Long Noncoding RNA MNX1-AS1 Knockdown Inhibits Cell Proliferation and Migration in Ovarian Cancer

Cancer Biotherapy & Radiopharmaceuticals Apr 2017, Vol. 32, No. 3: 91-99.


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Correction to: Cancer Biother Radiopharm 2017;32(3):101–110

Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.


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Expression of Long Noncoding RNA Urothelial Cancer Associated 1 Promotes Cisplatin Resistance in Cervical Cancer

Cancer Biotherapy & Radiopharmaceuticals Apr 2017, Vol. 32, No. 3: 101-110.


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Corrigenda

<span class="paragraphSection"><span style="font-style:italic;">Corrigendum to Toonen, Ma, and Gutman. Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction. Neuro Oncol</span> (<strong><a href="article.aspx?volume=&page=">doi:10.1093/neuonc/now267<span></span></a></strong>) <span style="font-style:italic;">first published online December 30, 2016.</span></span>

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Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category.<div class="boxTitle">Methods.</div>We assembled gene expression profiles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A first cohort was randomly split into training (<span style="font-style:italic;">n</span> = 170) and a validation dataset (<span style="font-style:italic;">n</span> = 163). A second validation set consisted of 41 expression profiles. An elastic-net penalized Cox proportional hazards model was applied to build a classifier model through cross-validation within the training dataset.<div class="boxTitle">Results.</div>The selected 35-gene signature was used to identify high-risk and low-risk groups in the validation set, which showed significantly different overall survival (<span style="font-style:italic;">P</span> = .00058, log-rank test). For time-to-death events, the high-risk group predicted by the gene signature yielded a hazard ratio of 1.78 (95% confidence interval, 1.02–3.11). The signature was also significantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDH-mutant 1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be significantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH–wild-type lower grade or IDH-mutant, non–co-deleted gliomas.<div class="boxTitle">Conclusion.</div>We identified a 35-gene signature that identifies high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratification.</span>

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Highlights from the Literature

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Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG.<div class="boxTitle">Methods.</div>Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150–200 mg/m² for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-¹⁸F-fluorothymidine (¹⁸F-FLT) PET imaging, to image proliferation before and after 7 days of MIB.<div class="boxTitle">Results.</div>Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). ¹⁸F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB.<div class="boxTitle">Conclusions.</div>MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.</span>

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Corrigenda

<span class="paragraphSection"><span style="font-style:italic;">Corrigendum to Wiedmann et al. The impact of body mass index and height on the risk for glioblastoma and other glioma subgroups: a large prospective cohort study. Neuro Oncol (doi:10.1093/neuonc/now272) first published online December 31, 2016.</span></span>

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Forthcoming Meetings

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Sex as a biological variable in response to temozolomide

<span class="paragraphSection">Although a majority of glioblastoma (GBM) patients are males at a ratio of 3 to 2,^{<a href="#CIT0001" class="reflinks">1</a>} sex is commonly overlooked as a biological variable in research. In June 2015, the National Institutes of Health recommended the inclusion of both sexes in research studies.^{<a href="#CIT0002" class="reflinks">2</a>} Studies investigating response to temozolomide (TMZ) in male versus female patients who have diagnoses of GBM have not been conclusive. Shah et al found female sex to be a prognostic indicator of improved overall survival in a retrospective review of >3300 elderly patients who received combination TMZ and radiotherapy.^{<a href="#CIT0003" class="reflinks">3</a>} However, in a second large population review using multivariate analysis, Rusthoven et al did not find a significant difference in response to chemotherapy and radiation combination treatment between elderly male and female patients.^{<a href="#CIT0004" class="reflinks">4</a>}</span>

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MEK and RAF inhibitors: time for a paradigm shift in the treatment of pediatric low-grade gliomas?

<span class="paragraphSection">See article in this issue by Sun et al., pp. 774–785.</span>

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Response assessment in high-grade glioma: tumor volume as endpoint

<span class="paragraphSection">See article in this issue by Gahrmann et al., pp. 853–861.</span>

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ABO blood group and risk of glioma

<span class="paragraphSection">Age, radiation, and rare hereditary syndromes are the only well-established risk factors for glioma.^{<a href="#CIT0001" class="reflinks">1</a>,<a href="#CIT0002" class="reflinks">2</a>} Several retrospective studies in the 1950s and 1960s investigated the relationship between ABO blood group and glioma occurrence; although some reported decreased risk of glioma in patients of group O blood, others found no association.^{<a href="#CIT0003" class="reflinks">3</a>,<a href="#CIT0004" class="reflinks">4</a>} Since then, our group showed that O blood type is inversely associated with pancreatic cancer, and non-O type is inversely related to non-melanoma skin cancer.^{<a href="#CIT0005" class="reflinks">5</a>,<a href="#CIT0006" class="reflinks">6</a>} We therefore analyzed the association between ABO blood group and risk of glioma in 2 large, prospective cohort studies, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS).</span>

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Comparison of 2D (RANO) and volumetric methods for assessment of recurrent glioblastoma treated with bevacizumab—a report from the BELOB trial

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>The current method for assessing progressive disease (PD) in glioblastoma is according to the Response Assessment in Neuro-Oncology (RANO) criteria. Bevacizumab-treated patients may show pseudo-response on postcontrast T1-weighted (T1w) MRI, and a more infiltrative non-enhancing growth pattern on T2w/fluid attenuated inversion recovery (FLAIR) images. We investigated whether the RANO criteria remain the method of choice for assessing bevacizumab-treated recurrent glioblastoma when compared with various volumetric methods.<div class="boxTitle">Methods.</div>Patients with assessable MRI data from the BELOB trial (<span style="font-style:italic;">n =</span> 148) were included. Patients were treated with bevacizumab, lomustine, or both. At first and second radiological follow-up (6 and 12 wk), PD was determined using the 2D RANO criteria and various volumetric methods based on enhancing tumor only and enhancing plus non-enhancing tumor. Differences in overall survival (OS) between PD and non-PD patients were assessed with the log-rank test and a Cox model. Hazard ratios (HRs) and their 95% CIs were determined.<div class="boxTitle">Results.</div>For all patients together, all methods (except subtraction of non-enhancing from enhancing volume at first follow-up) showed significant differences in OS between PD and non-PD patients (<span style="font-style:italic;">P <</span> .001). The largest risk increase for death in case of PD at both first and second follow-up was found with the RANO criteria: HR = 2.81 (95% CI, 1.92–4.10) and HR = 2.80 (95% CI, 1.75–4.49), respectively. In the bevacizumab-treated patients, all methods assessed showed significant differences in OS between PD and non-PD patients. There were no significant differences between methods.<div class="boxTitle">Conclusions.</div>In the first 12 weeks, volumetric methods did not provide significant improvement over the RANO criteria as a posttreatment prognostic marker.</span>

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The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC)

Abstract

Background

The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor for triple negative breast cancer (TNBC). Recent studies have shown that programmed cell death 1 (PD-1) or programmed death ligand 1 (PD-L1) is expressed on T lymphocytes or tumor cells modulating antitumor immunity. The regulation of immune checkpoints between tumor cells and T lymphocytes may serve as a target for improvement of TNBC prognosis. We investigated TILs and PD-L1 status in TNBCs before or after preoperative systemic therapy (PST) to elucidate the clinical significance of PD-L1 expression.

Methods

Ninety patients received PST, and materials of core needle biopsies (CNB) taken before PST were available for 32 patients. TILs were scored as "% stromal", and tumors were defined as High-TILs (≥30%) or Low-TILs (<30%). The expression of PD-L1 was assessed by immunohistochemistry.

Results

TILs status in CNB is significant in pathological therapeutic grade: 1 vs. 2 or 3 (p = 0.0359). Disease-free survival (DFS) in patients with Low-TIL tumors were significantly worse than those with High-TIL tumors (p = 0.0383), but overall survival (OS) showed no significance (p = 0.0772). However, in patients with Low-TIL tumors, both DFS and OS in patients with High-PD-L1 expression were extremely unfavorable than in patients with Low-PD-L1 expression (p = 0.0032, p = 0.0002).

Conclusion

The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.

