Validation of Immunohistochemical Assays for Integral Biomarkers in the NCI-MATCH EAY131 Clinical Trial

Biomarkers that guide therapy selection are gaining unprecedented importance as targeted therapy options increase in scope and complexity. In conjunction with high-throughput molecular techniques, therapy-guiding biomarker assays based upon immunohistochemistry (IHC) have a critical role in cancer care in that they inform about the presence of a protein target. Here, we describe the validation procedures for four clinically available IHC biomarker assays - PTEN, RB, MLH1 and MSH2 - for use as integral biomarkers in the nationwide NCI-MATCH (Molecular Analysis for Therapy Choice) EAY131 clinical trial. Validation procedures were developed through an iterative process based on collective experience and adaptation of broad guidelines from the United State Food and Drug Administration (FDA). The steps included primary antibody selection, assay optimization, development of assay interpretation criteria incorporating biological considerations and expected staining patterns, including indeterminate results, orthogonal validation, and tissue validation. Following assay lockdown, patient samples and cell lines were used for analytical and clinical validation. The assays were then approved as laboratory developed tests and used for clinical trial decisions for treatment selection. Calculations of sensitivity and specificity were undertaken using various definitions of gold standard references, and external validation was required for the PTEN IHC assay. In conclusion, validation of IHC biomarker assays critical for guiding therapy in clinical trials is feasible using comprehensive pre-analytical, analytical and post-analytical steps. Implementation of standardized guidelines provides a useful framework for validating IHC biomarker assays that allow for reproducibility across institutions for routine clinical use.

http://ift.tt/2wLi7Sr

Clinical correlates and prognostic value of different metastatic sites in metastatic renal cell carcinoma

Future Oncology, Ahead of Print.


http://ift.tt/2w8ULUp

County level incidence rates of chronic lymphocytic leukemia are associated with residential radon levels

Future Oncology, Ahead of Print.


http://ift.tt/2wt1kUe

Challenges faced when identifying patients for combination immunotherapy

Future Oncology, Ahead of Print.


http://ift.tt/2w9DbQ7

Cancer Self-Defense: An Immune Stealth

Abstract The hurdles in realizing immunotherapy success for cure stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment of a 'decoy flare' i.e., release or secretion of anomalous cancer-associated antigens. The cancer secretome, that resembles the parent cell make up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents resulting in a 'cancer-stealth' effect. A clinical evaluation of tumor-derived secretome and specific autoantibodies may change the therapeutic landscape

http://ift.tt/2ixnDCO

The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2Hi macrophages in breast cancer and pancreatic neuroendocrine tumors.

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation and metastasis, which can offset the effects of chemotherapy, radiation, and anti-angiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and pro-tumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, anti-angiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The anti-tumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by pro-tumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients.

http://ift.tt/2vu73Vh

T790M-selective EGFR-TKI combined with dasatinib as an optimal strategy for overcoming EGFR-TKI resistance in T790M-positive non-small cell lung cancer

T790M mutation-selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as co-oncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced anti-tumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI or osimertinib in EGFR mutation-positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M-positive cells, and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the annexin-V binding assay; this was associated with downregulation of the anti-apoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFR-TKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M.

http://ift.tt/2vbmGWn

Lack of constitutively active DNA repair sensitizes glioblastomas to Akt inhibition and induces synthetic lethality with radiation treatment in a p53-dependentmanner

