vs. 1.3%, p = 0.005), while in the HRM findings, the RE− group demonstrated a significantly longer abdominal esophagus (0 vs. 0.4 cm, p = 0.049) and maintained esophageal body motor function (DCI: 1054 vs. 1407 mmHg s cm, p = 0.021, Intact peristalsis ratio: 90 vs. 100%, p = 0.037). As to the comparison of the treatment effect before and after laparoscopic fundoplication (Toupet fundoplication for all), significant improvements were observed in both groups in various parameters regarding reflux including acid reflux time, total number of liquid reflux episodes and total number of reflux episodes. Moreover, for both groups, the total length of the lower esophageal sphincter (LES) (RE+ group: 2.7 vs. 3.2 cm, p = 0.001, RE− group: 3.0 vs. 3.4 cm, p = 0.003) and the total length of the abdominal esophagus (RE+ group: 0 vs. 1.6 cm, p < 0.001, RE− group: 0 vs. 1.8 cm, p = 0.001) were significantly extended following surgery; however, no change was observed in DCI before and after surgery.

Conclusions

Regardless of the presence of RE, cardiac function and LES function were improved following laparoscopic Toupet fundoplication, but no changes were observed in esophageal body motor function.

from Cancer via ola Kala on Inoreader https://ift.tt/2r075ou
via IFTTT

Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells

Abstract

Background

It has been proposed that cancer establishment, maintenance, and recurrence may be attributed to a unique population of tumor cells termed cancer-initiating cells (CICs) that may include characteristics of putative cancer stem cell-like cells. Studies in lung cancer have shown that such cells can be enriched and propagated in vitro by culturing tumor cells in serum-free suspension as tumorspheres. CICs have been characterized for their phenotype, stem cell-like qualities, and their role in establishing tumor and maintaining tumor growth. Less is known about the interaction of CICs with the immune system.

Methods

We established CIC-enriched tumorspheres from murine TC-1 lung cancer cells, expressing human papillomavirus 16 (HPV-16) E6/E7 antigens, and evaluated their susceptibility to antitumor immune responses both in vitro and in vivo.

Results

TC-1 CICs demonstrated reduced expression of surface major histocompatibility complex (MHC)-I molecules compared to non-CICs. We similarly determined decreased MHC-I expression in five of six human lung cancer cell lines cultured under conditions enriching for CICs. In vivo, TC-1 cells enriched for CICs were resistant to human papillomavirus 16 E6/E7 peptide vaccine-mediated killing. We found that vaccinated mice challenged with CIC enriched tumorspheres demonstrated shorter survivals and showed significantly fewer CD8⁺ tumor infiltrating lymphocytes compared to CIC non-enriched challenged mice. Furthermore, cultured cytotoxic T lymphocytes (CTLs) from vaccinated mice demonstrated reduced capacity to lyse TC-1 cells enriched for CICs compared to non-enriched TC-1 cells. Following treatment with IFN-γ, both CIC enriched and non-enriched TC-1 cells expressed similar levels of MHC-I, and the increased MHC-I expression on CICs resulted in greater CTL-mediated tumor lysis and improved tumor-free survival in mice.

Conclusions

These results suggest that the attenuated expression of MHC-I molecules by CICs represents a potential strategy of CICs to escape immune recognition, and that the development of successful immunotherapy strategies targeting CICs may decrease their resistance to T cell-mediated immune detection by enhancing CIC MHC-I expression.

from Cancer via ola Kala on Inoreader https://ift.tt/2JqZIgG
via IFTTT

FOLFOX activity in a rare case of metastatic colonic adenocarcinoma of the tongue: a case report

Abstract

Background

Adenocarcinomas of the oral cavity are rare neoplasms, and only four cases of primary colonic adenocarcinoma of the tongue have ever been described in literature. Very few information about chemotherapy sensitiveness of this type of neoplasia is available, with only one regimen that showed some activity in a metastatic patient.

Case presentation

We describe the case of a patient bearing a metastatic colonic adenocarcinoma of the tongue submitted to a first-line chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen). After chemotherapy the patient obtained the complete disappearance of the primitive neoplasia located in the body of the tongue, and a tumor size reduction > 50% of liver and lung metastases.

Conclusions

This case demonstrated the activity of the combination of oxaliplatin and 5-fluorouracil in this very rare neoplasia. The FOLFOX regimen might be considered either in advanced and especially in the neoadjuvant setting, when the reduction of the primary tumor is highly needed.

from Cancer via ola Kala on Inoreader https://ift.tt/2HTr6XF
via IFTTT

Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer-initiating cells

Abstract

Background

It has been proposed that cancer establishment, maintenance, and recurrence may be attributed to a unique population of tumor cells termed cancer-initiating cells (CICs) that may include characteristics of putative cancer stem cell-like cells. Studies in lung cancer have shown that such cells can be enriched and propagated in vitro by culturing tumor cells in serum-free suspension as tumorspheres. CICs have been characterized for their phenotype, stem cell-like qualities, and their role in establishing tumor and maintaining tumor growth. Less is known about the interaction of CICs with the immune system.

Methods

We established CIC-enriched tumorspheres from murine TC-1 lung cancer cells, expressing human papillomavirus 16 (HPV-16) E6/E7 antigens, and evaluated their susceptibility to antitumor immune responses both in vitro and in vivo.

Results

TC-1 CICs demonstrated reduced expression of surface major histocompatibility complex (MHC)-I molecules compared to non-CICs. We similarly determined decreased MHC-I expression in five of six human lung cancer cell lines cultured under conditions enriching for CICs. In vivo, TC-1 cells enriched for CICs were resistant to human papillomavirus 16 E6/E7 peptide vaccine-mediated killing. We found that vaccinated mice challenged with CIC enriched tumorspheres demonstrated shorter survivals and showed significantly fewer CD8⁺ tumor infiltrating lymphocytes compared to CIC non-enriched challenged mice. Furthermore, cultured cytotoxic T lymphocytes (CTLs) from vaccinated mice demonstrated reduced capacity to lyse TC-1 cells enriched for CICs compared to non-enriched TC-1 cells. Following treatment with IFN-γ, both CIC enriched and non-enriched TC-1 cells expressed similar levels of MHC-I, and the increased MHC-I expression on CICs resulted in greater CTL-mediated tumor lysis and improved tumor-free survival in mice.

Conclusions

These results suggest that the attenuated expression of MHC-I molecules by CICs represents a potential strategy of CICs to escape immune recognition, and that the development of successful immunotherapy strategies targeting CICs may decrease their resistance to T cell-mediated immune detection by enhancing CIC MHC-I expression.

https://ift.tt/2JqZIgG

FOLFOX activity in a rare case of metastatic colonic adenocarcinoma of the tongue: a case report

Abstract

Background

Adenocarcinomas of the oral cavity are rare neoplasms, and only four cases of primary colonic adenocarcinoma of the tongue have ever been described in literature. Very few information about chemotherapy sensitiveness of this type of neoplasia is available, with only one regimen that showed some activity in a metastatic patient.

Case presentation

We describe the case of a patient bearing a metastatic colonic adenocarcinoma of the tongue submitted to a first-line chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen). After chemotherapy the patient obtained the complete disappearance of the primitive neoplasia located in the body of the tongue, and a tumor size reduction > 50% of liver and lung metastases.

Conclusions

This case demonstrated the activity of the combination of oxaliplatin and 5-fluorouracil in this very rare neoplasia. The FOLFOX regimen might be considered either in advanced and especially in the neoadjuvant setting, when the reduction of the primary tumor is highly needed.

https://ift.tt/2HTr6XF

Genetic correction of serum AFP level improves risk prediction of primary hepatocellular carcinoma in the Dongfeng–Tongji cohort study

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2r2EtdH
via IFTTT

Efficacy of two types of palliative sedation therapy defined using intervention protocols: proportional vs. deep sedation

Abstract

Purpose

This study investigated the effect of two types of palliative sedation defined using intervention protocols: proportional and deep sedation.

Methods

We retrospectively analyzed prospectively recorded data of consecutive cancer patients who received the continuous infusion of midazolam in a palliative care unit. Attending physicians chose the sedation protocol based on each patient's wish, symptom severity, prognosis, and refractoriness of suffering. The primary endpoint was a treatment goal achievement at 4 h: in proportional sedation, the achievement of symptom relief (Support Team Assessment Schedule (STAS) ≤ 1) and absence of agitation (modified Richmond Agitation-Sedation Scale (RASS) ≤ 0) and in deep sedation, the achievement of deep sedation (RASS ≤ − 4). Secondary endpoints included mean scores of STAS and RASS, deep sedation as a result, and adverse events.

Results

Among 398 patients who died during the period, 32 received proportional and 18 received deep sedation. The treatment goal achievement rate was 68.8% (22/32, 95% confidence interval 52.7–84.9) in the proportional sedation group vs. 83.3% (15/18, 66.1–100) in the deep sedation group. STAS decreased from 3.8 to 0.8 with proportional sedation at 4 h vs. 3.7 to 0.3 with deep sedation; RASS decreased from + 1.2 to − 1.7 vs. + 1.4 to − 3.7, respectively. Deep sedation was needed as a result in 31.3% (10/32) of the proportional sedation group. No fatal events that were considered as probably or definitely related to the intervention occurred.