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The role of miR-130a in cancer

Abstract

MicroRNAs (miRs) are short and highly conserved non-coding RNAs molecules consisting of 18–25 nucleotides that regulate gene expression at post-transcriptional level by direct binding to complementary binding sites within the 3′untranslated region (3′UTR) of target mRNAs. New evidences have demonstrated that miRNAs play an important role in diverse physiological processes, including regulating cell growth, apoptosis, metastasis, drug resistance, and invasion. In chromosomes 11 and 22 of the miR-130 family, paralogous miRNA sequences, miR-130a and miR-130b are situated, respectively. MiR-130a has participated in different pathogenesis, including hepatocellular carcinoma, cervical cancer, ovarian cancer, glioblastoma, prostate carcinoma, leukemia, etc. Most important of all, more and more evidences indicate that miR-130a is associated with drug resistance and acts as an intermediate in PI3 K/Akt/PTEN/mTOR, Wnt/β-catenin and NF-kB/PTEN drug resistance signaling pathways. Drug resistance has emerged as a major obstacle to successful treatment of cancer nowadays and in this review, we will reveal the function of miR-130a in cancer, especially in drug resistance. Therefore, it will provide a new therapeutic target for the treatment of cancer, especially in chemotherapy.

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Preemptive treatment with Xonrid®, a medical device to reduce radiation induced dermatitis in head and neck cancer patients receiving curative treatment: a pilot study

Abstract

Purpose

The purpose of this study was to investigate efficacy, safety and tolerability of Xonrid®, a new medical device, in preventing radiation dermatitis associated with head and neck cancer (HNC) radiotherapy (RT).

Methods

In this monocentric, prospective pilot study, adult consecutive HNC patients who were planned to receive curative RT with or without chemotherapy were enrolled. Patients were instructed to apply Xonrid® on the irradiated area during treatment continuing until 2 weeks after the completion of RT or the development of severe skin toxicity. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 scale. The patient reported outcome measures included the Skindex-16 questionnaire and patient satisfaction. Skin reflectance spectra were analyzed to objectively evaluate dermatitis.

Results

In total, 41 subjects were enrolled (30 males, median age 60 years). No skin adverse events were recorded either in the skin area where the product was applied or in the nearby skin over the entire period of administration. At the end of RT, nine patients (22%) presented G1, 31 (76%) G2, and one patient (2%) G3 skin toxicity (after 5 weeks). Seven and 20 patients reached skin maximum toxicity at the fourth week and after the seventh week, respectively. An increasing trend of median spectrophotometry scores along with skin toxicity grades was observed. A correlation between Skindex-16 scores and skin toxicity grade during treatment was found.

Conclusions

Our study results suggest that Xonrid® is well tolerated, safe, and effective in minimizing and delaying high-grade radiation dermatitis in HNC patients.

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Development of depression in survivors of childhood and adolescent cancer: a multi-level life course conceptual framework

Abstract

As therapeutic and supportive care interventions become increasingly effective, growing numbers of childhood and adolescent cancer survivors face a myriad of physical and psychological sequelae secondary to their disease and treatment. Mental health issues, in particular, present a significant problem in this unique patient population, with depression affecting a sizable number of childhood and adolescent cancer survivors. Multiple key determinants impact a survivor's risk of developing depression, with variables traversing across biologic, individual, family, community, and global levels, as well as spanning throughout the life course of human development from the preconception and prenatal periods to adulthood. A multi-level life course conceptual model offers a valuable framework to identify and organize the diverse variables that modulate the risk of developing depression in survivors of childhood and adolescent cancer. This review describes the first multi-level life course perspective applied to development of depression in childhood and adolescent cancer survivors. This conceptual framework may be used to guide the investigation of mental health interventions for SCACs to ensure that key determinants of depression occurrence are adequately addressed across various levels and throughout the life trajectory.

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Emesis and nausea related to single agent trabectedin in ovarian cancer patients: a sub-study of the MITO15 project

Abstract

The MITO 15 was a prospective, single-arm trial, evaluating trabectedin monotherapy in patients with recurrent ovarian cancer (OC) who were BRCA mutation-carriers or had a BRCAness phenotype. It is largely reported that trabectedin may induce nausea and vomiting but the real emetogenic potential of the drug, in the different schedules, has never been fully described; furthermore, OC patients are known to have an enhanced risk of developing nausea and vomiting due to female gender, abdominal spreading of the disease, and major surgery experienced by most of them. We thought to carry on a sub-study in the MITO 15 context focused on chemotherapy-induced nausea and vomiting (CINV) associated with trabectedin single agent. For all patients enrolled in the trial, we evaluated the antiemetic regimen at the first cycle, acute and delayed CINV, any rescue therapy, any change in the prophylactic antiemetic regimen, and the potential relationship between dexamethasone dosage and incidence of CINV. Overall, our findings were consistent with literature and confirmed that trabectedin can be classified as moderately emetogenic. We observed slightly higher rates of both nausea and vomiting compared to previous experiences with trabectedin monotherapy, probably due to intrinsic features of our population: all females and suffering from ovarian cancer. It seems that in preventing acute CINV, the combination of three drugs was more effective than the doublet; however, the difference did not reach statistical significance; further studies are required to verify such hypothesis. Given the extreme heterogeneity of the antiemetic regimens used, it appears that a standard antiemetic protocol does not exist and more specific guidelines for clinicians are needed.

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Adenoid cystic carcinoma of the breast, 20 years of experience in a single center with review of literature

Abstract

Background

Adenoid cystic carcinoma (ACC) of the breast is a rare type of breast cancer, which presents inconsistencies in the optimal management strategy.

Methods

A retrospective review of prospectively collected data, spanning the last 20 years, was performed using the cancer registry database at our institution.

Results

Six patients were diagnosed with ACC of the breast, out of 5,813 total patients diagnosed with breast cancer (0.1%). Our identified patients had a median age of 66, all with the early stage cancer (Stage I/II). The average size of the breast lesion was 1.62 cm, and nodal status was negative for all cases. All patients had resection as primary therapy (partial or total mastectomy), with one patient also undergoing external beam radiation and tamoxifen hormonal therapy. Median follow-up was 85 months, with all patients being disease-free at last follow-up.

Conclusions

ACC of the breast has an indolent course, despite triple negative status. Our study suggests that radiation may not be warranted and confirms the rarity of axillary node metastases, indicating that sentinel node excision may also not be necessary. Ultimately, the hope is that our findings along with the reviewed literature will aid in determining the most appropriate options for management of ACC of the breast.

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Nothing left to chance? The impact of locus of control on physical and mental quality of life in terminal cancer patients

Abstract

Purpose

The purpose of this study is to evaluate if locus of control (LOC) predicts various quality of life (QOL) and mental well-being measures among terminally ill cancer patients at the time of palliative care consult.

Methods

Multi-site analysis of patients with advanced cancer being seen as new patients in a Palliative and Supportive Care outpatient clinic. Patients completed the following surveys: locus of control (LOC) scale, Functional Assessment of Chronic Illness Therapy-General (FACT-G), Functional Assessment of Chronic Illness Therapy–Spiritual (FACIT-Sp), Hospital Anxiety Depression Scale (HADS), and Herth Hope Index (HHI).

Regression models were created to examine the effect of LOC upon QOL, symptoms, and other measures of mental well-being. These models adjusted for the effect of age, gender, race, partnership status, education, and months since diagnosis as potential confounders.

Results

This study enrolled 100 patients. After adjusting for site, race, and partnership status, higher levels of LOC chance predicted decreased QOL (FACT-G) (p < 0.01). Higher levels of LOC chance also correlated with increased depression and anxiety (p ≤ 0.01) and decreased meaning/peace and faith (p ≤ 0.01). Additionally, higher levels of LOC chance predicted decreased hope (HHI) (p ≤ 0.001).

Conclusions

Terminally ill cancer patients with a high LOC chance may be at risk for decreased physical and mental well-being at the end of life. Efforts should be made to identify these patients and design interventions to increase their feeling of control over the situation in order to improve physical and mental well-being at the end of life.

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Impact of recommended weight-based dosing of granulocyte-colony stimulating factors in acute leukemia and stem cell transplant patients

Abstract

Purpose

Febrile neutropenia (FN) is a major risk factor for infection-related morbidity and mortality. The National Comprehensive Cancer Network recommends the prophylactic use of granulocyte-colony stimulating factors (G-CSF), dosed at 5 mcg/kg and rounded to the nearest vial size. A previous medication use evaluation conducted within a multi-hospital healthcare system demonstrated that only 67% of patients were started on appropriate weight-based dosing. The purpose of this study was to evaluate the effect of appropriate weight-based G-CSF dosing in patients on clinical outcomes.

Methods

A retrospective chart review of patients with acute leukemia or stem cell transplant recipients who received G-CSF from May 2009 to September 2015 was conducted. Patient admissions were reviewed in regards to neutropenia length, incidence of FN, length of stay, and final disposition (alive or deceased). Admissions were divided into one of three weight-based dosing groups of under 5 mcg/kg, recommended 5 mcg/kg within a 10% range, and over 5 mcg/kg which were named under, recommended, and over, respectively.