Treatment refractory glioblastoma (GBM) remains a major clinical problem globally and targeted therapies in GBM have not been promising to date. TCGA integrative analysis of GBM reported the striking finding of genetic alterations in the p53 and PI3K pathways in over 80% of GBMs. Given the role of these pathways in making cell-fate decisions and responding to genotoxic stress, we investigated the reliance of these two pathways in mediating radiation-resistance. We selected a panel of GBM cell lines and glioma stem cells (GSC) with wild-type TP53 (p53-wt) and mutant TP53, mutations known to interfere with p53 functionality (p53-mt). Cell lines were treated with a brain permeable inhibitor of P-Akt (ser473), phosphatidylinositol ether lipid analogue (PIA), with and without radiation treatment. Sensitivity to treatment was measured using Annexin-V/PI flow cytometry and western blot analysis for the markers of apoptotic signaling, alkaline COMET assay. All results were verified in p53 isogenic cell lines. p53-mt cell lines were selectively radiosensitized by PIA. This radiosensitization effect corresponded with an increase in DNA damage and a decrease in DNA-PKcs levels. TP53 silencing in p53-wt cells showed a similar response as the p53-mt cells. Additionally, the radiosensitization effects of Akt inhibition were not observed in normal human astrocytes suggesting this treatment strategy could have limited off-target effects. We demonstrate that the inhibition of the PI3K/Akt pathway by PIA radiosensitizes p53-mt cells by antagonizing DNA repair. In principle, this strategy could provide a large therapeutic window for the treatment of TP53 mutant tumors.

http://ift.tt/2vu3nCU

Animacroxam, a novel dual-mode compound targeting histone deacetylases and cytoskeletal integrity of testicular germ cell cancer cells

Novel approaches for the medical treatment of advanced solid tumors including testicular germ cell tumors (TGCT) are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual mode compound animacroxam for TGCT treatment. Animacroxam consists of a HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell cycle arresting, and apoptosis inducing effects in TGCT cell lines with different cisplatin sensitivities. The IC50 values of animacroxam ranged from 0.22 to 0.42 µM and were not correlated to the cisplatin sensitivity of the tumor cells. No unspecific cytotoxicity of animacroxam was observed in either cisplatin sensitive or resistant TGCT cells - even at doses as high as 10 µM. Furthermore, animacroxam induced the formation of actin stress fibers in cancer cells thereby confirming the cytoskeleton disrupting and antimigratory properties of its imidazole moiety. When compared with the clinically established HDAC-inhibitor vorinostat, the novel dual mode compound animacroxam exhibited superior antitumoral efficacy in vitro. Animacroxam also reduced the tumor size of TGCT tumors in vivo, as evidenced by performing xenograft experiments on tumor bearing chorio-allantoic membranes of fertilizes chicken eggs (CAM assay). The in vivo experiments also revealed a very good tolerability of the compound and hence, aniamcroxam may be a promising candidate for innovative treatment of TGCT in general and the more so for platinum-insensitive or -refractory TGCT.

http://ift.tt/2vu1tm8

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors

The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8 and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC) and its depletion by siRNA inhibits the proliferation of human papilloma virus negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme (NAE) inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments.

http://ift.tt/2w2hrHl

Radiosensitisation in vivo by histone deacetylase inhibition with no increase in early normal tissue radiation toxicity

As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitising agents minimally toxic to normal tissues, including bowel and bladder, for such patients. We developed methods to determine normal tissue toxicity severity in intestine and bladder in vivo, using novel radiotherapy techniques on a small animal radiation research platform (SARRP). The effects of panobinostat (PAN) on in vivo tumour growth delay were evaluated using subcutaneous xenografts in athymic nude mice. PAN concentration levels in xenografts, plasma and normal tissues were measured in CD1-nude mice. CD1-nude mice were treated with drug/irradiation combinations to assess acute normal tissue effects in small intestine using the intestinal crypt assay, and later effects in small and large intestine at 11 weeks by stool assessment and at 12 weeks by histological examination. In vitro effects of PAN were assessed by qPCR and of PAN, TMP195 and mocetinostat by clonogenic assay, and western blot. PAN resulted in growth delay in RT112 bladder cancer xenografts but did not significantly increase acute (3.75 days) or 12 weeks' normal tissue radiation toxicity. Radiosensitisation by PAN was effective in hypoxic bladder cancer cells and associated with class I HDAC inhibition, and protein downregulation of HDAC2 and MRE11. Pan-HDAC inhibition is a promising strategy for radiosensitisation, but more selective agents may be more useful radiosensitisers clinically, resulting in fewer systemic side effects.

http://ift.tt/2xhfTrN

Are PROMs sufficient to record late outcome of breast cancer patients treated with radiotherapy? A comparison between patient and clinician reported outcome through an outpatient clinic after 10years of follow up

To investigate whether breast cancer patients' visits to an outpatient clinic for late outcome (OCLO) can be replaced by patient reported outcome measures (PROMs), by comparing late toxicity scored at the OCLO with PROMs.

http://ift.tt/2vl0JQG

Automated anesthesia delivery systems in cardiac surgical patients with left ventricular dysfunction: All systems go?