Conclusion

The two types of intervention protocol well reflected the treatment intention and expected outcomes. Further, large-scale cohort studies are promising.

from Cancer via ola Kala on Inoreader https://ift.tt/2HTjRiu
via IFTTT

Response to letter to the editor

from Cancer via ola Kala on Inoreader https://ift.tt/2HR8FTe
via IFTTT

Sexual health in patients with hematological malignancies: a neglected issue

Abstract

Current evidence, although limited, outlines that sexual dysfunction may represent a prominent part of the symptom burden experienced by the patients with hematologic malignancies (HM). However, despite their presumed negative effects on quality of life (QoL), sexual health is not typically considered in the QoL assessment of HM patients. In addition, very few studies have been conducted in this area. Therefore, it would be important to further investigate how newer drugs developed in recent years for patients with HM, including targeted therapies and impact on sexual health, and how this influence overall patients' QoL outcomes.

from Cancer via ola Kala on Inoreader https://ift.tt/2HxXQT3
via IFTTT

Chemotherapy-induced nausea and vomiting (CINV) in patients with advanced lung cancer during the first-line treatment: assessment by physicians, nurses, and patients from an Italian multicenter survey

Abstract

Purpose

Chemotherapy-induced nausea and vomiting (CINV) still represents a common side-effect of chemotherapy, and often, its perception differs between patients and healthcare professionals. The aim of this study was to evaluate the agreement on the perception of CINV and other items among clinicians, patients, and nurses.

Methods

This observational prospective study was part of an evaluation program promoted by the Women Against Lung Cancer in Europe (WALCE) Onlus. From August 2015 to February 2016, a survey was administered in 11 oncologic institutions to 188 stage IV lung cancer patients and to their oncologists and nurses during first-line chemotherapy. Our survey investigated 11 aspects: anxiety, mood, weakness, appetite, nausea, vomiting, pain, drowsiness, breath, general condition, and trust in treatments. These items were assessed through Numerical Rating Scale at four consecutive evaluations: at T0 (immediately prior to the first cycle), at T1 (immediately prior to the second cycle), at T2 (immediately prior to the third cycle), and at T3 (immediately prior to the fourth cycle). Clinician versus patient (CvP), nurse versus patient (NvP), and clinician versus nurse (CvN) agreements were estimated applying Weighted Cohen's kappa. A multivariate logistic model and generalized equation estimates were applied to evaluate factors possibly influencing CINV development.

Results

The incidence of patients reporting CINV varied from 40% at T0 to 71% at T3. Both CvP and NvP agreement on the investigated items were mainly moderate, slightly increasing over time, and becoming substantial for some items, in particular for NvP. Pre-chemotherapy anxiety in its mild, moderate, and severe manifestations, as well as mild, moderate, and severe anxiety experienced after chemotherapy start, exposed patients to a higher risk of anticipatory and acute/delayed CINV, respectively.

Conclusions

Despite clinical staff awareness of patients' status and perceptions, CINV still represents a clinical problem. This study confirms that particular attention should be paid to anxiety due to its key role in CINV development.

from Cancer via ola Kala on Inoreader https://ift.tt/2qYFHam
via IFTTT

Associations among physical symptoms, fear of cancer recurrence, and emotional well-being among Chinese American breast cancer survivors: a path model

Abstract

Purpose

Most existing studies on fear of cancer recurrence (FCR) are exploratory without theoretical underpinnings and have been conducted among non-Hispanic Whites. Based on theoretical models, we hypothesized that more physical symptoms (pain and fatigue) would be associated with higher FCR, which, in turn would be related to lower emotional well-being among Chinese American breast cancer survivors.

Methods

Participants were 77 Chinese American women who were diagnosed with breast cancer of stages 0–III. A cross-sectional path analysis was conducted with a bootstrapping method.

Results

The final model showed that indirect paths from pain interference to emotional well-being and from fatigue to emotional well-being via FCR were significant. That is, higher levels of pain interference and fatigue were associated with higher FCR, which was further related to lower emotional well-being.

Conclusions

To our best knowledge, this is the first theory-driven study that investigates FCR experiences among Chinese American breast cancer survivors. Our study might provide a more comprehensive understanding of FCR as it simultaneously shows predictors and a psychological consequence of FCR. Results need to be replicated in large, racially/ethnically diverse samples and longitudinal studies.

from Cancer via ola Kala on Inoreader https://ift.tt/2r2SCHw
via IFTTT

Administrating docetaxel, doxorubicin, and cyclophosphamide as a neoadjuvant treatment may decrease lymphedema risk in breast cancer patients

from Cancer via ola Kala on Inoreader https://ift.tt/2Js8yLi
via IFTTT

Diagnostic-driven antifungal approach in neutropenic patients at high risk for chronic disseminated candidiasis: preliminary observations on the role of 1,3-β-D-glucan antigenemia and multiphasic contrast-enhanced computed tomography

from Cancer via ola Kala on Inoreader https://ift.tt/2HT2iim
via IFTTT

Sleep disturbance among Chinese breast cancer survivors living in the USA

Abstract

Purpose

Emerging evidence suggests Chinese breast cancer survivors, a largely understudied population, are at increased risk of sleep disturbance which can have significant impacts on quality of life and other important outcomes. This study aims to describe sleep disturbance among Chinese breast cancer survivors and to examine demographic and clinical correlates as well as psychosocial correlates of sleep disturbance.

Methods

Data from 80 Chinese breast cancer survivors in the USA completed the Chinese version of the Pittsburgh Sleep Quality Index as well as measures of quality of life, depressive symptoms, and perceived stress. Participants also completed measures of demographic factors and acculturation.

Results

Two thirds (66%) of survivors experienced elevated sleep disturbance. Approximately half (49%) reported sleep efficiency, the percentage of time in bed that is spent asleep, that was below the recommended cutoff. Compared to those without sleep disturbance, those with sleep disturbance had worse quality of life, more depressive symptoms, and more perceived stress (ps ≤ .01).

Conclusions

This study is among the first to examine sleep disturbance among any Asian cancer population in the USA. Findings indicate Chinese breast cancer survivors may experience significant disparities in sleep disturbance relative to non-Hispanic Whites and suggest an urgent need for interventions to address sleep disturbance among Chinese breast cancer survivors.

from Cancer via ola Kala on Inoreader https://ift.tt/2Hw1nBg
via IFTTT

Stenotrophomonas maltophilia bacteremia and pneumonia at a tertiary-care oncology center: a review of 16 years

Abstract

Purpose

The aim of this study was to describe the clinical characteristics and antimicrobial patterns of Stenotrophomonas maltophilia bloodstream infections (BSI) and pneumonia episodes in patients with cancer.

Methods

Patients with S. maltophilia BSI or pneumonia admitted from 1 Jan. 2000 to 31 Dec. 2016 were identified at the Instituto Nacional de Cancerología (INCan), a tertiary-care oncology hospital in Mexico City.

Results

During the study period, there were 171 isolates identified. The mean age of the whole group was 46.9 ± 17.4 years; 99 (57.9%) were women. There were 95 BSI: 64 ambulatory catheter-related BSI (CRBSI), 20 nosocomial CRBSI, and 11 secondary BSI. Mortality was higher in nosocomial CRBSI (40%) vs. that in ambulatory CRBSI (7.8%) (p = 0.001). There were 76 pneumonia episodes; all were nosocomial acquired; 46 (60.5%) ventilator-associated. From all the group, nine strains (5.2%) were resistant to sulfamethoxazole/trimethoprim/(SMX/TMP). At the first month, 54 patients (31.6%) have died, 38 due to pneumonia (70%) and 16 due to BSI (30%, p < 0.001). Multivariate analysis showed that removal of central venous catheter was associated with a favorable outcome in patients with bacteremia. For patients with pneumonia, age ≥ 65 years and inappropriate antimicrobial treatment were risk factors associated with 30-day mortality.

Conclusions

S. maltophilia related with ambulatory CRBSI have a better prognosis than other sources of BSI. Older patients with pneumonia who do not receive appropriate antibiotics have higher mortality. SMX/TMP is still the antibiotic of choice.

from Cancer via ola Kala on Inoreader https://ift.tt/2HsnQPC
via IFTTT

Digestive toxicities after palliative three-dimensional conformal radiation therapy (3D-CRT) for cervico-thoracic spinal metastases

Abstract

Objective

The palliative treatment for cervico-thoracic spinal metastases is based on a three-dimensional conformal radiation therapy (3D-CRT). Digestive toxicities are common and cause a clinical impact frequently underestimated in patients. We performed a retrospective study of digestive side effects occurring after palliative 3D-CRT for cervico-thoracic spinal metastases.

Patients and methods

All patients receiving palliative 3D-CRT at Jean Bernard Center from January 2013 to December 2014 for spinal metastases between the 5th cervical vertebra (C5) and the 12th thoracic vertebra (T12) were eligible. Three-dimensional conformal RT was delivered by a linear accelerator (CLINAC, Varian). Premedication to prevent digestive toxicities was not used. Adverse events ("esophagitis" and "nausea and/or vomiting") were evaluated according to the NCI-CTCae (version 4).

Results

From January 2013 to December 2014, 128 patients met the study criteria. The median age was 68.6 years [31.8; 88.6]. Most patients (84.4%) received 30 Gy in 10 fractions. The median overall time of treatment was 13 days [3–33]. Forty patients (31.3%) suffered from grade ≥ 2 of "esophagitis" (35 grade 2 (27.4%) and 5 grade 3 (3.9%)). Eight patients (6.3%) suffered from grade ≥ 2 of "nausea and/or vomiting" (6 grade 2 (4.7%), 1 grade 3 (0.8%), and 1 grade 4 (0.8%)).

Conclusion

The high incidence of moderate to severe digestive toxicities after palliative 3D-CRT for cervico-thoracic spinal metastases led to consider static or dynamic intensity-modulated radiation therapy (IMRT) to reduce the dose to organ at risk (the esophagus and stomach). Dosimetric studies and implementation in the clinic should be the next steps.

from Cancer via ola Kala on Inoreader https://ift.tt/2qXuCGU
via IFTTT

Influence of family on expected benefits of complementary and alternative medicine (CAM) in cancer patients

Abstract

Background

Cancer patients often use complementary and alternative medicine (CAM) based on recommendations from family. However, the relationship between family endorsement of CAM and the patient's expectation of its benefits has never been quantified.