Results

Ninety-four admissions were included. Average age of this patient population was 58 years old, and the majority of patients were male (53%) and Caucasian (55%). Majority of patients had been diagnosed with acute myeloid leukemia (91%). Data showed average duration of neutropenia was around 10 days regardless if the patient received under 5 mcg/kg, the recommended 5 mcg/kg or over 5 mcg/kg G-CSF (10.1 ± 6.7 days, 8.9 ± 9.2 days, 10.1 ± 9.1 days, respectively). Length of stay was similar for patients regardless of initial G-CSF dose (29.6 ± 16.0 days, 29.1 ± 18.4 days, and 24.5 ± 17.0, respectively). However, the incidence of FN was significantly greater for those who received under 5 mcg/kg of G-CSF (87% for under, 68% for recommended, and 54% for over).

Conclusions

In this retrospective analysis, variations from the recommended 5 mcg/kg G-CSF dose did not significantly impact length of neutropenia, length of stay, nor mortality. However, patients who received under the 5 mcg/kg of G-CSF dose may be at a greater risk of FN.

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Disease burden and pain in obese cancer patients with chemotherapy-induced peripheral neuropathy

Abstract

Purpose

Chemotherapy-induced peripheral neuropathy (CIPN) and obesity are prevalent in cancer survivors and decrease quality of life; however, the impact of the co-occurrence of these conditions has garnered little attention. This study investigated differences between obese and non-obese cancer survivors with CIPN and predictors of symptom burden and pain.

Methods

Patients with CIPN were administered the MD Anderson Symptom Inventory and a modified version of pain descriptors from the McGill Pain Inventory. Independent t tests assessed group differences between obese and non-obese survivors, and linear regression analyses explored predictors of patient outcomes.

Results

Results indicated a significant difference in symptom severity scores for obese (M = 32.89, SD = 25.53) versus non-obese (M = 19.35, SD = 16.08) patients (t(37.86) = −2.49, p = .02). Significant differences were also found for a total number of pain descriptors endorsed by obese (M = 4.21, SD = 3.45) versus non-obese (M = 2.42, SD = 2.69) participants (t(74) = −2.53, p = .01). Obesity was a significant predictor of symptom severity and total pain descriptors endorsed. Other significant predictors included age and months since treatment.

Conclusions

Cancer survivors with CIPN and co-occurring obesity may be more at risk for decreased quality of life through increased symptom severity and pain compared to non-obese survivors. This paper identified risk factors, including obesity, age, and months since treatment, that can be clinically identified for monitoring distress in CIPN patients. Future research should focus on the longitudinal relationship between obesity and CIPN, and robust interventions to address the multifaceted issues faced by cancer survivors.

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Perceptions of family members of palliative medicine and hospice patients who experienced music therapy

Abstract

Purpose

Evidence shows that music therapy aids in symptom management and improves quality of life for palliative medicine and hospice patients. The majority of previous studies have addressed patient needs, while only a few addressed the needs of family members. The primary purpose of this study was to understand family members' perceptions of music therapy experienced by a relative in palliative medicine or hospice. Patient self-reported scales and music therapist assessment of change were also investigated.

Methods

Patients scored their symptoms (pain, anxiety, depression, shortness of breath, and mood) before and after music therapy sessions. One family member present during the session assessed perceived effect on the patient's pain, anxiety, depression, shortness of breath, stress level, restlessness, comfort level, mood, and quality of life. The effect on family member's stress level, quality of life, and mood and helpfulness of the music therapy session for the patient and self were studied. Recommendations about future patient participation in music therapy and qualitative comments were also solicited.

Results

Fifty family member/patient dyads participated in the study. Family member perceptions were positive, with 82% of responders indicating improvement for self and patient in stress, mood, and quality of life; 80% rating the session as extremely helpful; and 100% of 49 recommending further music therapy sessions for the patient. Patients reported statistically significant improvement in pain, depression, distress, and mood scores.

Conclusions

Family members of patients in palliative medicine and hospice settings reported an immediate positive impact of music therapy on the patient and on themselves. More research needs to be conducted to better understand the benefits of music therapy for family members.

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Comparison of integrative medicine centers in the USA and Germany: a mixed method study

Abstract

Purpose

Integrative medicine (IM) has received increasing attention since the 1990s, but few studies have explored the key factors of the IM model in health care. This study aimed to describe the IM model in leading centers operating in the USA and Germany.

Methods

A 28-item structured survey and semi-structured interviews were conducted in six centers providing integrative medicine in the USA and Germany, and were analyzed using a convergent mixed-method approach.

Results

The elements in common across all six centers were the following: (1) involvement of general physicians (GP) in delivering complementary and alternative medicine (CAM) services; (2) requirement for GP or medical referral or recommendation to CAM services; (3) involvement of an integrative physician (IP) as a "gatekeeper"; (4) focus on research, education, and clinical practice; and (5) ongoing academic activities. The key elements differentiating the two countries were the following: (1) level of requirements for GP referral to CAM services; (2) differences in IM service delivery, including treatment modalities used; (3) accessibility of CAM services to patients; (4) interaction between team members and patients; (5) perception of CAM/IM; and (6) perception of patient-centered care. Themes underpinning these elements are the following: cultural aspects in conceptualizing IM health care; communication within IM programs; and resource availability for delivering IM services, which impacts patient engagement and team collaboration in the IM framework.

Conclusions

Delivering IM health care requires a model of care that encourages interaction between all stakeholders. Developing a comprehensive conceptual framework to support IM practice is required to facilitate efficient and safe patient care.

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A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients

Abstract

Background

Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient's ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients.

Methods

Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy.

Results

Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b < 0.08 ng/ml) demonstrated a better sensitivity and specificity for this outcome (0.70 and 0.86, respectively) than any individual cytokine or tumor marker.

Conclusions

Cachexia is frequent in pancreatic cancer; one in three patients met our endpoint of 10% weight loss or death within 60 days. Inflammatory cytokines are better than conventional tumor markers at predicting this outcome. Recursive partitioning analysis suggests that a model of CXCL-16 and IL-1B may offer a better ability than individual cytokines to predict this outcome.

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Association between bone scan index and activities of daily living in patients with advanced non-small cell lung cancer

Abstract

Purpose

The aim of this retrospective cross-sectional study was to investigate the association between the bone scan index (BSI) and activities of daily living (ADL) in patients with advanced non-small cell lung cancer (NSCLC).

Methods

Among patients with advanced NSCLC, subjects who underwent bone scintigraphy were recruited from this study. Clinical information about patients, including the Barthel Index of ADL, was extracted from their medical charts. Variables including the age, sex, BSI, presence/absence skeletal-related events (SREs), diagnostic state (initial vs. relapse), and history of use of certain medications (e.g. opiates) were evaluated as factors possibly associated with the Barthel Index. In Addition, associations between these factors, including the Barthel Index, with the overall survival were also assessed.

Results

A total of 111 patients with bone metastases were selected. The BSI and Barthel Index of the patients were 1.59 ± 2.25 and 69.7 ± 19.6, respectively. Multivariable analysis identified age (≥70 years), a high BSI (≥1.0), and presence of SREs were as factors statistically significantly associated with lower values of the Barthel Index (<75). On the other hand, Cox proportional hazards analysis identified low values of the Barthel Index (<75), use of opiates, and male sex as significant factors associated with a shorter overall survival; the BSI was not associated with the overall survival in the patients with advanced NSCLC in this study.

Conclusion

The results suggest that a high BSI (≥1.0) is an independent predictor of poor ADL in patients with NSCLC, while showing no correlation with the overall survival.

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Longitudinal patterns of bone-targeted agent use among patients with solid tumors and bone metastases in the United States

Abstract

Purpose

This study examined real-world long-term use of guideline-recommended bone targeted agents (BTA) among patients with metastatic solid tumors.

Methods

Adults with a solid tumor diagnosis followed by a bone metastasis diagnosis in 2012–2014 were identified from electronic medical records in the Oncology Services Comprehensive Electronic Records (OSCER) database. Patients initiated zoledronic acid (ZA) or denosumab on or after the bone metastasis diagnosis and were followed through last clinic visit by 30 June 2015. We describe time to BTA initiation, compliance (≥12 administrations in a year), switching, and non-persistence (switch or ≥90 day gap in therapy), by agent and follow-up period.

Results

The majority of the 14,881 study patients (50% female, 65% age ≥65 years) had breast (33%), prostate (26%), or lung (26%) tumors. Half of all patients initiated on each agent, with denosumab initiations exceeding ZA initiations in 2014. Most (91% denosumab, 93% ZA) initiations occurred within 3 months of bone metastasis diagnosis. At 1, 2, and 3 years post-initiation, denosumab patients were less likely to switch agents (4, 3, and 1% versus 14, 12, and 11%) and more likely to be compliant (50, 37, and 31% versus 41, 26, and 6%). Median time to non-persistence was 25.9 months for denosumab and 17.2 months for ZA, p < 0.0001.