The interest in the use of automated drug infusion systems to deliver anesthesia has grown amongst both clinicians and researchers since their inception decades ago. Presently, two major types of automated anesthesia delivery systems exist, both of which have been used predominantly to deliver intravenous medications as part of a general anesthetic.

http://ift.tt/2vkY0H6

Maternal use of household pesticides during pregnancy and risk of neuroblastoma in offspring. A pooled analysis of the ESTELLE and ESCALE French studies (SFCE)

Abstract

Purpose

Neuroblastoma (NB) is an embryonic tumor that occurs almost exclusively in infancy and early childhood. While considerable evidence suggests that it may be initiated during embryonic development, the etiology of NB is still unknown. The aim of this study was to explore whether there is an association between maternal use of household pesticides during pregnancy and the risk of NB in the offspring.

Methods

We conducted a pooled analysis of two French national-based case–control studies. The mothers of 357 NB cases and 1,783 controls younger than 6 years, frequency-matched by age and gender, responded to a telephone interview that focused on sociodemographic and perinatal characteristics, childhood environment, and life-style. Unconditional logistic regression was used to estimate pooled odds ratios and 95% confidence intervals.

Results

After controlling for matching variables, study of origin, and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with NB (OR 1.5 [95% CI 1.2–1.9]). The most commonly used type of pesticides were insecticides and there was a positive association with their use alone (OR 1.4 [95% CI 1.1–1.9]) or with other pesticides (OR 2.0 [95% CI 1.1–3.4]).

Conclusions

Although there is the potential for recall bias due to the study design, our findings add to the evidence of an association between the household use of pesticides and NB. Until a better study design can be found, our findings add yet another reason why to advise pregnant women to limit pesticide exposure during the periconceptional period.

http://ift.tt/2vtlDN3

Acute hypopituitarism associated with periorbital swelling and cardiac dysfunction in a patient with pituitary tumor apoplexy: a case report

Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, men...

http://ift.tt/2xgeyRT

Extensive intramuscular manifestation of sarcoidosis with initially missed diagnosis and delayed therapy: a case report

Sarcoidosis is a multisystemic granulomatous disorder, which in nearly all cases involves the lungs and other organs. Isolated forms of sarcoidosis within the muscles, but without lung involvement, are extreme...

http://ift.tt/2w1STOO

Adverse Health Outcomes and Associations with Self-Reported General Health in Childhood Lymphoma Survivors

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


http://ift.tt/2wK2RoT

Therapeutic antibodies against cancer stem cells: a promising approach

Abstract

Monoclonal antibodies have been extensively used to treat malignancy along with routine chemotherapeutic drugs. Chemotherapy for metastatic cancer has not been successful in securing long-term remission of disease. This is in part due to the resistance of cancer cells to drugs. One aspect of the drug resistance is the inability of conventional drugs to eliminate cancer stem cells (CSCs) which often constitute less than 1–2% of the whole tumor. In some tumor types, it is possible to identify these cells using surface markers. Monoclonal antibodies targeting these CSCs are an attractive option for a new therapeutic approach. Although administering antibodies has not been effective, when combined with chemotherapy they have proved synergistic. This review highlights the potential of improving treatment efficacy using functional antibodies against CSCs, which could be combined with chemotherapy in the future.

http://ift.tt/2vjRX5E

Therapeutic antibodies against cancer stem cells: a promising approach

Abstract

Monoclonal antibodies have been extensively used to treat malignancy along with routine chemotherapeutic drugs. Chemotherapy for metastatic cancer has not been successful in securing long-term remission of disease. This is in part due to the resistance of cancer cells to drugs. One aspect of the drug resistance is the inability of conventional drugs to eliminate cancer stem cells (CSCs) which often constitute less than 1–2% of the whole tumor. In some tumor types, it is possible to identify these cells using surface markers. Monoclonal antibodies targeting these CSCs are an attractive option for a new therapeutic approach. Although administering antibodies has not been effective, when combined with chemotherapy they have proved synergistic. This review highlights the potential of improving treatment efficacy using functional antibodies against CSCs, which could be combined with chemotherapy in the future.