Methods

Between 2010 and 2011, we conducted a cross-sectional survey study among patients with a diagnosis of cancer recruited from thoracic, breast, and gastrointestinal medical oncology clinics at a single academic cancer center. We performed multivariate linear regression analyses to evaluate the relationship between perceived family endorsement of and expected benefits from CAM, adjusting for covariates.

Results

Among the 962 participants, 303 (31.3%) reported family endorsement of CAM use. Younger patients and those who had college or higher education were more likely to report family endorsement (both p < 0.05). Patients with family support had expectation scores that were 15.9 higher than patients without family support (coefficient 15.9, 95% CI 13.5, 18.2, p < 0.001). Participants with family encouragement of CAM use were also more likely to expect CAM to cure their cancer (12 vs. 37%) and prolong their life (24 vs. 61%). These relationships remained highly significant after adjusting for covariates).

Conclusions

Family endorsement of CAM use is strongly associated with patient expectation of its clinical efficacy, including expectations for cure and improved survival. These findings underscore the importance of including family in counseling and education on CAM use in order to achieve realistic patient expectations, maximize benefits, and avoid potential medical adverse effects through herb-drug interactions or rejections of conventional care.

from Cancer via ola Kala on Inoreader https://ift.tt/2Hrc4ca
via IFTTT

An investigation into the nutritional status of patients receiving an Enhanced Recovery After Surgery (ERAS) protocol versus standard care following Oesophagectomy

Abstract

Purpose

Enhanced Recovery After Surgery (ERAS) protocols have been effectively expanded to various surgical specialities including oesophagectomy. Despite nutrition being a key component, actual nutrition outcomes and specific guidelines are lacking. This cohort comparison study aims to compare nutritional status and adherence during implementation of a standardised post-operative nutritional support protocol, as part of ERAS, compared to those who received usual care.

Methods

Two groups of patients undergoing resection of oesophageal cancer were studied. Group 1 (n = 17) underwent oesophagectomy between Oct 2014 and Nov 2016 during implementation of an ERAS protocol. Patients in group 2 (n = 16) underwent oesophagectomy between Jan 2011 and Dec 2012 prior to the implementation of ERAS. Demographic, nutritional status, dietary intake and adherence data were collected. Ordinal data was analysed using independent t tests, and categorical data using chi-square tests.

Results

There was no significant difference in nutrition status, dietary intake or length of stay following implementation of an ERAS protocol. Malnutrition remained prevalent in both groups at day 42 post surgery (n = 10, 83% usual care; and n = 9, 60% ERAS). A significant difference was demonstrated in adherence with earlier initiation of oral free fluids (p <0.008), transition to soft diet (p <0.004) and continuation of jejunostomy feeds on discharge (p <0.000) for the ERAS group.

Conclusion

A standardised post-operative nutrition protocol, within an ERAS framework, results in earlier transition to oral intake; however, malnutrition remains prevalent post surgery. Further large-scale studies are warranted to examine individualised decision-making regarding nutrition support within an ERAS protocol.

from Cancer via ola Kala on Inoreader https://ift.tt/2Jsz0o0
via IFTTT

Transfusion practices at end of life for hematopoietic stem cell transplant patients

Abstract

Purpose

Limited data exist regarding transfusion practices at end of life (EOL) for hematopoietic stem cell transplant (HSCT) patients. The purpose of this study was to examine red blood cell (RBC) and platelet transfusion practices in HSCT patients who enrolled or did not enroll in hospice.

Methods

This was a single-center, retrospective chart review in deceased HSCT patients. The primary objective was to determine the mean difference between the last transfusion and death in HSCT patients (n = 116) who enrolled or did not enroll in hospice.

Results

Sixteen (14%) and 100 (86%) patients were enrolled in hospice and not enrolled in hospice, respectively. Hospice patients observed a larger mean difference between death and last transfusion (45.9 ± 66.7 vs. 14.6 ± 48.1 days, p < 0.0001). A higher amount of platelet, but not RBC, transfusions occurred in patients not enrolled in hospice (p = 0.04). The last transfusion that occurred more than 96 h before death was observed in 12 (75%) and 22 (22%) in hospice and non-hospice patients, respectively. For HSCT patients not enrolled in hospice, 17 patients received a transfusion on the same day of death and 31 patients received the last transfusion 24 h before death.

Conclusions

Blood transfusion practices differed in HSCT patients enrolled and not enrolled in hospice. For most patients not enrolled in hospice, the last transfusion occurred 24 h before death. Future efforts should explore if limited access to blood products is a barrier to hospice enrollment for HSCT patients.

from Cancer via ola Kala on Inoreader https://ift.tt/2HUJq2N
via IFTTT

Applying pre-participation exercise screening to breast cancer survivors: a cross-sectional study

Abstract

Purpose

Clinical guidelines recommend that breast cancer (BrCa) survivors be prescribed exercise. However, clinicians often do not prescribe exercise citing the presence of multiple health issues found among cancer survivors. No study has examined the proportion of BrCa survivors that can be prescribed a community/home-based unsupervised exercise program safely and independently, without further medical investigations or supervision.

Methods

Participants included BrCa survivors who received treatment at a university healthcare system between 2009 and 2014. We applied previously identified published guidelines for health conditions that may impede BrCa survivors from completing a community/home-based exercise program. Logistic regression models were used to quantify the magnitude of the association between demographic and clinical characteristics and the ability to perform community/home-based exercise.

Results

Among 667 BrCa survivors, 65 to 75% was classified as able to complete community/home-based exercise as recommended by the clinical guidelines. Older age, black race, treatment with chemotherapy, and treatment with radiation were associated with the potential need for further medical evaluation prior to starting exercise.

Conclusions

A large proportion of BrCa survivors can be prescribed community/home-based exercise program safely and independently, without further medical investigations or supervision. Future research will be needed to determine how to identify the subset of BrCa survivors that may benefit from medical evaluation prior to starting exercise in a manner that does not interrupt clinical oncology workflow. Approximately 35% of BrCa survivors may benefit from medical evaluation prior to starting community/home-based exercise.

from Cancer via ola Kala on Inoreader https://ift.tt/2r61oF5
via IFTTT

Convergent priorities and tensions: a qualitative study of the integration of complementary and alternative therapies with conventional cancer treatment

Abstract

Purpose

Demand for complementary and alternative medicine (CAM) is high among cancer patients. This, alongside growing evidence for the efficacy of some CAM therapies, is driving change within cancer centres, where evidence-based CAM therapies are increasingly provided alongside standard cancer treatments. In Australia, commitment to equitable access to healthcare is strong, and some cancer centres are now providing integrative services at no cost to the patient. This represents a significant shift in healthcare provision. This study aimed to examine health professional and patient dynamics in an integrated cancer service where CAM is provided at no cost to patients alongside standard cancer treatments. It specifically sought to understand what might drive or hinder further integration of CAM with standard treatment in the cancer context.

Methods

Qualitative interviews were undertaken with twenty key stakeholders—cancer patients, cancer nurses, and oncologists—who were delivering or receiving care in an Australian public hospital where acupuncture services are provided at no cost to patients alongside standard chemotherapy and radiation treatments.

Results

Findings point to key areas where the concerns and priorities of cancer patients, cancer nurses, and oncologists converge and diverge in ways that reflect core personal and professional interests regarding patient care needs, the evidence base for CAM efficacy and safety, and rising healthcare costs.

Conclusions

Understanding points of convergence and divergence could assist clinicians and service providers in negotiating ways forward for integrative cancer services.

from Cancer via ola Kala on Inoreader https://ift.tt/2Hq1LFc
via IFTTT

Efficacy of two types of palliative sedation therapy defined using intervention protocols: proportional vs. deep sedation

Abstract

Purpose

This study investigated the effect of two types of palliative sedation defined using intervention protocols: proportional and deep sedation.

Methods

We retrospectively analyzed prospectively recorded data of consecutive cancer patients who received the continuous infusion of midazolam in a palliative care unit. Attending physicians chose the sedation protocol based on each patient's wish, symptom severity, prognosis, and refractoriness of suffering. The primary endpoint was a treatment goal achievement at 4 h: in proportional sedation, the achievement of symptom relief (Support Team Assessment Schedule (STAS) ≤ 1) and absence of agitation (modified Richmond Agitation-Sedation Scale (RASS) ≤ 0) and in deep sedation, the achievement of deep sedation (RASS ≤ − 4). Secondary endpoints included mean scores of STAS and RASS, deep sedation as a result, and adverse events.

Results

Among 398 patients who died during the period, 32 received proportional and 18 received deep sedation. The treatment goal achievement rate was 68.8% (22/32, 95% confidence interval 52.7–84.9) in the proportional sedation group vs. 83.3% (15/18, 66.1–100) in the deep sedation group. STAS decreased from 3.8 to 0.8 with proportional sedation at 4 h vs. 3.7 to 0.3 with deep sedation; RASS decreased from + 1.2 to − 1.7 vs. + 1.4 to − 3.7, respectively. Deep sedation was needed as a result in 31.3% (10/32) of the proportional sedation group. No fatal events that were considered as probably or definitely related to the intervention occurred.

Conclusion

The two types of intervention protocol well reflected the treatment intention and expected outcomes. Further, large-scale cohort studies are promising.

https://ift.tt/2HTjRiu

Predictors of analgesic efficacy of neurolytic celiac plexus block in patients with unresectable pancreatic cancer: the importance of timing

Abstract

Background

Neurolytic celiac plexus block (NCPB) is a safe and effective method for reducing abdominal cancer pain. However, the analgesic efficacy of NCPB is not always guaranteed. The aim of this retrospective study was to identify predictors for the analgesic efficacy of NCPB in patients with unresectable pancreatic cancer.