Conclusions

This is the first study reporting long-term treatment patterns for the two primary BTAs used in the USA. The greater compliance and longer persistence observed among denosumab patients may improve treatment effectiveness achieved in the real-world setting.

http://ift.tt/2oEorUY

Characteristics of advanced cancer patients who were readmitted to an acute palliative/supportive care unit

Abstract

Objectives

The aim of this study was to assess the characteristics of patients readmitted to an acute supportive/palliative care unit (ASPCU), the reasons for readmission, and the outcome after receiving specialistic assessment and treatment.

Methods

A consecutive sample of patients was assessed for a period of 10 months. Epidemiological characteristics, including age, gender, Karnofsky level, diagnosis, caregivers, education, disease awareness, kind of admission, and anticancer treatment in the previous 30 days, were recorded, as well as hospital stay, death, and discharge at home. The principal reasons for admission were recorded. Symptom intensity and opioid doses, expressed as oral morphine equivalents, were also measured.

Results

In the study period, 79 (25.2%) readmissions were recorded. Thirty-seven (46.8%) readmissions occurred within 30 days after discharge. Pain was more frequently reported as indication for admission at the first and the second readmission in comparison with the first admission. The burden of symptoms was significantly higher in patients with a readmission in comparison with patients at the first admission. Opioid doses, expressed as oral morphine equivalents, were significantly different between the first admission and readmissions. In both patients at the first admission or readmission, a significant decrease in symptom intensity has been reported at discharge.

Conclusion

About 25% of patients discharged from an ASCPU are expected to be readmitted for reemerging of clinical problems. Re-exacerbation of pain seems to be the most frequent reason. A further clinical reassessment and treatment were equally effective in controlling the symptom burden of these patients at any readmission.

http://ift.tt/2onFMFr

Effectiveness of antiemetic triplet therapy with aprepitant, palonosetron, and dexamethasone for gynecologic cancer patients receiving carboplatin and paclitaxel: a prospective single-arm study

Abstract

Purpose

There is no positive evidence for the efficacy of antiemetic triplet therapy with aprepitant (APR), palonosetron (PALO), and dexamethasone (DEX) for moderate emetogenic chemotherapy, especially for gynecologic malignancies. Thus, the present study evaluated the efficacy of this triplet therapy in patients receiving carboplatin and paclitaxel (CP) for gynecologic malignancy.

Methods

Seventy patients with gynecologic cancer receiving CP were enrolled into a prospective single-arm study with APR (125 mg on day 1, 80 mg on days 2–3), PALO (0.75 mg), and DEX (20 mg) before initiating chemotherapy. The primary endpoint was delayed complete response (CR) rate, i.e., no vomiting and no rescue, at 24–120 h after chemotherapy administration.

Results

Seventy patients were enrolled. The delayed CR rate was 97.1% (68/70). No serious adverse events were observed. Younger patient age (≤50 years) tended to be associated with a poor delayed CR rate.

Conclusions

This study demonstrated a notable efficacy of antiemetic triplet therapy with APR, PALO, and DEX in female patients receiving CP. Further evaluation with a larger phase III trial is warranted.

http://ift.tt/2oEh1kC

Enhancing accrual to chemotherapy trials for patients with early stage triple-negative breast cancer: a survey of physicians and patients

Abstract

Purpose

The optimal chemotherapy regimen for patients with early stage triple-negative breast cancer (TNBC) remains unknown. The purpose of the study is to survey physicians and breast cancer patients about preferred chemotherapy regimens for early stage TNBC and clinical trial strategies.

Methods

A standardised online questionnaire was developed and circulated to medical oncologists known to treat breast cancer. A separate questionnaire was given to patients who had received chemotherapy for breast cancer.

Results

The questionnaire was completed by 41/84 medical oncologists (48.8% response rate) and 74 patients. The most commonly used neoadjuvant and adjuvant chemotherapy regimens for TNBC were dose-dense doxorubicin and cyclophosphamide (AC)–paclitaxel (P), dose-dense AC followed by weekly P and fluorouracil, epirubicin, cyclophosphamide–docetaxel (FEC-D). The majority of medical oncologists (80%) would be willing to enrol patients in trials evaluating the most effective chemotherapy regimen for TNBC. Oncologists favoured a three arm trial design comparing currently available standard of care treatments (36%) and trials of novel or non-standard of care agents 22% (9/41). Sixty percent (41/74) of patients indicated that they would be willing to be enrolled in trials evaluating various adjuvant regimens for TNBC. Both oncologists and patients were interested in novel consent approaches such as using the integrated consent model.

Conclusion

Optimisation of chemotherapy for TNBC is an important and unmet clinical need. It is apparent that various chemotherapy regimens are used for patients with early stage TNBC. The majority of medical oncologists and patients are interested in entering trials to optimise chemotherapy choices.

http://ift.tt/2pdhNZ1

Patient’s experiences of being discharged home from hospital following a diagnosis of malignant spinal cord compression

Abstract

Purpose

The purpose of this study is to explore experiences in the days and weeks following discharge home following diagnosis and treatment for metastatic spinal cord compression (MSCC).

Methods

Eleven participants took part in audio-recorded semi-structured interviews about their experiences at 1 and 3–4 weeks post-discharge home following a diagnosis of MSCC. Transcripts were analysed using a framework approach.

Results

Time emerged as an overarching theme within the framework of four time points: past, present, near future and distant future. Themes included getting home, challenges at home, community support, getting back to normal, in limbo, long-term goals and coping strategies.

Conclusion

Getting to a level of coping at home after discharge following MSCC can take time. Services need to address this so that patients can live well within the limitations they face.

http://ift.tt/2oEmszS

Effects of compensatory cognitive training intervention for breast cancer patients undergoing chemotherapy: a pilot study

Abstract

Purpose

Numerous breast cancer patients experience cognitive changes during and after chemotherapy. Chemotherapy-related cognitive impairment can significantly affect quality of life. This pilot study attempted to determine the effects of a compensatory cognitive training on the objective and subjective cognitive functioning of breast cancer patients receiving adjuvant chemotherapy.

Methods

Fifty-four patients were assigned to either a compensatory cognitive training or waitlist condition. They were assessed at baseline (T1), the completion of the 12-week intervention (T2), and 6 months after intervention completion (T3). Outcomes were assessed using the standardized neuropsychological tests and the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), version 3. Raw data were converted to T-scores based on baseline scores, and a repeated-measures ANCOVA, adjusting for age, intelligence, depression, and treatment, was used for analysis. The effect sizes for differences in means were calculated.

Results

The intervention group improved significantly over time compared to the waitlist group on objective cognitive function. Among ten individual neuropsychological measures, immediate memory, delayed memory, verbal fluency in category, and verbal fluency in letter showed significant group × time interaction. In subjective cognitive function, scores of the waitlist group significantly decrease over time on perceived cognitive impairments, in contrast to those of the intervention group.

Conclusion

The 12-week compensatory cognitive training significantly improved the objective and subjective cognitive functioning of breast cancer patients. Because this was a pilot study, further research using a larger sample and longer follow-up durations is necessary.

http://ift.tt/2pdcDMB

Urine drug screen findings among ambulatory oncology patients in a supportive care clinic

Abstract

Purpose

Professional organizations provide no guidelines regarding assessment and management of opioid abuse risk in cancer. Universal precautions (UP) developed for non-cancer pain, include assessments for aberrant behavior, screening questionnaires, and urine drug screens (UDS). The role of UDS for identifying opioid abuse risk in cancer is uncertain. Our aim is to characterize inappropriate UDS, and identify a potential role for UDS in therapeutic decision-making.

Methods

An observational retrospective chart review of 232 consecutive supportive care clinic patients were seen during the study. Twenty-eight of the two hundred thirty-two did not meet inclusion criteria. One hundred fifty of the two hundred four had active cancer, while 54 had no evidence of active disease. Clinicians ordered UDS based on their clinical judgment of patients' substance misuse risk. Edmonton symptom assessment scores, history of substance abuse, alcohol use, tobacco use, aberrant behavior, and morphine equivalent daily dose (MEDD) were obtained.

Results

Pain scores and MEDD were higher (p = 0.021; p < 0.001) in the UDS group vs non-UDS. Forty percent of the patients (n = 82/204) had at least one UDS and 70% (60/82) had an inappropriate result. Thirty-nine percent (32) were inappropriately negative, showing no prescribed opioids. Forty-nine of the eighty-two were positive for non-prescribed opioids, benzodiazepine, or illicit substance. Eleven of the forty-nine had only cannabis metabolites in their urine. There were no significant differences between appropriate and inappropriate UDS groups regarding pain scores, MEDD or referral to psychology, psychiatry, or substance abuse specialists.