http://ift.tt/2vjRX5E

Trends in Financial Access to Prescription Drugs Among Cancer Survivors

Abstract

Little is known about the competing effects of increasing prescription drug costs and expansions in insurance coverage on prescription drug access and whether trends vary for adults with and without a cancer history. Using the 2010–2015 National Health Interview Survey, we examined trends in limited prescription drug access, operationalized as forgoing needed prescription drugs because of cost. The percentages of adults age 18 to 64 years with limited prescription drug access decreased over time: predicted margins from multivariable logistic regression models were 13.8% in 2010 vs 8.6% in 2015 for cancer survivors and 11.0% vs 6.8% for adults without a cancer history (adjusted odds ratio [aOR] for trend = 0.89, 95% confidence interval [CI] = 0.88 to 0.90). Access changed little for adults age 65 years and older. Among adults age 18 to 64 years, cancer survivors were more likely than those without a cancer history to report limited access to any prescription drug in all years (aOR from multivariable logistic regression model = 1.45, 95% CI = 1.31 to 1.61). However, trends did not differ by cancer history. Our findings suggest that expansions in health insurance coverage mitigated the effects of growing prescription drug costs to some extent for many individuals with and without a history of cancer.

http://ift.tt/2vt6xHb

Long-term Peripheral Neuropathy in Breast Cancer Patients Treated With Adjuvant Chemotherapy: NRG Oncology/NSABP B-30

Abstract

Background

The long-term effects of chemotherapy are sparsely reported. Peripheral neuropathy (PN) is one of the most frequent toxicities associated with taxane use for the treatment of early-stage breast cancer. We investigated the impact of the three different docetaxel-based regimens and patient characteristics on long-term, patient-reported outcomes of PN and the impact of PN on long-term quality of life (QOL).

Methods

The National Surgical Adjuvant Breast and Bowel Project Protocol B-30 was a randomized trial comparing sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T) (AC→T), concurrent ACT, or AT in women with node-positive, early-stage breast cancer. The AC→T group had a higher cumulative dose of T. PN was one of the symptoms assessed in a QOL substudy. Statistical methods included simple and mixed ordinal logistic regression and general linear models. All statistical tests were two-sided.

Results

Of 1512 patients, 41.9% reported PN two years after treatment initiation. Treatment with AT and ACT was associated with less severe long-term PN compared with AC→T (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.35 to 0.58; OR = 0.59, 95% CI = 0.46 to 0.75). Preexisting PN, older age, obesity, mastectomy, and greater number of positive nodes were also associated with higher risk of long-term PN. Patients who reported worse PN symptoms at 24 months had statistically significantly worse QOL (P_trend < .001).

Conclusions

The administration of docetaxel is associated with long-term PN. The lower rate of long-term PN in AT and ACT patients might be an important consideration in supporting choosing these therapies for individuals with preexisting neuropathic symptoms or other risk factors for neuropathy.

http://ift.tt/2v9CIAp

Chemotherapy-Associated Peripheral Neuropathy in Patients With Early-Stage Breast Cancer: A Systematic Review

Abstract

Breast cancer is the most common cancer among women worldwide, and survival rates are increasing. Chemotherapy-associated peripheral neuropathy (PN) is clinically important because of effects on quality of life (QOL) and potential effects on dose limitations. This adverse drug reaction is associated with certain classes of chemotherapy and commonly presents as peripheral sensory neuropathy whose natural course is largely unknown. The literature was reviewed to determine the frequency and characteristics of PN associated with adjuvant chemotherapy in early-stage breast cancer (ESBC) to explore the potential impact on long-term (one or more years after diagnosis) health outcomes and QOL. MEDLINE, PubMed, Embase, and the Cochrane Library were searched for relevant English-language randomized controlled trials, systematic reviews, meta-analyses, and case-control and cohort studies published between January 1990 and July 1996. Included studies were limited to current adjuvant regimens (eg, anthracyclines, taxanes, cyclophosphamide, platinum compounds). Two investigators independently reviewed abstracts, full-text articles, and extracted data from fair- and good-quality studies. Discrepancies in quality assessment and data extraction were resolved by consensus. We identified 364 articles; 60 were eligible for full-text review. Only five reports of four studies provided data beyond one year post–treatment initiation. Studies used different measures to assess PN. Neuropathic symptoms persisted in 11.0% to more than 80% of participants at one to three years following treatment. There is a paucity of data describing persistent PN in ESBC patients. Consistent use of validated measures and well-conducted randomized clinical trials or observational studies are needed to evaluate the incidence, persistence, and QOL associated with the long-term effects of PN.