Methods

Patients with unresectable pancreatic cancer who underwent NCPB from 2006 to 2015 were enrolled. Good analgesia after NCPB was defined as ≥ 50% reduction in pain score at day 30. Patient demographics, cancer characteristics, and pain-related factors were evaluated using a logistic regression analysis to identify predictors for good analgesia after NCPB. Additionally, survival outcomes were compared between patients with poor and good analgesia after NCPB.

Results

A total of 112 patients satisfied the study protocol requirements. Forty-seven patients (41.9%) showed good analgesia after NCPB. Better performance status, lower serum CA 19-9 level, shorter pain duration, and lower opioid dose were observed in patients with good analgesia after NCPB. Good performance status (ECOG performance status 1 vs. 2 or 3, OR = 2.737, 95% CI = 1.149 to 6.518, P = 0.023) and low daily opioid use (< 150 vs. ≥ 150 mg, OR = 2.813, 95% CI = 1.159 to 6.831, P = 0.022) before NCPB were independent predictors of good analgesia after NCPB. The median survival was significantly lower for patients with poor analgesia after NCPB (68 vs. 150 days, P < 0.001).

Conclusion

NCPB should be offered early to selected patients to improve its analgesic efficacy in advance of deterioration from disease and pain in this population.

https://ift.tt/2JqYEte

Response to letter to the editor

https://ift.tt/2HR8FTe

Sexual health in patients with hematological malignancies: a neglected issue

Abstract

Current evidence, although limited, outlines that sexual dysfunction may represent a prominent part of the symptom burden experienced by the patients with hematologic malignancies (HM). However, despite their presumed negative effects on quality of life (QoL), sexual health is not typically considered in the QoL assessment of HM patients. In addition, very few studies have been conducted in this area. Therefore, it would be important to further investigate how newer drugs developed in recent years for patients with HM, including targeted therapies and impact on sexual health, and how this influence overall patients' QoL outcomes.

https://ift.tt/2HxXQT3

The views of patients with metastatic prostate cancer towards physical activity: a qualitative exploration

Abstract

Purpose

Patients with metastatic cancer can experience debilitating symptoms, which may influence attitudes towards and engagement in physical activity. This study aimed to examine the attitudes of patients living with metastatic prostate cancer towards physical activity.

Materials and methods

Semi-structured interviews were completed with male patients living with metastatic prostate cancer. Interviews included eight questions related to patients' attitudes towards physical activity. Content analysis was conducted on the transcribed interview data. Twenty men with metastatic prostate cancer (mean age 71 ± 8.5 years; body mass index 30.19 ± 5.37 kg/cm²) and associated bone metastases (55% with > 2 regions affected) participated in the study.

Results

Men's views towards physical activity were coded into the following major themes: (1) barriers to physical activity, (2) benefits of physical activity, (3) a reduction in physical activity levels post diagnosis and (4) social support for physical activity. Symptoms of metastatic prostate cancer and treatment side effects including pain and fatigue negatively influenced activity participation. In addition, many generic barriers to physical activity were described such as bad weather and a lack of suitable facilities for exercising in rural areas.

Conclusion

Men living with metastatic prostate cancer have unique needs regarding physical activity related to symptoms of both their cancer and cancer treatment. There is a need to increase prompts that encourage those with metastatic prostate cancer to maintain/increase physical activity levels post diagnosis. Given the individualised needs of this patient group, referral to a cancer exercise specialist should be considered for prescription of tailored physical activity programmes.

Trial registration

Clinicaltrials.gov NLM Identifier: NCT02453139

https://ift.tt/2qWd0u2

Chemotherapy-induced nausea and vomiting (CINV) in patients with advanced lung cancer during the first-line treatment: assessment by physicians, nurses, and patients from an Italian multicenter survey

Abstract

Purpose

Chemotherapy-induced nausea and vomiting (CINV) still represents a common side-effect of chemotherapy, and often, its perception differs between patients and healthcare professionals. The aim of this study was to evaluate the agreement on the perception of CINV and other items among clinicians, patients, and nurses.

Methods

This observational prospective study was part of an evaluation program promoted by the Women Against Lung Cancer in Europe (WALCE) Onlus. From August 2015 to February 2016, a survey was administered in 11 oncologic institutions to 188 stage IV lung cancer patients and to their oncologists and nurses during first-line chemotherapy. Our survey investigated 11 aspects: anxiety, mood, weakness, appetite, nausea, vomiting, pain, drowsiness, breath, general condition, and trust in treatments. These items were assessed through Numerical Rating Scale at four consecutive evaluations: at T0 (immediately prior to the first cycle), at T1 (immediately prior to the second cycle), at T2 (immediately prior to the third cycle), and at T3 (immediately prior to the fourth cycle). Clinician versus patient (CvP), nurse versus patient (NvP), and clinician versus nurse (CvN) agreements were estimated applying Weighted Cohen's kappa. A multivariate logistic model and generalized equation estimates were applied to evaluate factors possibly influencing CINV development.

Results

The incidence of patients reporting CINV varied from 40% at T0 to 71% at T3. Both CvP and NvP agreement on the investigated items were mainly moderate, slightly increasing over time, and becoming substantial for some items, in particular for NvP. Pre-chemotherapy anxiety in its mild, moderate, and severe manifestations, as well as mild, moderate, and severe anxiety experienced after chemotherapy start, exposed patients to a higher risk of anticipatory and acute/delayed CINV, respectively.

Conclusions

Despite clinical staff awareness of patients' status and perceptions, CINV still represents a clinical problem. This study confirms that particular attention should be paid to anxiety due to its key role in CINV development.

https://ift.tt/2qYFHam

Bismuth adjuvant and adverse effects of chemotherapy: issues with statistical analyses

https://ift.tt/2HxXvjf

Vitamin “G”arden: a qualitative study exploring perception/s of horticultural therapy on a palliative care ward

Abstract

Purpose

In a palliative care setting, the preservation of quality of life is of particular importance. Horticultural therapy (HT) is reported as an excellent way to improve physical as well as psychological well-being, reduce levels of anxiety and depression, and promote social interaction. The use of horticultural interventions in palliative care has not yet been explored. The aim of this study was to explore the effects of HT in patients and team members on a palliative care ward.

Methods

This study was based on a qualitative methodology, comprising 20 semistructured interviews with 15 advanced cancer patients participating in HT and with 5 members of the palliative care team. Interviews were analyzed using NVivo 10 software based on thematic analysis.

Results

The results revealed the following themes: (1) well-being, (2) variation of clinical routine, (3) creation, and (4) building relationships. Patients experienced positive stimulation through HT, were distracted from daily clinical routines, enjoyed creative work, and were able to build relationships with other patients. HT was also welcomed by the members of the palliative care team. Thirty-six percent of the patients did not meet the inclusion criteria, and 45% could not participate in the second or third HT session.

Conclusions

Our study showed that the availability of HT was highly appreciated by the patients as well as by the palliative care team. Nevertheless, the dropout rate was high, and therefore, it might be more feasible to integrate green spaces into palliative care wards.

https://ift.tt/2HT2iPo

Administrating docetaxel, doxorubicin, and cyclophosphamide as a neoadjuvant treatment may decrease lymphedema risk in breast cancer patients

https://ift.tt/2Js8yLi

Diagnostic-driven antifungal approach in neutropenic patients at high risk for chronic disseminated candidiasis: preliminary observations on the role of 1,3-β-D-glucan antigenemia and multiphasic contrast-enhanced computed tomography

https://ift.tt/2HT2iim

Sleep disturbance among Chinese breast cancer survivors living in the USA

Abstract

Purpose

Emerging evidence suggests Chinese breast cancer survivors, a largely understudied population, are at increased risk of sleep disturbance which can have significant impacts on quality of life and other important outcomes. This study aims to describe sleep disturbance among Chinese breast cancer survivors and to examine demographic and clinical correlates as well as psychosocial correlates of sleep disturbance.

Methods

Data from 80 Chinese breast cancer survivors in the USA completed the Chinese version of the Pittsburgh Sleep Quality Index as well as measures of quality of life, depressive symptoms, and perceived stress. Participants also completed measures of demographic factors and acculturation.

Results

Two thirds (66%) of survivors experienced elevated sleep disturbance. Approximately half (49%) reported sleep efficiency, the percentage of time in bed that is spent asleep, that was below the recommended cutoff. Compared to those without sleep disturbance, those with sleep disturbance had worse quality of life, more depressive symptoms, and more perceived stress (ps ≤ .01).

Conclusions

This study is among the first to examine sleep disturbance among any Asian cancer population in the USA. Findings indicate Chinese breast cancer survivors may experience significant disparities in sleep disturbance relative to non-Hispanic Whites and suggest an urgent need for interventions to address sleep disturbance among Chinese breast cancer survivors.

https://ift.tt/2Hw1nBg

Transfusion practice patterns in patients with anemia receiving myelosuppressive chemotherapy for nonmyeloid cancer: results from a prospective observational study

Abstract

Purpose

The decision to prescribe packed red blood cell (PRBC) transfusions in patients with chemotherapy-induced anemia (CIA) includes assessment of clinical features such as the patient's cancer type and treatment regimen, severity of anemia symptoms, and presence of comorbidities. We examined contemporary transfusion practices in patients with nonmyeloid cancer and CIA.