Conclusions

UDS on the 82 oncology patients at high risk for substance misuse were frequently positive (46%) for non-prescribed opioids, benzodiazepines or potent illicit drugs such as heroin or cocaine, and 39% had inappropriately negative UDS, raising concerns for diversion.

http://ift.tt/2onQvzE

MRI features predict survival and molecular markers in diffuse lower-grade gliomas

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Previous studies have shown that MR imaging features can be used to predict survival and molecular profile of glioblastoma. However, no study of a similar type has been performed on lower-grade gliomas (LGGs).<div class="boxTitle">Methods.</div>Presurgical MRIs of 165 patients with diffuse low- and intermediate-grade gliomas (histological grades II and III) were scored according to the Visually Accessible Rembrandt Images (VASARI) annotations. Radiomic models using automated texture analysis and VASARI features were built to predict isocitrate dehydrogenase 1 (IDH1) mutation, 1p/19q codeletion status, histological grade, and tumor progression.<div class="boxTitle">Results.</div>Interrater analysis showed significant agreement in all imaging features scored (<span style="font-style:italic;">k</span> = 0.703–1.000). On multivariate Cox regression analysis, no enhancement and a smooth non-enhancing margin were associated with longer progression-free survival (PFS), while a smooth non-enhancing margin was associated with longer overall survival (OS) after taking into account age, grade, tumor location, histology, extent of resection, and IDH1 1p/19q subtype. Using logistic regression and bootstrap testing evaluations, texture models were found to possess higher prediction potential for IDH1 mutation, 1p/19q codeletion status, histological grade, and progression of LGGs than VASARI features, with areas under the receiver-operating characteristic curves of 0.86 ± 0.01, 0.96 ± 0.01, 0.86 ± 0.01, and 0.80 ± 0.01, respectively.<div class="boxTitle">Conclusion.</div>No enhancement and a smooth non-enhancing margin on MRI were predictive of longer PFS, while a smooth non-enhancing margin was a significant predictor of longer OS in LGGs. Textural analyses of MR imaging data predicted IDH1 mutation, 1p/19q codeletion, histological grade, and tumor progression with high accuracy.</span>

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Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Adaptive immune resistance in the tumor microenvironment appears to attenuate the immunotherapeutic targeting of glioblastoma (GBM). In this study, we identified a tumor-infiltrating myeloid cell (TIM) population that expands in response to dendritic cell (DC) vaccine treatment. The aim of this study was to understand how this programmed death ligand 1 (PD-L1)–expressing population restricts activation and tumor-cytolytic function of vaccine-induced tumor-infiltrating lymphocytes (TILs).<div class="boxTitle">Methods.</div>To test this hypothesis in our in vivo preclinical model, we treated mice bearing intracranial gliomas with DC vaccination ± murine anti–PD-1 monoclonal antibody (mAb) blockade or a colony stimulating factor 1 receptor inhibitor (CSF-1Ri) (PLX3397) and measured overall survival. We then harvested and characterized the PD-L1+ TIM population and its role in TIL activation and tumor cytolysis in vitro.<div class="boxTitle">Results.</div>Our data indicated that the majority of PD-L1 expression in the GBM environment is contributed by TIMs rather than by tumor cells themselves. While PD-1 blockade partially reversed the TIL dysfunction, targeting TIMs directly with CSF-1Ri altered TIM expression of key chemotactic factors associated with promoting increased TIL infiltration after vaccination. Neither PD-1 mAb nor CSF-1Ri had a demonstrable therapeutic benefit alone, but when combined with DC vaccination, a significant survival benefit was observed. When the tripartite regimen was given (DC vaccine, PD-1 mAb, PLX3397), long-term survival was noted together with an increase in the number of TILs and TIL activation.<div class="boxTitle">Conclusion.</div>Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.</span>

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A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Activating mutations or structural rearrangements in <span style="font-style:italic;">BRAF</span> are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood–brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA.<div class="boxTitle">Methods.</div>A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF.<div class="boxTitle">Results.</div>We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures.<div class="boxTitle">Conclusion.</div>MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.</span>

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Dissecting inherent intratumor heterogeneity in patient-derived glioblastoma culture models

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Molecular profile of glioblastoma multiforme (GBM) revealed 4 subtypes, 2 of which, proneural and mesenchymal, have been predominantly observed, with the latter displaying a more aggressive phenotype and increased therapeutic resistance. Single-cell RNA sequencing revealed that multiple subtypes actually reside within the same tumor, suggesting cellular heterogeneity in GBM. Further, plasticity between these 2 subtypes is observed during tumor recurrence and in response to radiation therapy.<div class="boxTitle">Methods.</div>Patient-derived GBM stemlike cells were cultured as neurospheres. These cells were differentiated in serum by attaching to the culture dishes. The "floating" cells that were not attached/differentiated were harvested from the conditioned medium. The characteristics of these cells were studied with limiting dilution assays and immunofluorescence staining. Cell growth and nuclear factor-kappaB (NFkB) activation were monitored using bioluminescent assays as well as quantitative polymerase chain reaction and western blotting. In vivo tumorigenesis was evaluated in orthotopic xenograft models using bioluminescence imaging.<div class="boxTitle">Results.</div>Patient-derived GBM stemlike cells undergo differentiation by attaching to the culture dish in serum-containing medium. We observed that a small subset of these cells escape this adhesion/differentiation and grow as floating cells. These cells displayed enhanced cancer stem cell properties with a molecular and phenotypic mesenchymal signature, including resistance to radiation and targeted therapies, a more aggressive tumor formation, and NFkB activation.<div class="boxTitle">Conclusion.</div>Our results endorse inherent intratumor molecular subtype heterogeneity in glioblastoma and provide a valuable approach to study phenotypic plasticity, which could be applied to find novel therapeutic strategies to eradicate this aggressive tumor and can be extended to other cancer types.</span>

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Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Optic gliomas arising in the neurofibromatosis type 1 (NF1) cancer predisposition syndrome cause reduced visual acuity in 30%–50% of affected children. Since human specimens are rare, genetically engineered mouse (GEM) models have been successfully employed for preclinical therapeutic discovery and validation. However, the sequence of cellular and molecular events that culminate in retinal dysfunction and vision loss has not been fully defined relevant to potential neuroprotective treatment strategies.<div class="boxTitle">Methods.</div><span style="font-style:italic;">Nf1</span>^flox/mut GFAP-Cre (FMC) mice and age-matched <span style="font-style:italic;">Nf1</span>^flox/flox (FF) controls were euthanized at defined intervals from 2 weeks to 24 weeks of age. Optic nerve volumes were measured, and optic nerves/retinae analyzed by immunohistochemistry. Optical coherence tomography (OCT) was performed on anesthetized mice. FMC mice were treated with lovastatin from 12 to 16 weeks of age.<div class="boxTitle">Results.</div>The earliest event in tumorigenesis was a persistent elevation in proliferation (4 wk), which preceded sustained microglia numbers and incremental increases in S100+ glial cells. Microglia activation, as evidenced by increased interleukin (IL)-1β expression and morphologic changes, coincided with axonal injury and retinal ganglion cell (RGC) apoptosis (6 wk). RGC loss and retinal nerve fiber layer (RNFL) thinning then ensued (9 wk), as revealed by direct measurements and live-animal OCT. Lovastatin administration at 12 weeks prevented further RGC loss and RNFL thinning both immediately and 8 weeks after treatment completion.<div class="boxTitle">Conclusion.</div>By defining the chronology of the cellular and molecular events associated with optic glioma pathogenesis, we demonstrate critical periods for neuroprotective intervention and visual preservation, as well as establish OCT as an accurate biomarker of RGC loss.</span>

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Integrated genomic analysis of survival outliers in glioblastoma