http://ift.tt/2vsSCRD

Predictors of high healthcare costs in elderly patients with liver cancer in end-of-life: a longitudinal population-based study

Abstract

Background

Studies have indicated a pervasive pattern of decreasing healthcare costs during elderly patients' last year of life. The aim of this study was to explore the predictors of high healthcare costs (HC) in elderly liver cancer patients in Taiwan during their last month of life (LML).

Methods

Costs of hospitalization, outpatient visits, aggressiveness of care, and associated costs for elderly (age ≥ 65 y) patients with liver cancer in the LML were analyzed using a national insurance database. An HC was defined as being greater than the 90th percentile (US $5093) in the LML, amounting to 38.95% of total healthcare costs.

Results

We enrolled 2121 subjects who died during 1997–2011. Mean healthcare costs per person in their LML were US $8042 ± 3477 in the HC group and US $1407 ± 1464 in the non-HC group (p < 0.001). For patients receiving aggressive end-of-life (EOL) cancer care (e.g. intensive care, cardiopulmonary resuscitation, anticancer treatment, and a high number of admission days), comorbidities of chronic kidney disease, esophageal bleeding, and receiving opioids in the LML, were significantly independent positive predictors of HCs; but admission times, comorbidities of ascites, and hypertension were negative predictors.

Conclusion

These findings could inform healthcare providers by avoiding aggressive treatments during EOL for elderly patients with liver cancer and to save on healthcare costs. Shorter admission days and more admission times in the last month of life could decrease healthcare costs.

http://ift.tt/2v9y31n

Erratum to: Identification of endonuclease domain-containing 1 as a novel tumor suppressor in prostate cancer

http://ift.tt/2vsjPE0

Quantitative Single-Photon Emission Computed Tomography/Computed Tomography for Glomerular Filtration Rate Measurement

Abstract

Purpose

We propose a quantitative Tc-99m diethylenetriaminepentaacetic acid (DTPA) single-photon emission computed tomography/computed tomography (SPECT/CT) for glomerular filtration rate (GFR) measurement.

Methods

Quantitative SPECT/CT data obtained at 2–3 min post-Tc-99m DTPA injection (370 MBq) were used to determine % injected doses (%IDs) for individual kidneys. The reproducibility of %ID measurement was tested and compared with planar scintigraphy. Cr-51 ethylenediaminetetraacetic acid (EDTA) GFR was used as reference standard. Nine young volunteers, representing normal GFR, and ten older volunteers, reflecting impaired GFR, were enrolled. The established GFR equation derived from these volunteers was applied to 19 renal tumor patients post-partial nephrectomy.

Results

At 2−3 min, %ID was most reproducible with the highest intraclass correlation (ICC) (0.9379) and lowest % coefficient of variation (CV) (6.5259%), which were more reliable than the ICC (0.9368) and %CV (6.7689%) of planar scintigraphy. Cr-51 EDTA GFR (93.16 ± 24.81 ml/min) correlated significantly with %ID (7.66 ± 2.15%, r = 0.7906, p = 0.0001), yielding an equation: Cr-51 EDTA GFR (ml/min) = (%ID × 9.1462) + 23.0653. This equation revealed significant decreases in total and nephrectomized kidney GFR (p = 0.0012 and p < 0.0001, respectively) from preoperative to 3-month postoperative measurements.