Methods

Key inclusion criteria were age ≥ 18 years with nonmyeloid cancer, receiving first/second-line myelosuppressive chemotherapy, baseline hemoglobin (Hb) ≤ 10.0 g/dL, and planned to receive ≥ 1 PRBC transfusions. Exclusion criteria were receipt of erythropoiesis-stimulating agents within 8 weeks of screening and/or chronic renal insufficiency. Data were collected from patients' medical records, laboratory values, and physician/provider questionnaires. Proportion of patients for each clinical consideration leading to a decision to prescribe a PRBC transfusion and 95% exact binomial confidence intervals were determined.

Results

The study enrolled 154 patients at 18 sites in USA; 147 (95.5%) received a PRBC transfusion. Fatigue was the most common symptom affecting the decision to prescribe a PRBC transfusion (101 [69.2%] patients). Of the three reasons selected as primary considerations for prescribing a PRBC transfusion, anemia symptoms (106 [72.1%] patients) was the most frequently reported, followed by Hb value (37 [25.2%] patients) and medical history (4 [2.7%] patients).

Conclusions

In this study, the primary consideration for prescribing a PRBC transfusion was anemia symptoms in 72.1% of patients, with only 25.2% of patients prescribed a transfusion based exclusively on Hb value. Results indicate that clinical judgment and patient symptoms, not just Hb value, were used in decisions to prescribe PRBC transfusions.

https://ift.tt/2HPlfCx

Digestive toxicities after palliative three-dimensional conformal radiation therapy (3D-CRT) for cervico-thoracic spinal metastases

Abstract

Objective

The palliative treatment for cervico-thoracic spinal metastases is based on a three-dimensional conformal radiation therapy (3D-CRT). Digestive toxicities are common and cause a clinical impact frequently underestimated in patients. We performed a retrospective study of digestive side effects occurring after palliative 3D-CRT for cervico-thoracic spinal metastases.

Patients and methods

All patients receiving palliative 3D-CRT at Jean Bernard Center from January 2013 to December 2014 for spinal metastases between the 5th cervical vertebra (C5) and the 12th thoracic vertebra (T12) were eligible. Three-dimensional conformal RT was delivered by a linear accelerator (CLINAC, Varian). Premedication to prevent digestive toxicities was not used. Adverse events ("esophagitis" and "nausea and/or vomiting") were evaluated according to the NCI-CTCae (version 4).

Results

From January 2013 to December 2014, 128 patients met the study criteria. The median age was 68.6 years [31.8; 88.6]. Most patients (84.4%) received 30 Gy in 10 fractions. The median overall time of treatment was 13 days [3–33]. Forty patients (31.3%) suffered from grade ≥ 2 of "esophagitis" (35 grade 2 (27.4%) and 5 grade 3 (3.9%)). Eight patients (6.3%) suffered from grade ≥ 2 of "nausea and/or vomiting" (6 grade 2 (4.7%), 1 grade 3 (0.8%), and 1 grade 4 (0.8%)).

Conclusion

The high incidence of moderate to severe digestive toxicities after palliative 3D-CRT for cervico-thoracic spinal metastases led to consider static or dynamic intensity-modulated radiation therapy (IMRT) to reduce the dose to organ at risk (the esophagus and stomach). Dosimetric studies and implementation in the clinic should be the next steps.

https://ift.tt/2qXuCGU

Influence of family on expected benefits of complementary and alternative medicine (CAM) in cancer patients

Abstract

Background

Cancer patients often use complementary and alternative medicine (CAM) based on recommendations from family. However, the relationship between family endorsement of CAM and the patient's expectation of its benefits has never been quantified.

Methods

Between 2010 and 2011, we conducted a cross-sectional survey study among patients with a diagnosis of cancer recruited from thoracic, breast, and gastrointestinal medical oncology clinics at a single academic cancer center. We performed multivariate linear regression analyses to evaluate the relationship between perceived family endorsement of and expected benefits from CAM, adjusting for covariates.

Results

Among the 962 participants, 303 (31.3%) reported family endorsement of CAM use. Younger patients and those who had college or higher education were more likely to report family endorsement (both p < 0.05). Patients with family support had expectation scores that were 15.9 higher than patients without family support (coefficient 15.9, 95% CI 13.5, 18.2, p < 0.001). Participants with family encouragement of CAM use were also more likely to expect CAM to cure their cancer (12 vs. 37%) and prolong their life (24 vs. 61%). These relationships remained highly significant after adjusting for covariates).

Conclusions

Family endorsement of CAM use is strongly associated with patient expectation of its clinical efficacy, including expectations for cure and improved survival. These findings underscore the importance of including family in counseling and education on CAM use in order to achieve realistic patient expectations, maximize benefits, and avoid potential medical adverse effects through herb-drug interactions or rejections of conventional care.

https://ift.tt/2Hrc4ca

An investigation into the nutritional status of patients receiving an Enhanced Recovery After Surgery (ERAS) protocol versus standard care following Oesophagectomy

Abstract

Purpose

Enhanced Recovery After Surgery (ERAS) protocols have been effectively expanded to various surgical specialities including oesophagectomy. Despite nutrition being a key component, actual nutrition outcomes and specific guidelines are lacking. This cohort comparison study aims to compare nutritional status and adherence during implementation of a standardised post-operative nutritional support protocol, as part of ERAS, compared to those who received usual care.

Methods

Two groups of patients undergoing resection of oesophageal cancer were studied. Group 1 (n = 17) underwent oesophagectomy between Oct 2014 and Nov 2016 during implementation of an ERAS protocol. Patients in group 2 (n = 16) underwent oesophagectomy between Jan 2011 and Dec 2012 prior to the implementation of ERAS. Demographic, nutritional status, dietary intake and adherence data were collected. Ordinal data was analysed using independent t tests, and categorical data using chi-square tests.

Results

There was no significant difference in nutrition status, dietary intake or length of stay following implementation of an ERAS protocol. Malnutrition remained prevalent in both groups at day 42 post surgery (n = 10, 83% usual care; and n = 9, 60% ERAS). A significant difference was demonstrated in adherence with earlier initiation of oral free fluids (p <0.008), transition to soft diet (p <0.004) and continuation of jejunostomy feeds on discharge (p <0.000) for the ERAS group.

Conclusion

A standardised post-operative nutrition protocol, within an ERAS framework, results in earlier transition to oral intake; however, malnutrition remains prevalent post surgery. Further large-scale studies are warranted to examine individualised decision-making regarding nutrition support within an ERAS protocol.

https://ift.tt/2Jsz0o0

Transfusion practices at end of life for hematopoietic stem cell transplant patients

Abstract

Purpose

Limited data exist regarding transfusion practices at end of life (EOL) for hematopoietic stem cell transplant (HSCT) patients. The purpose of this study was to examine red blood cell (RBC) and platelet transfusion practices in HSCT patients who enrolled or did not enroll in hospice.

Methods

This was a single-center, retrospective chart review in deceased HSCT patients. The primary objective was to determine the mean difference between the last transfusion and death in HSCT patients (n = 116) who enrolled or did not enroll in hospice.

Results

Sixteen (14%) and 100 (86%) patients were enrolled in hospice and not enrolled in hospice, respectively. Hospice patients observed a larger mean difference between death and last transfusion (45.9 ± 66.7 vs. 14.6 ± 48.1 days, p < 0.0001). A higher amount of platelet, but not RBC, transfusions occurred in patients not enrolled in hospice (p = 0.04). The last transfusion that occurred more than 96 h before death was observed in 12 (75%) and 22 (22%) in hospice and non-hospice patients, respectively. For HSCT patients not enrolled in hospice, 17 patients received a transfusion on the same day of death and 31 patients received the last transfusion 24 h before death.

Conclusions

Blood transfusion practices differed in HSCT patients enrolled and not enrolled in hospice. For most patients not enrolled in hospice, the last transfusion occurred 24 h before death. Future efforts should explore if limited access to blood products is a barrier to hospice enrollment for HSCT patients.

https://ift.tt/2HUJq2N

Applying pre-participation exercise screening to breast cancer survivors: a cross-sectional study

Abstract

Purpose

Clinical guidelines recommend that breast cancer (BrCa) survivors be prescribed exercise. However, clinicians often do not prescribe exercise citing the presence of multiple health issues found among cancer survivors. No study has examined the proportion of BrCa survivors that can be prescribed a community/home-based unsupervised exercise program safely and independently, without further medical investigations or supervision.

Methods

Participants included BrCa survivors who received treatment at a university healthcare system between 2009 and 2014. We applied previously identified published guidelines for health conditions that may impede BrCa survivors from completing a community/home-based exercise program. Logistic regression models were used to quantify the magnitude of the association between demographic and clinical characteristics and the ability to perform community/home-based exercise.

Results

Among 667 BrCa survivors, 65 to 75% was classified as able to complete community/home-based exercise as recommended by the clinical guidelines. Older age, black race, treatment with chemotherapy, and treatment with radiation were associated with the potential need for further medical evaluation prior to starting exercise.

Conclusions

A large proportion of BrCa survivors can be prescribed community/home-based exercise program safely and independently, without further medical investigations or supervision. Future research will be needed to determine how to identify the subset of BrCa survivors that may benefit from medical evaluation prior to starting exercise in a manner that does not interrupt clinical oncology workflow. Approximately 35% of BrCa survivors may benefit from medical evaluation prior to starting community/home-based exercise.

https://ift.tt/2r61oF5

Convergent priorities and tensions: a qualitative study of the integration of complementary and alternative therapies with conventional cancer treatment

Abstract

Purpose

Demand for complementary and alternative medicine (CAM) is high among cancer patients. This, alongside growing evidence for the efficacy of some CAM therapies, is driving change within cancer centres, where evidence-based CAM therapies are increasingly provided alongside standard cancer treatments. In Australia, commitment to equitable access to healthcare is strong, and some cancer centres are now providing integrative services at no cost to the patient. This represents a significant shift in healthcare provision. This study aimed to examine health professional and patient dynamics in an integrated cancer service where CAM is provided at no cost to patients alongside standard cancer treatments. It specifically sought to understand what might drive or hinder further integration of CAM with standard treatment in the cancer context.