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>To elucidate molecular features associated with disproportionate survival of glioblastoma (GB) patients, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide); "GB outliers" were identified: long-term survivor of 33 months (LTS; <span style="font-style:italic;">n =</span> 8) versus short-term survivor of 7 months (STS; <span style="font-style:italic;">n =</span> 10).<div class="boxTitle">Methods.</div>We implemented exome, RNA, whole genome sequencing, and DNA methylation for collection of deep genomic data from STS and LTS GB patients.<div class="boxTitle">Results.</div>LTS GB showed frequent chromosomal gains in 4q12 (platelet derived growth factor receptor alpha and KIT) and 12q14.1 (cyclin-dependent kinase 4), and deletion in 19q13.33 (BAX, branched chain amino-acid transaminase 2, and cluster of differentiation 33). STS GB showed frequent deletion in 9p11.2 (forkhead box D4-like 2 and aquaporin 7 pseudogene 3) and 22q11.21 (Hypermethylated In Cancer 2). LTS GB showed 2-fold more frequent copy number deletions compared with STS GB. Gene expression differences showed the STS cohort with altered transcriptional regulators: activation of signal transducer and activator of transcription (STAT)5a/b, nuclear factor–kappaB (NF-κB), and interferon-gamma (IFNG), and inhibition of mitogen-activated protein kinase (MAPK1), extracellular signal-regulated kinase (ERK)1/2, and estrogen receptor (ESR)1. Expression-based biological concepts prominent in the STS cohort include metabolic processes, anaphase-promoting complex degradation, and immune processes associated with major histocompatibility complex class I antigen presentation; the LTS cohort features genes related to development, morphogenesis, and the mammalian target of rapamycin signaling pathway. Whole genome methylation analyses showed that a methylation signature of 89 probes distinctly separates LTS from STS GB tumors.<div class="boxTitle">Conclusion.</div>We posit that genomic instability is associated with longer survival of GB (possibly with vulnerability to standard therapy); conversely, genomic and epigenetic signatures may identify patients where up-front entry into alternative, targeted regimens would be a preferred, more efficacious management.</span>

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Pediatric low-grade gliomas: implications of the biologic era

<span class="paragraphSection"><div class="boxTitle">Abstract</div>For the past decade, it has been recognized that pediatric low-grade gliomas (LGGs) and glial-neuronal tumors carry distinct molecular alterations with resultant aberrant intracellular signaling in the Ras–mitogen-activated protein kinase pathway. The conclusions and recommendations of a consensus conference of how best to integrate the growing body of molecular genetic information into tumor classifications and, more importantly, for future treatment of pediatric LGGs are summarized here. There is uniform agreement that molecular characterization must be incorporated into classification and is increasingly critical for appropriate management. Molecular-targeted therapies should be integrated expeditiously, but also carefully into the management of these tumors and success measured not only by radiographic responses or stability, but also by functional outcomes. These trials need to be carried out with the caveat that the long-term impact of molecularly targeted therapy on the developing nervous system, especially with long duration treatment, is essentially unknown.</span>

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Management of hormone-secreting pituitary adenomas

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Pituitary adenomas are one of the most common primary central nervous system tumors and have an estimated prevalence of 17%. Approximately half of pituitary adenomas secrete distinct pituitary hormones (most often prolactin, growth hormone, or adrenocorticotropic hormone). While these tumors are histologically benign, they have potent endocrine effects that lead to significant morbidity and shortened lifespan. Because of their pathophysiologic endocrine secretion and anatomic location near critical neural/vascular structures, hormone-secreting pituitary adenomas require defined management paradigms that can include relief of mass effect and biochemical remission. Management of hormone-secreting pituitary adenomas involves a multidisciplinary approach that can incorporate surgical, medical, and/or radiation therapies. Early and effective treatment of hormone-secreting pituitary adenomas can reduce morbidity and mortality. Consequently, understanding clinical features as well as therapeutic options in the context of the specific biological features of each type of hormone-secreting pituitary adenoma is critical for optimal management.</span>

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A malignant solitary fibrous tumour arising from the first lumbar vertebra and mimicking an osteosarcoma: a case report

Abstract

Background

A solitary fibrous tumour (SFT) is an unusual neoplasm typically found in soft tissues. Although SFTs can arise in the bones, they very rarely arise in the vertebral arch. Here, we describe a case of a SFT that arose in the vertebral arch of the first lumbar (L1) spinal vertebrae and mimicked osteosarcoma.

Case presentation

A 49-year-old woman presented with a 2-month history of lower back pain and a lumbar region mass. Magnetic resonance imaging demonstrated a heterogeneously enhanced mass in the L1 vertebral arch. The patient received neoadjuvant chemotherapy, followed by a surgical procedure comprising an anterior spinal fusion and en bloc resection. Histologically, our initial diagnosis was osteosarcoma. The postoperative course was uneventful, and the patient received adjuvant chemotherapy. However, the tumour metastasised to the lung 5 years after the first surgery, and a second surgery was performed for lung tumour resection. The histology of the metastatic lung tumour appeared similar to that of the malignant SFT, and the specimen from the first surgery was re-examined. Immunohistochemically, the tumour was positive for STAT6. Reverse transcription-polymerase chain reaction revealed a NAB2-STAT6 fusion gene, thus confirming our final diagnosis of malignant SFT. The patient died of disease progression 8 years after the first surgery; however, there was no evidence of local recurrence.

Conclusions

Malignant SFT in the vertebral arch is extremely rare and very difficult to distinguish histologically an osteoid from lace-like collagen. STAT6 immunostaining is useful for distinguishing malignant SFTs from other neoplasms. Although it is difficult to completely resect a SFT arising from the spine, we demonstrated the feasibility of an en bloc resection of spinal tumours arising from posterior elements, without local recurrence.

http://ift.tt/2r3ZVhC

Influence of neoadjuvant chemotherapy on prognosis of patients with synovial sarcoma

Abstract

Background

This study aimed to explore the clinical efficacy of neoadjuvant chemotherapy combined with surgery in primary synovial sarcoma of the limbs and trunk through retrospective analysis of patients with primary synovial sarcoma of the limbs and trunk treated by this treatment in our hospital.

Methods

A total of 89 patients diagnosed with synovial sarcoma were enrolled in this study between January 2005 and December 2011 in PLA General Hospital. Most of the patients received neoadjuvant chemotherapy combined with operative treatment (84.3%), 10.1% of them received adjuvant chemotherapy combined with operative treatment, and only 5.6% received merely operative treatment. The influence on the prognosis of patients with synovial sarcoma was analyzed by the statistics overall survival (OS), progression-free survival (PFS), local control (LC), and freedom from distant metastasis (FFDM).

Results

The median follow-up time was 68.6 months. The 5-year OS, 5-year PFS, 5-year LC, and 5-year FFDM of the patients were 80.2, 60.5, 78.8, and 80.8%, respectively. The OS of the patients with a tumor size >5 cm was lower (91.4 vs 73.1%, P < 0.05). Besides, the OS and FFDM of neoadjuvant chemotherapy were better than those of adjuvant chemotherapy (84.5 vs 55.6%, P = 0.015, and 83.8 vs 55.6%, P = 0.028, respectively). However, there was no significant difference in the LC and PFS.

Conclusions

Neoadjuvant chemotherapy was beneficial for patients with synovial sarcoma, and it could improve survival time and control distant metastasis. Tumor size was an important factor influencing patients' prognosis.

http://ift.tt/2quqQG6

Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients

Abstract

Background

Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients.

Methods

A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated.

Results

A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected.

Conclusions

The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional.

http://ift.tt/2r3R0wx

A malignant solitary fibrous tumour arising from the first lumbar vertebra and mimicking an osteosarcoma: a case report

Abstract

Background

A solitary fibrous tumour (SFT) is an unusual neoplasm typically found in soft tissues. Although SFTs can arise in the bones, they very rarely arise in the vertebral arch. Here, we describe a case of a SFT that arose in the vertebral arch of the first lumbar (L1) spinal vertebrae and mimicked osteosarcoma.

Case presentation

A 49-year-old woman presented with a 2-month history of lower back pain and a lumbar region mass. Magnetic resonance imaging demonstrated a heterogeneously enhanced mass in the L1 vertebral arch. The patient received neoadjuvant chemotherapy, followed by a surgical procedure comprising an anterior spinal fusion and en bloc resection. Histologically, our initial diagnosis was osteosarcoma. The postoperative course was uneventful, and the patient received adjuvant chemotherapy. However, the tumour metastasised to the lung 5 years after the first surgery, and a second surgery was performed for lung tumour resection. The histology of the metastatic lung tumour appeared similar to that of the malignant SFT, and the specimen from the first surgery was re-examined. Immunohistochemically, the tumour was positive for STAT6. Reverse transcription-polymerase chain reaction revealed a NAB2-STAT6 fusion gene, thus confirming our final diagnosis of malignant SFT. The patient died of disease progression 8 years after the first surgery; however, there was no evidence of local recurrence.

Conclusions

Malignant SFT in the vertebral arch is extremely rare and very difficult to distinguish histologically an osteoid from lace-like collagen. STAT6 immunostaining is useful for distinguishing malignant SFTs from other neoplasms. Although it is difficult to completely resect a SFT arising from the spine, we demonstrated the feasibility of an en bloc resection of spinal tumours arising from posterior elements, without local recurrence.

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Influence of neoadjuvant chemotherapy on prognosis of patients with synovial sarcoma

Abstract

Background

This study aimed to explore the clinical efficacy of neoadjuvant chemotherapy combined with surgery in primary synovial sarcoma of the limbs and trunk through retrospective analysis of patients with primary synovial sarcoma of the limbs and trunk treated by this treatment in our hospital.