Methods

Qualitative interviews were undertaken with twenty key stakeholders—cancer patients, cancer nurses, and oncologists—who were delivering or receiving care in an Australian public hospital where acupuncture services are provided at no cost to patients alongside standard chemotherapy and radiation treatments.

Results

Findings point to key areas where the concerns and priorities of cancer patients, cancer nurses, and oncologists converge and diverge in ways that reflect core personal and professional interests regarding patient care needs, the evidence base for CAM efficacy and safety, and rising healthcare costs.

Conclusions

Understanding points of convergence and divergence could assist clinicians and service providers in negotiating ways forward for integrative cancer services.

https://ift.tt/2Hq1LFc

Impact of clinical trial participation on survival in patients with castration-resistant prostate cancer: a multi-center analysis

Abstract

Background

Clinical trial (CT) participation may confer access to new, potentially active agents before their general availability. This study aimed to investigate the potential survival benefit of participation in investigational CTs of novel hormonal, chemotherapeutic, and radiopharmaceutical agents in patients with castration-resistant prostate cancer (CRPC).

Methods

This multi-center, retrospective analysis included 299 consecutive patients with newly diagnosed, non-metastatic or metastatic CRPC between September 2009 and March 2017. Of these, 65 (21.7%) patients participated in CTs pertaining to systemic treatment targeting CRPC and 234 (78.3%) patients received pre-established, standard systemic treatment outside of a CT setting. The survival advantage of CT participation regarding cancer-specific survival (CSS) was investigated.

Results

An Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at CRPC diagnosis was found in a lower proportion CT participants than in non-participants (4.6% vs. 14.9%; p = 0.033). During the median follow-up period of 16.0 months, CT participants exhibited significantly higher 2-year CSS survival rates (61.3% vs. 42.4%; p = 0.003) than did non-participants. Multivariate analysis identified prostate-specific antigen and alkaline phosphatase levels at CRPC onset, Gleason score ≥ 8, ECOG PS ≥2, less number of docetaxel cycles administered, and non-participation in CTs as independent predictors for a lower risk of CSS.

Conclusions

Patients diagnosed with CRPC who participated in CTs exhibited longer CSS durations than non-participants who received pre-established, standard systemic therapy outside of a CT setting. Our findings imply that CT participation is associated with CSS, and that CT participation should be offered to patients with CRPC whenever indicated.

from Cancer via ola Kala on Inoreader https://ift.tt/2HPfHYJ
via IFTTT

Bevacizumab biosimilars: scientific justification for extrapolation of indications

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader https://ift.tt/2Ff9Zu1
via IFTTT

Present role and future perspectives of interventional radiology in the treatment of painful bone lesions

Future Oncology, Ahead of Print.


from Cancer via ola Kala on Inoreader https://ift.tt/2KgeE2j
via IFTTT

Impact of clinical trial participation on survival in patients with castration-resistant prostate cancer: a multi-center analysis

Abstract

Background

Clinical trial (CT) participation may confer access to new, potentially active agents before their general availability. This study aimed to investigate the potential survival benefit of participation in investigational CTs of novel hormonal, chemotherapeutic, and radiopharmaceutical agents in patients with castration-resistant prostate cancer (CRPC).

Methods

This multi-center, retrospective analysis included 299 consecutive patients with newly diagnosed, non-metastatic or metastatic CRPC between September 2009 and March 2017. Of these, 65 (21.7%) patients participated in CTs pertaining to systemic treatment targeting CRPC and 234 (78.3%) patients received pre-established, standard systemic treatment outside of a CT setting. The survival advantage of CT participation regarding cancer-specific survival (CSS) was investigated.

Results

An Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 at CRPC diagnosis was found in a lower proportion CT participants than in non-participants (4.6% vs. 14.9%; p = 0.033). During the median follow-up period of 16.0 months, CT participants exhibited significantly higher 2-year CSS survival rates (61.3% vs. 42.4%; p = 0.003) than did non-participants. Multivariate analysis identified prostate-specific antigen and alkaline phosphatase levels at CRPC onset, Gleason score ≥ 8, ECOG PS ≥2, less number of docetaxel cycles administered, and non-participation in CTs as independent predictors for a lower risk of CSS.

Conclusions

Patients diagnosed with CRPC who participated in CTs exhibited longer CSS durations than non-participants who received pre-established, standard systemic therapy outside of a CT setting. Our findings imply that CT participation is associated with CSS, and that CT participation should be offered to patients with CRPC whenever indicated.

https://ift.tt/2HPfHYJ

Difference in prostate cancer incidence around sixty years: effects of age and metabolic diseases

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2vMO123
via IFTTT

Multicenter analysis of stereotactic radiotherapy of the resection cavity in patients with brain metastases

Cancer Medicine, EarlyView.


from Cancer via ola Kala on Inoreader https://ift.tt/2qZMK2R
via IFTTT

Bevacizumab biosimilars: scientific justification for extrapolation of indications

Future Oncology, Ahead of Print.


https://ift.tt/2Ff9Zu1

Present role and future perspectives of interventional radiology in the treatment of painful bone lesions

Future Oncology, Ahead of Print.


https://ift.tt/2KgeE2j

Difference in prostate cancer incidence around sixty years: effects of age and metabolic diseases

Cancer Medicine, EarlyView.


https://ift.tt/2vMO123

Multicenter analysis of stereotactic radiotherapy of the resection cavity in patients with brain metastases

Cancer Medicine, EarlyView.


https://ift.tt/2qZMK2R

Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides

Summary

Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Rα) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Rα upregulates Foxp3 expression and induces the development of regulatory T (T_reg) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing T_reg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Rα. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL-2Rα binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL-2Rα signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-γ]) and granules (perforin/granzyme B) was preserved in CD8⁺ T cells co-cultured with IL-2–stimulated CD4⁺ T cells that had been pretreated with CMD178 compared to CD8⁺ cells co-cultured with untreated IL-2–stimulated CD4⁺ T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL-2Rα signaling and inhibit T_reg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies.

from Cancer via ola Kala on Inoreader https://ift.tt/2KgD3ov
via IFTTT

Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides

Summary

Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Rα) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Rα upregulates Foxp3 expression and induces the development of regulatory T (T_reg) cells. Methods To inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of Foxp3 and decreasing T_reg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Rα. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL-2Rα binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL-2Rα signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-γ]) and granules (perforin/granzyme B) was preserved in CD8⁺ T cells co-cultured with IL-2–stimulated CD4⁺ T cells that had been pretreated with CMD178 compared to CD8⁺ cells co-cultured with untreated IL-2–stimulated CD4⁺ T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL-2Rα signaling and inhibit T_reg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies.

https://ift.tt/2KgD3ov

Quantitative dynamic susceptibility contrast perfusion-weighted imaging-guided customized gamma knife re-irradiation of recurrent high-grade gliomas

Abstract

Introduction

Treatment of recurrent high-grade gliomas (rHGG) has always been challenging. This study aimed to explore the treatment effect of quantitative dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI)-guided gamma knife radiosurgery (GKRS) on rHGG.

Methods

Between April 2014 and July 2016, 26 consecutive patients were treated by quantitative DSC-PWI-guided GKRS as salvage treatment for rHGG. The gross tumor volume (GTV) was defined as the high perfusion area on absolute cerebral blood volume maps, with a cutoff value of 22 ml/100 g. The clinical target volume (CTV) encompassed the GTV by 3 mm. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan–Meier method. Prognostic factors were tested by the log-rank (Mantel–Cox) test.

Results

With a median follow-up of 32 months, the median PFS after GKRS was 8 months (95% CI [6, 12]); the 1- and 2-year survival rates were 30.8 and 11.5%, respectively. The median OS was 25.5 months (95% CI [18, 40]); the 1- and 2-year survival rates were 96.2 and 57.7%, respectively. Pathology grade and CTV were identified as prognostic factors for PFS. However, none of the parameters tested were independent prognostic factors for OS among these selected patients. No severe radiotoxicity was observed among all patients.

Conclusions

Quantitative DSC-PWI-guided GKRS is feasible for the treatment of rHGG and that these outcomes remain to be validated. Despite this, we think that carefully selected patients can benefit from this treatment method.

from Cancer via ola Kala on Inoreader https://ift.tt/2r1pEb1
via IFTTT

Quantitative dynamic susceptibility contrast perfusion-weighted imaging-guided customized gamma knife re-irradiation of recurrent high-grade gliomas

Abstract

Introduction

Treatment of recurrent high-grade gliomas (rHGG) has always been challenging. This study aimed to explore the treatment effect of quantitative dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI)-guided gamma knife radiosurgery (GKRS) on rHGG.

Methods

Between April 2014 and July 2016, 26 consecutive patients were treated by quantitative DSC-PWI-guided GKRS as salvage treatment for rHGG. The gross tumor volume (GTV) was defined as the high perfusion area on absolute cerebral blood volume maps, with a cutoff value of 22 ml/100 g. The clinical target volume (CTV) encompassed the GTV by 3 mm. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan–Meier method. Prognostic factors were tested by the log-rank (Mantel–Cox) test.

Results

With a median follow-up of 32 months, the median PFS after GKRS was 8 months (95% CI [6, 12]); the 1- and 2-year survival rates were 30.8 and 11.5%, respectively. The median OS was 25.5 months (95% CI [18, 40]); the 1- and 2-year survival rates were 96.2 and 57.7%, respectively. Pathology grade and CTV were identified as prognostic factors for PFS. However, none of the parameters tested were independent prognostic factors for OS among these selected patients. No severe radiotoxicity was observed among all patients.