Methods

A total of 89 patients diagnosed with synovial sarcoma were enrolled in this study between January 2005 and December 2011 in PLA General Hospital. Most of the patients received neoadjuvant chemotherapy combined with operative treatment (84.3%), 10.1% of them received adjuvant chemotherapy combined with operative treatment, and only 5.6% received merely operative treatment. The influence on the prognosis of patients with synovial sarcoma was analyzed by the statistics overall survival (OS), progression-free survival (PFS), local control (LC), and freedom from distant metastasis (FFDM).

Results

The median follow-up time was 68.6 months. The 5-year OS, 5-year PFS, 5-year LC, and 5-year FFDM of the patients were 80.2, 60.5, 78.8, and 80.8%, respectively. The OS of the patients with a tumor size >5 cm was lower (91.4 vs 73.1%, P < 0.05). Besides, the OS and FFDM of neoadjuvant chemotherapy were better than those of adjuvant chemotherapy (84.5 vs 55.6%, P = 0.015, and 83.8 vs 55.6%, P = 0.028, respectively). However, there was no significant difference in the LC and PFS.

Conclusions

Neoadjuvant chemotherapy was beneficial for patients with synovial sarcoma, and it could improve survival time and control distant metastasis. Tumor size was an important factor influencing patients' prognosis.

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Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients

Abstract

Background

Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients.

Methods

A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated.

Results

A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected.

Conclusions

The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional.

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Does age really matter? Radiotherapy in elderly patients with glioblastoma, the Munich experience

Glioblastoma is usually diagnosed around the age of 60–70 years. Patients older than 65 years are frequently described as "elderly". Several trials with monotherapy have established treatment regimens that off...

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Does age really matter? Radiotherapy in elderly patients with glioblastoma, the Munich experience

Glioblastoma is usually diagnosed around the age of 60–70 years. Patients older than 65 years are frequently described as "elderly". Several trials with monotherapy have established treatment regimens that off...

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Erratum to: Effects of aging on the relationship between cognitive demand and step variability during dual-task walking

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MEN2 Syndrome-Related Medullary Thyroid Carcinoma with Focal Tyrosine Hydroxylase Expression: Does It Represent a Hybrid Cellular Phenotype or Functional State of Tumor Cells?

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Litigation and complaints associated with day-case anaesthesia

<span class="paragraphSection">1F012A033A06</span>

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Anaesthetic management of patients requiring vascular access surgery for renal dialysis

<span class="paragraphSection">1A012A033A05</span>

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Anaesthesia and critical care for patients in the criminal justice system

<span class="paragraphSection">1E032A103I00</span>

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The immune microenvironment and HPV in anal cancer: Rationale to complement chemoradiation with immunotherapy

Publication date: Available online 10 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Daniel Martin, Franz Rödel, Panagiotis Balermpas, Claus Rödel, Emmanouil Fokas
Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world, and 70–90% of all cases originate from infection with human papilloma viruses (HPV). Primary chemoradiotherapy (CRT) is the standard treatment for ASCC, but local and/or distant failure still occur in up to 30% of patients. HPV-associated ASCC and tumors with a higher density of tumor infiltrating lymphocytes (TIL) carry a better prognosis. Furthermore, HPV can render tumors more immunogenic, whereas it correlates with elevated TIL densities. This comprehensive review highlights the progress made in understanding the immune microenvironment of anal intraepithelial neoplasias and ASCC in the context of HPV. Here, we discuss the immunomodulatory potential of CRT, the prognostic impact of immune checkpoint markers, and the rationale for including immunotherapies to further improve the clinical outcome in patients with ASCC.



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The sleeping ugly: tumour microenvironment's act to make or break the spell of dormancy

Publication date: Available online 10 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Laurie Gay, Ilaria Malanchi
Metastasis is the main cause of death for most cancer patients. It appears clear from clinical observations that the majority of cancers, particularly carcinoma do not follow a linear model of metastatic progression, where cancer cells shed from the primary tumour, disseminate to a distant organ and immediately outgrow to form clinical metastasis. Certainly, while cancer spreading is an early event, metastasis occurs much later during tumour progression and frequently arises several years after primary tumour resection. The time spent by disseminated cancer cells (DTCs) in a distant organ before their outgrowth is term metastatic latency. We will examine here the current knowledge of the mechanisms allowing metastatic latency and discuss the crucial role of the DTCs' tissue microenvironment in this process.



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Sclerema Neonatorum Treated Successfully with Parenteral Steroids: An Experience from a Resource Poor Country

Sclerema neonatorum is a form of panniculitides characterized by diffuse hardening of subcutaneous tissue with minimal inflammation. It usually affects ill and preterm neonates. Prognosis is usually poor in many cases despite aggressive management. Various treatment modalities (antibiotics, intravenous immunoglobulin, steroids, and exchange transfusion) have been explained in literature. Steroids due to its easy availability and low cost can prove to be lifesaving in such cases, especially in resource poor countries. Here, we report a case of sclerema neonatorum in a one-week preterm baby treated successfully with parenteral steroids and antibiotics.

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Parotitis as an Initial Symptom of Kawasaki Disease

We report the case of a 13-month-old boy who developed right side parotitis as a first symptom of Kawasaki disease (KD). The data presented herein suggest that physicians should be aware that nonsuppurative parotitis is a possible manifestation of KD.

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RET signaling in prostate cancer

Purpose: Large diameter perineural prostate cancer is associated with poor outcomes. GDNF, with its co-receptor GFRα1, binds RET and activates downstream pro-oncogenic signaling. Since both GDNF and GFRα1 are secreted by nerves, we examined the role of RET signaling in prostate cancer. <p>Experimental Design: Expression of RET, GDNF and/or GFRα1 was assessed. The impact of RET signaling on proliferation, invasion and soft agar colony formation, perineural invasion and growth in vivo was determined. Cellular signaling downstream of RET was examined by Western blotting.</p> <p>Results: RET is expressed in all prostate cancer cell lines. GFRα1 is only expressed in 22Rv1 cells, which is the only line that responds to exogenous GDNF. In contrast, all cell lines respond to GDNF plus GFRα1. Conditioned medium from dorsal root ganglia contains secreted GFRα1 and promotes transformation related phenotypes, which can be blocked by anti-GFRα1 antibody. Perineural invasion in the dorsal root ganglion assay is inhibited by anti-GFRα antibody and RET knockdown. In vivo, knockdown of RET inhibits tumor growth. RET signaling activates ERK or AKT signaling depending on context, but phosphorylation of p70S6 kinase is markedly increased in all cases. Knockdown of p70S6 kinase markedly decreases RET induced transformed phenotypes. Finally, RET is expressed in 18% of adenocarcinomas and all three small cell carcinomas examined.</p> <p>Conclusions: RET promotes transformation associated phenotypes, including perineural invasion in prostate cancer via activation of p70S6 kinase. GFRα1, which is secreted by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur.</p> <p> 

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Genome-wide DNA methylation analysis reveals GABBR2 as a novel epigenetic target for EGFR 19 deletion lung adenocarcinoma with induction erlotinib treatment

Purpose: The last decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR) mutated lung cancer. <p>Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N=2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.</p> <p>Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6 and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.</p> Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma.

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Perioperative COX-2 and {beta}-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial

Purpose: <br /> <p>Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined perioperative blockade of these pathways in breast cancer patients.</p> <br />Experimental Design: <br /> <p>In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a beta-adrenergic antagonist (propranolol) and a cyclooxygenase-2 (COX-2) inhibitor (etodolac), beginning five days before surgery. Excised tumors and sequential blood samples were assessed for pro-metastatic biomarkers.</p> <br /><br />Results: <br /> <p>Drugs were well tolerated with adverse event rates comparable to placebo. Transcriptome profiling of the primary tumor tested a priori hypotheses and indicated that drug treatment significantly (i) decreased epithelial-to-mesenchymal transition, (ii) reduced activity of pro-metastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and (iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells. Drug treatment also significantly abrogated presurgical increases in serum interleukin-6 (IL-6) and C-reactive protein levels, abrogated perioperative declines in stimulated interleukin-12 and interferon-gamma production, abrogated postoperative mobilization of CD16^- "classical" monocytes, and enhanced expression of CD11a on circulating natural killer cells. </p> <br /><br />Conclusions:<br /> <p>Perioperative inhibition of COX-2 and b-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer. 

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Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition

Purpose: <br /> <p>EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma (MM) and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on MM and prostate cancer.</p> <br /><br />Experimental Design: <br /> <p>In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in MM cell lines, primary patient cells and in a xenograft model. RNA-seq and ChIP-seq were performed to uncover the targets of UNC1999 in MM. The efficacy of the combination therapy was validated in prostate cancer cell lines.</p> <br /><br />Results:<br /> <p>Proteasome inhibitors repressed EZH2 transcription via abrogation of RB-E2F pathway, thereby sensitizing EZH2-dependent MM cells to EZH1 inhibition by UNC1999. Correspondingly, combination of proteasome inhibitors with UNC1999, but not with an EZH2-specific inhibitor, induced synergistic anti-myeloma activity in vitro. Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells in vivo. Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene NR4A1. Derepression of NR4A1 by UNC1999 resulted in suppression of MYC, which was enhanced by the combination with bortezomib, suggesting the cooperative blockade of PRC2 function. Notably, this combination also exhibited strong synergy in prostate cancer cells.</p> <br />Conclusions:<br /> <p>Our results identify dual inhibition of EZH2 and EZH1 together with proteasome inhibition as a promising epigenetics-based therapy for PRC2-dependent cancers.

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A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3K{alpha} Isoform Inhibitor, in Patients with Advanced Solid Malignancies

Purpose: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors. <p>Experimental Design: Seventy-one patients received oral TAK-117 once daily (QD, 100-300 mg [n = 24]), or 3 days per week (Mon-Wed-Fri [MWF], 200-1200 mg [n = 27]; Mon-Tue-Wed [MTuW], 200-900 mg [n = 20]), in 21-day cycles. Dose escalation proceeded via a 3+3 design.</p> <p>Results: TAK-117 QD dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg QD). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg QD. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of QD/MWF/MTuW patients. TAK-117 (100-1200 mg) exhibited moderately fast oral absorption, a generally dose-proportional increase in exposure, and plasma half-life of ~11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were ~four times greater than with 150 mg QD. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (QD/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated).</p> <p>Conclusion: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus QD dosing. While the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.

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RET signaling in prostate cancer

Purpose: Large diameter perineural prostate cancer is associated with poor outcomes. GDNF, with its co-receptor GFRα1, binds RET and activates downstream pro-oncogenic signaling. Since both GDNF and GFRα1 are secreted by nerves, we examined the role of RET signaling in prostate cancer. <p>Experimental Design: Expression of RET, GDNF and/or GFRα1 was assessed. The impact of RET signaling on proliferation, invasion and soft agar colony formation, perineural invasion and growth in vivo was determined. Cellular signaling downstream of RET was examined by Western blotting.</p> <p>Results: RET is expressed in all prostate cancer cell lines. GFRα1 is only expressed in 22Rv1 cells, which is the only line that responds to exogenous GDNF. In contrast, all cell lines respond to GDNF plus GFRα1. Conditioned medium from dorsal root ganglia contains secreted GFRα1 and promotes transformation related phenotypes, which can be blocked by anti-GFRα1 antibody. Perineural invasion in the dorsal root ganglion assay is inhibited by anti-GFRα antibody and RET knockdown. In vivo, knockdown of RET inhibits tumor growth. RET signaling activates ERK or AKT signaling depending on context, but phosphorylation of p70S6 kinase is markedly increased in all cases. Knockdown of p70S6 kinase markedly decreases RET induced transformed phenotypes. Finally, RET is expressed in 18% of adenocarcinomas and all three small cell carcinomas examined.</p> <p>Conclusions: RET promotes transformation associated phenotypes, including perineural invasion in prostate cancer via activation of p70S6 kinase. GFRα1, which is secreted by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur.</p> <p> 

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Genome-wide DNA methylation analysis reveals GABBR2 as a novel epigenetic target for EGFR 19 deletion lung adenocarcinoma with induction erlotinib treatment

Purpose: The last decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR) mutated lung cancer. <p>Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N=2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response.</p> <p>Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6 and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway.</p> Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma.

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Perioperative COX-2 and {beta}-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial

Purpose: <br /> <p>Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined perioperative blockade of these pathways in breast cancer patients.</p> <br />Experimental Design: <br /> <p>In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a beta-adrenergic antagonist (propranolol) and a cyclooxygenase-2 (COX-2) inhibitor (etodolac), beginning five days before surgery. Excised tumors and sequential blood samples were assessed for pro-metastatic biomarkers.</p> <br /><br />Results: <br /> <p>Drugs were well tolerated with adverse event rates comparable to placebo. Transcriptome profiling of the primary tumor tested a priori hypotheses and indicated that drug treatment significantly (i) decreased epithelial-to-mesenchymal transition, (ii) reduced activity of pro-metastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and (iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells. Drug treatment also significantly abrogated presurgical increases in serum interleukin-6 (IL-6) and C-reactive protein levels, abrogated perioperative declines in stimulated interleukin-12 and interferon-gamma production, abrogated postoperative mobilization of CD16^- "classical" monocytes, and enhanced expression of CD11a on circulating natural killer cells. </p> <br /><br />Conclusions:<br /> <p>Perioperative inhibition of COX-2 and b-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer. 

http://ift.tt/2q7gfhf

Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition

Purpose: <br /> <p>EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma (MM) and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on MM and prostate cancer.</p> <br /><br />Experimental Design: <br /> <p>In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in MM cell lines, primary patient cells and in a xenograft model. RNA-seq and ChIP-seq were performed to uncover the targets of UNC1999 in MM. The efficacy of the combination therapy was validated in prostate cancer cell lines.</p> <br /><br />Results:<br /> <p>Proteasome inhibitors repressed EZH2 transcription via abrogation of RB-E2F pathway, thereby sensitizing EZH2-dependent MM cells to EZH1 inhibition by UNC1999. Correspondingly, combination of proteasome inhibitors with UNC1999, but not with an EZH2-specific inhibitor, induced synergistic anti-myeloma activity in vitro. Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells in vivo. Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene NR4A1. Derepression of NR4A1 by UNC1999 resulted in suppression of MYC, which was enhanced by the combination with bortezomib, suggesting the cooperative blockade of PRC2 function. Notably, this combination also exhibited strong synergy in prostate cancer cells.</p> <br />Conclusions:<br /> <p>Our results identify dual inhibition of EZH2 and EZH1 together with proteasome inhibition as a promising epigenetics-based therapy for PRC2-dependent cancers.

http://ift.tt/2q4Bti6

A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3K{alpha} Isoform Inhibitor, in Patients with Advanced Solid Malignancies

Purpose: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3Kα-selective inhibitor, in patients with advanced solid tumors. <p>Experimental Design: Seventy-one patients received oral TAK-117 once daily (QD, 100-300 mg [n = 24]), or 3 days per week (Mon-Wed-Fri [MWF], 200-1200 mg [n = 27]; Mon-Tue-Wed [MTuW], 200-900 mg [n = 20]), in 21-day cycles. Dose escalation proceeded via a 3+3 design.</p> <p>Results: TAK-117 QD dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg QD). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg QD. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of QD/MWF/MTuW patients. TAK-117 (100-1200 mg) exhibited moderately fast oral absorption, a generally dose-proportional increase in exposure, and plasma half-life of ~11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were ~four times greater than with 150 mg QD. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (QD/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated).</p> <p>Conclusion: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus QD dosing. While the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.

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ATOH1 promotes leptomeningeal dissemination and metastasis of Sonic Hedgehog subgroup medulloblastomas

Medulloblastoma (MB) arising from the cerebellum is the most common pediatric brain malignancy, with leptomeningeal metastases often present at diagnosis and recurrence associated with poor clinical outcome. In this study, we employed mouse MB models to explore the relationship of tumor pathophysiology and dysregulated expression of the Notch pathway transcription factor ATOH1, which is present in aggressive MB subtypes driven by aberrant Sonic Hedgehog/Patched (SHH/PTCH) signaling. In experiments with conditional Atoh1 mouse mutants crossed to Ptch1+/- mice which develop SHH-driven MB[63], animals with Atoh1 transgene expression developed highly penetrant MB at a young age with extensive leptomeningeal disease and metastasis to the spinal cord and brain, resembling xenografts of human SHH MB. Metastatic tumors retained abnormal SHH signaling like tumor xenografts. Conversely, Atoh1 expression was detected consistently in recurrent and metastatic SHH MB. ChIP-seq and gene expression profiling identified candidate ATOH1 targets in tumor cells involved in development and tumorigenesis. Among these targets specific to metastatic tumors, there was an enrichment in those implicated in extracellular matrix remodeling activity, cytoskeletal network and interaction with microenvironment, indicating a shift in transcriptomic and epigenomic landscapes during metastasis. Treatment with bone morphogenetic protein (BMP) or SHH pathway inhibitors decreased tumor cell proliferation and suppressed metastatic tumor growth, respectively. Our work reveals a dynamic ATOH1-driven molecular cascade underlying MB metastasis that offers possible therapeutic opportunities.

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