Conclusions

Quantitative DSC-PWI-guided GKRS is feasible for the treatment of rHGG and that these outcomes remain to be validated. Despite this, we think that carefully selected patients can benefit from this treatment method.

https://ift.tt/2r1pEb1

An international survey on hybrid imaging: do technology advances preempt our training and education efforts?

Abstract

Background

Hybrid PET/CT and PET/MRI are increasingly important technologies in the evaluation of malignancy and require cooperation between radiologists and specialists in molecular imaging. The aim of our study was to probe the mindsets of radiological and nuclear medicine professionals in regard to current hybrid imaging practice and to assess relevant training aspirations and perceived shortfalls, particularly amongst young professionals. In this context, we initiated an international survey on "Hybrid Imaging Training".

Methods

An online survey was prepared on-line and launched on October-2, 2016. It was composed of 17 multiple-choice and open questions regarding the professional background, a perspective on hybrid imaging training efforts and lessons to be learned from disparate craft groups. The survey ran for 2 weeks. We report total responses per category and individual free-text responses.

Results

In total, 248 responses were collected with a mean age of all responders of (41 ± 11) y. Overall, 36% were within the target age range of (20–35) y. Across all responders, the majority (72%) commented on there being too few hybrid imaging experts in their country, whereas only 1% said that there were too many. Three quarters of the responders were in favour of a curriculum allowing sub-specialisation in hybrid imaging. With respect to reporting of hybrid imaging, confidence increased with age. The average rating across all responders on the level of cooperation among the two specialties suggested a low overall level of satisfaction. However, the survey feedback indicated the local (on-site) cooperation being somewhat better than the perceived cooperation between the relevant associations on a European level.

Conclusion

We consider these results to represent an appropriate cross-section of professional opinions of imaging experts across different demographic and hierarchical levels. Collectively they provide evidence supporting a need to address current shortfalls in developing hybrid imaging expertise through national educational plans, and, thus, contribute to helping improve patient care.

from Cancer via ola Kala on Inoreader https://ift.tt/2HY7Fuc
via IFTTT

An international survey on hybrid imaging: do technology advances preempt our training and education efforts?

Abstract

Background

Hybrid PET/CT and PET/MRI are increasingly important technologies in the evaluation of malignancy and require cooperation between radiologists and specialists in molecular imaging. The aim of our study was to probe the mindsets of radiological and nuclear medicine professionals in regard to current hybrid imaging practice and to assess relevant training aspirations and perceived shortfalls, particularly amongst young professionals. In this context, we initiated an international survey on "Hybrid Imaging Training".

Methods

An online survey was prepared on-line and launched on October-2, 2016. It was composed of 17 multiple-choice and open questions regarding the professional background, a perspective on hybrid imaging training efforts and lessons to be learned from disparate craft groups. The survey ran for 2 weeks. We report total responses per category and individual free-text responses.

Results

In total, 248 responses were collected with a mean age of all responders of (41 ± 11) y. Overall, 36% were within the target age range of (20–35) y. Across all responders, the majority (72%) commented on there being too few hybrid imaging experts in their country, whereas only 1% said that there were too many. Three quarters of the responders were in favour of a curriculum allowing sub-specialisation in hybrid imaging. With respect to reporting of hybrid imaging, confidence increased with age. The average rating across all responders on the level of cooperation among the two specialties suggested a low overall level of satisfaction. However, the survey feedback indicated the local (on-site) cooperation being somewhat better than the perceived cooperation between the relevant associations on a European level.

Conclusion

We consider these results to represent an appropriate cross-section of professional opinions of imaging experts across different demographic and hierarchical levels. Collectively they provide evidence supporting a need to address current shortfalls in developing hybrid imaging expertise through national educational plans, and, thus, contribute to helping improve patient care.

https://ift.tt/2HY7Fuc

PROs in regulatory decision making

Paul Kleutz from the US FDA discusses the issues surrounding the use of patient-reported outcomes in regulatory decision making.

https://ift.tt/2Hy4Lv6

A high-content screening of anti-cancer compounds suggests the multiple tyrosine kinase inhibitor ponatinib for repurposing in neuroblastoma therapy

Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anti-cancer compounds library. In the primary screening we employed three NB cell lines, grown as 3D multicellular spheroids, which were treated with 10 μM of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in 2D and 3D models. Dose-response curves were then supplemented with the data on side-effects, therapeutic index and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy.

https://ift.tt/2Jqzhrs

Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and up-regulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1 resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1 resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways.

https://ift.tt/2KfWy0K

Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient derived xenografts in vivo

Overexpression or activation of AKT is very well known to control cell growth, survival and gene expression in solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens, has exhibited various pharmacological and physiological properties, including anti-tumor, anti-bacterial and anti-inflammatory effects. In this study, we demonstrated that oridonin is an inhibitor of AKT and suppresses proliferation of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. The role of AKT in ESCC was studied using immuno- histochemical analysis of a tumor microarray, the effect of AKT knockdown on cell growth, and treatment of cells with MK-2206, an AKT inhibitor. Oridonin blocked AKT kinase activity and interacted with the ATP-binding pocket of AKT. It inhibited growth of KYSE70, KYSE410 and KYSE450 esophageal cancer cells in a time- and concentration-dependent manner. Oridonin induced arrest of cells in the G2/M cell cycle phase, stimulated apoptosis and increased expression of apoptotic biomarkers, including cleaved PARP, caspase-3, caspase-7 and Bims in ESCC cell lines. Mechanistically, we found that oridonin diminished the phosphorylation and activation of AKT signaling. Furthermore, a combination of oridonin and 5-fluorouracil (FU) or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. The effects of oridonin were verified in patient derived xenograft tumors expressing high levels of AKT. In summary, our results indicate that oridonin acts as an AKT inhibitor to suppress the growth of ESCC by attenuating AKT signaling.

https://ift.tt/2Fi0avj

Molecular Profile of Advanced Thyroid Carcinomas by Next-Generation Sequencing: Characterizing tumors beyond diagnosis for targeted therapy

Next generation sequencing (NGS) for molecular diagnostics allows simultaneous testing of activating oncogenes and tumor suppressor mutations in multiple signal pathways. Extended mutational profiling of advanced thyroid cancers may enhance considerations for targeted therapies. We analyzed clinically derived molecular profiling of 216 patients with advanced thyroid carcinoma using NGS (Ion Torrent Personal Genome Machine) from 4/2012-2/2014. We examined substitutions and small indels in 46/50 cancer-related genes using Ampliseq Cancer Hotspot panel in respect to tumor diagnosis and clinical correlations. Mutations were common in advanced thyroid carcinomas 154 (71%) predominately in targetable MAPK pathway (146/216, 68%), and several PI3K/AKT pathway (8, 4%; 6 as co-mutations). BRAF V600E mutation associated with papillary (94/139, 68%), poorly differentiated (4/39, 10%) and anaplastic (3/12, 25%) carcinomas. NRAS mutations occurred in follicular (5/12, 40%) and poorly differentiated thyroid carcinoma (12/39, 31%). Tumor suppressor mutations (16, 7%) occurred predominantly in TP53 in Hurthle cell (2/5, 40%, the only mutation), in anaplastic (3/12, 25%), and poorly differentiated thyroid carcinoma (4/39, 10%) some co-mutations and in papillary thyroid carcinoma (5/139, 4%) always a co-mutation. Kaplan-Meier analysis showed patients with poorly differentiated thyroid carcinoma containing activating mutations who received targeted therapeutics showed improved survival compared to similarly treated patients without mutations in targetable pathways (p=0.02). In conclusion, MAPK pathway is the predominant target for therapy in advance thyroid carcinomas; adding NGS enables the identification of co-mutations associated with resistance (PI3K/AKT). Within poorly differentiated thyroid carcinoma, the molecular profile may hold prognostic value in the era of targeted therapy.

https://ift.tt/2Kd1cfI

Improving the in vivo efficacy of an anti-Tac (CD25) immunotoxin by Pseudomonas exotoxin A domain II engineering

Tac (CD25) is expressed on multiple hematological malignancies and is a target for cancer therapies. LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38kDa fragment of Pseudomonas exotoxin A (PE38). While LMB-2 has shown high cytotoxicity towards Tac-expressing cancer cells in clinical trials, its efficacy was hampered by the formation of anti-drug antibodies against the immunogenic bacterial toxin and by dose-limiting off-target toxicity. To reduce toxin immunogenicity and non-specific toxicity, we introduced six point mutations into domain III that were previously shown to reduce T cell immunogenicity and deleted domain II from the toxin, leaving only the 11aa furin cleavage site which is required for cytotoxic activity. While this strategy has been successfully implemented for mesothelin and CD22 targeting immunotoxins, we found that removal of domain II significantly lowered the cytotoxic activity of αTac immunotoxins. To restore cytotoxic activity in the absence of PE domain II, we implemented a combined rational design and screening approach to isolate highly active domain II deleted toxin variants. The domain II deleted variant with the highest activity contained an engineered disulfide-bridged furin cleavage site designed to mimic its native conformation within domain II. We found that this approach restored five-fold of the cytotoxic activity and dramatically improved the maximum tolerated dose. Both of these improvements led to significantly increased anti-tumor efficacy in vivo. We conclude that the next generation anti-Tac immunotoxin is an improved candidate for targeting Tac expressing malignancies.

https://ift.tt/2Jvf7wK

ASTX660, a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP, potently induces TNF-{alpha} dependent apoptosis in cancer cell lines and inhibits tumor growth

Due to their roles in the evasion of apoptosis, Inhibitor of Apoptosis Proteins (IAPs) are considered attractive targets for anti-cancer therapy. Antagonists of these proteins have the potential to switch pro-survival signaling pathways in cancer cells towards cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single agent efficacy. ASTX660 is a potent, non-peptidomimetic, antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of non-canonical NF-B signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNF-α-dependent induction of apoptosis in various cancer cell lines in vitro, while dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase 1-2 clinical trial (NCT02503423) and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective.

https://ift.tt/2KhS2ie

Selective targeting and eradication of LGR5+ CSCs using RSPO conjugated doxorubicin liposomes

Cancer stem cells (CSCs) that may account for only a small fraction of tumor mass were found to play crucial roles during tumor initiating, progression and metastasis. However, they are usually difficult to be treated and notoriously resilient to drug eradication. In this study we aimed at the Wnt signaling characteristic of cancer stem cells and designed a liposomal drug delivery system to target CSCs. Liposomes decorated with RSPO1 on the surface were constructed for specific interactions with the Wnt pathway co-receptor LGR5. Doxorubicin carried by the RSPO1-liposomes was more effective at lower concentrations than the same drug loaded in PEG-liposomes. More importantly, we showed using a Patient Derived Xerograft (PDX) tumor model where LGR5+ CSCs co-existed with LGR5- cells, the RSPO1-liposomes were able to access more CSC cells and deliver the drug specifically and efficiently. Such a focused effect in eradicating LGR5+ cells led to massive tumor tissue necrosis and growth inhibition even when only a fraction of the conventional drug dose was used. These data clearly demonstrated the advantages of CSC targeted drug delivery and would support the development of such approaches as a new cancer treatment strategy.

https://ift.tt/2r0i80Z

Tumor-independent host secretomes induced by angiogenesis and immune-checkpoint inhibitors

The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. While TIS can derive from tumor cells directly, non-tumor 'host' treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral 'side-effects' of treatment. Here we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKIs) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared to antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare 'off-target' host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or 'therasomes') may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches.

https://ift.tt/2vJPIgM

Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and up-regulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1 resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1 resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways.

from Cancer via ola Kala on Inoreader https://ift.tt/2KfWy0K
via IFTTT

Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient derived xenografts in vivo

Overexpression or activation of AKT is very well known to control cell growth, survival and gene expression in solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens, has exhibited various pharmacological and physiological properties, including anti-tumor, anti-bacterial and anti-inflammatory effects. In this study, we demonstrated that oridonin is an inhibitor of AKT and suppresses proliferation of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. The role of AKT in ESCC was studied using immuno- histochemical analysis of a tumor microarray, the effect of AKT knockdown on cell growth, and treatment of cells with MK-2206, an AKT inhibitor. Oridonin blocked AKT kinase activity and interacted with the ATP-binding pocket of AKT. It inhibited growth of KYSE70, KYSE410 and KYSE450 esophageal cancer cells in a time- and concentration-dependent manner. Oridonin induced arrest of cells in the G2/M cell cycle phase, stimulated apoptosis and increased expression of apoptotic biomarkers, including cleaved PARP, caspase-3, caspase-7 and Bims in ESCC cell lines. Mechanistically, we found that oridonin diminished the phosphorylation and activation of AKT signaling. Furthermore, a combination of oridonin and 5-fluorouracil (FU) or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. The effects of oridonin were verified in patient derived xenograft tumors expressing high levels of AKT. In summary, our results indicate that oridonin acts as an AKT inhibitor to suppress the growth of ESCC by attenuating AKT signaling.

from Cancer via ola Kala on Inoreader https://ift.tt/2Fi0avj
via IFTTT

Molecular Profile of Advanced Thyroid Carcinomas by Next-Generation Sequencing: Characterizing tumors beyond diagnosis for targeted therapy

Next generation sequencing (NGS) for molecular diagnostics allows simultaneous testing of activating oncogenes and tumor suppressor mutations in multiple signal pathways. Extended mutational profiling of advanced thyroid cancers may enhance considerations for targeted therapies. We analyzed clinically derived molecular profiling of 216 patients with advanced thyroid carcinoma using NGS (Ion Torrent Personal Genome Machine) from 4/2012-2/2014. We examined substitutions and small indels in 46/50 cancer-related genes using Ampliseq Cancer Hotspot panel in respect to tumor diagnosis and clinical correlations. Mutations were common in advanced thyroid carcinomas 154 (71%) predominately in targetable MAPK pathway (146/216, 68%), and several PI3K/AKT pathway (8, 4%; 6 as co-mutations). BRAF V600E mutation associated with papillary (94/139, 68%), poorly differentiated (4/39, 10%) and anaplastic (3/12, 25%) carcinomas. NRAS mutations occurred in follicular (5/12, 40%) and poorly differentiated thyroid carcinoma (12/39, 31%). Tumor suppressor mutations (16, 7%) occurred predominantly in TP53 in Hurthle cell (2/5, 40%, the only mutation), in anaplastic (3/12, 25%), and poorly differentiated thyroid carcinoma (4/39, 10%) some co-mutations and in papillary thyroid carcinoma (5/139, 4%) always a co-mutation. Kaplan-Meier analysis showed patients with poorly differentiated thyroid carcinoma containing activating mutations who received targeted therapeutics showed improved survival compared to similarly treated patients without mutations in targetable pathways (p=0.02). In conclusion, MAPK pathway is the predominant target for therapy in advance thyroid carcinomas; adding NGS enables the identification of co-mutations associated with resistance (PI3K/AKT). Within poorly differentiated thyroid carcinoma, the molecular profile may hold prognostic value in the era of targeted therapy.

from Cancer via ola Kala on Inoreader https://ift.tt/2Kd1cfI
via IFTTT

Improving the in vivo efficacy of an anti-Tac (CD25) immunotoxin by Pseudomonas exotoxin A domain II engineering

Tac (CD25) is expressed on multiple hematological malignancies and is a target for cancer therapies. LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38kDa fragment of Pseudomonas exotoxin A (PE38). While LMB-2 has shown high cytotoxicity towards Tac-expressing cancer cells in clinical trials, its efficacy was hampered by the formation of anti-drug antibodies against the immunogenic bacterial toxin and by dose-limiting off-target toxicity. To reduce toxin immunogenicity and non-specific toxicity, we introduced six point mutations into domain III that were previously shown to reduce T cell immunogenicity and deleted domain II from the toxin, leaving only the 11aa furin cleavage site which is required for cytotoxic activity. While this strategy has been successfully implemented for mesothelin and CD22 targeting immunotoxins, we found that removal of domain II significantly lowered the cytotoxic activity of αTac immunotoxins. To restore cytotoxic activity in the absence of PE domain II, we implemented a combined rational design and screening approach to isolate highly active domain II deleted toxin variants. The domain II deleted variant with the highest activity contained an engineered disulfide-bridged furin cleavage site designed to mimic its native conformation within domain II. We found that this approach restored five-fold of the cytotoxic activity and dramatically improved the maximum tolerated dose. Both of these improvements led to significantly increased anti-tumor efficacy in vivo. We conclude that the next generation anti-Tac immunotoxin is an improved candidate for targeting Tac expressing malignancies.

from Cancer via ola Kala on Inoreader https://ift.tt/2Jvf7wK
via IFTTT

ASTX660, a novel non-peptidomimetic antagonist of cIAP1/2 and XIAP, potently induces TNF-{alpha} dependent apoptosis in cancer cell lines and inhibits tumor growth

Due to their roles in the evasion of apoptosis, Inhibitor of Apoptosis Proteins (IAPs) are considered attractive targets for anti-cancer therapy. Antagonists of these proteins have the potential to switch pro-survival signaling pathways in cancer cells towards cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single agent efficacy. ASTX660 is a potent, non-peptidomimetic, antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of non-canonical NF-B signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNF-α-dependent induction of apoptosis in various cancer cell lines in vitro, while dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase 1-2 clinical trial (NCT02503423) and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective.

from Cancer via ola Kala on Inoreader https://ift.tt/2KhS2ie
via IFTTT

Selective targeting and eradication of LGR5+ CSCs using RSPO conjugated doxorubicin liposomes

Cancer stem cells (CSCs) that may account for only a small fraction of tumor mass were found to play crucial roles during tumor initiating, progression and metastasis. However, they are usually difficult to be treated and notoriously resilient to drug eradication. In this study we aimed at the Wnt signaling characteristic of cancer stem cells and designed a liposomal drug delivery system to target CSCs. Liposomes decorated with RSPO1 on the surface were constructed for specific interactions with the Wnt pathway co-receptor LGR5. Doxorubicin carried by the RSPO1-liposomes was more effective at lower concentrations than the same drug loaded in PEG-liposomes. More importantly, we showed using a Patient Derived Xerograft (PDX) tumor model where LGR5+ CSCs co-existed with LGR5- cells, the RSPO1-liposomes were able to access more CSC cells and deliver the drug specifically and efficiently. Such a focused effect in eradicating LGR5+ cells led to massive tumor tissue necrosis and growth inhibition even when only a fraction of the conventional drug dose was used. These data clearly demonstrated the advantages of CSC targeted drug delivery and would support the development of such approaches as a new cancer treatment strategy.

from Cancer via ola Kala on Inoreader https://ift.tt/2r0i80Z
via IFTTT

Tumor-independent host secretomes induced by angiogenesis and immune-checkpoint inhibitors

The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. While TIS can derive from tumor cells directly, non-tumor 'host' treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral 'side-effects' of treatment. Here we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKIs) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared to antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare 'off-target' host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or 'therasomes') may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches.

from Cancer via ola Kala on Inoreader https://ift.tt/2vJPIgM
via IFTTT