Conclusions

Quantitative Tc-99m DTPA SPECT/CT produces reliable and clinically applicable %ID estimates that translate to the GFR of individual kidneys.

http://ift.tt/2v9Fm97

Hereditary breast cancer: molecular biology and management update

http://ift.tt/2xwe89k

Does antithrombotic therapy improve survival with colorectal cancer?

Abstract

Background

The study aimed to evaluate the prognosis for patients with colorectal cancer who underwent surgery while receiving antithrombotic therapy (ATT) across all disease stages and for patients at disease stages 0–III.

Methods

This retrospective cohort study included 710 Japanese patients who underwent surgery for colorectal cancer between January 2009 and November 2015 at our institution. Approximately 35% of these patients received ATT. Of these, 199 (28.0%) received antiplatelet therapy, and 76 (10.7%) received anticoagulant therapy. We investigated the prognosis among patients with colorectal cancer receiving ATT, antiplatelet therapy, or anticoagulant therapy in all-stage and stage 0–III cancers.

Results

For all disease stages combined, no benefit was observed for ATT, antiplatelet therapy, and anticoagulant therapy groups in the overall survival rates (ATT: 87.8 vs. 78.4%, P = 0.23; antiplatelet therapy: 87.8 vs. 78.6%, P = 0.25; and anticoagulant therapy: 92.2 vs. 80.2%, P = 0.26). However, overall survival rates of patients with stage 0–III colorectal cancer undergoing ATT, antiplatelet therapy, and anticoagulant therapy significantly improved. (ATT: 98.5 vs. 92.7%, P = 0.01; antiplatelet therapy: 98.3 vs. 91.1%, P = 0.02; and anticoagulant therapy: 100 vs. 92.1%, P = 0.00).

Conclusion

Receiving ATT significantly improves overall survival rates in patients with stage 0–III colorectal cancer.

http://ift.tt/2vjxu0C

Impact of nutritional status in the era of FOLFOX/FIRI-based chemotherapy

Abstract

Background

The nutritional status plays a pivotal role during anticancer therapy. This study analyzed whether nutritional status influences the outcomes in the era of FOLFOX/FIRI therapy.

Methods

The patients were divided into two groups according to whether the nutritional status was well (serum albumin level ≥ 3.8 g/dL or a ≥ 1.0 g/dL increase as compared with the value before chemotherapy) or not before and 2 and 6 months after the start of chemotherapy. Chemotherapy-related adverse events (AE), treatment effect, and compliance were evaluated according to the nutritional status. The progression-free survival (PFS) and overall survival (OS) were assessed based on the nutritional status at 6 months.

Results

Between 2010 and 2013, data on 108 consecutive patients were analyzed. At 2 months after chemotherapy, the hematotoxicic AE and the value of tumor markers did not differ significantly. The non-hematotoxic AE were less frequent in patients in the well-nourished group (grade 2, 15.9 vs. 38.5%, p < 0.01). Based on the nutritional status at 6 months after chemotherapy, the hematotoxicic AE (grade 3, 9 vs. 19.5%, p = 0.03) and non-hematotoxic AE (grade 2, 31.3 vs. 51.2%, p = 0.04; grade 3, 6.0 vs. 24.4%, p < 0.01) were less frequent, and the median CEA value (5.3 vs. 27.75 mg/L, p < 0.01) was significantly lower in the well-nourished group. The median PFS (364 vs. 233 days, p < 0.01) and 5-year OS (26.5 vs. 11.1%, p = 0.01) are significantly better in the well-nourished group.

Conclusions

The well-nourished at initial 6 months may predict a better treatment response and fewer adverse events in FOLFOX/FIRI chemotherapy.

http://ift.tt/2wJfjp0

Reply to Second malignancies in Ewing sarcoma survivors

http://ift.tt/2vjwI3O

Second malignancies in Ewing sarcoma survivors

http://ift.tt/2wJ1dE2

Modeling DNA damage-induced pneumopathy in mice: insight from danger signaling cascades

Abstract

Radiation-induced pneumonitis and fibrosis represent severe and dose-limiting side effects in the radiotherapy of thorax-associated neoplasms leading to decreased quality of life or - as a consequence of treatment with suboptimal radiation doses - to fatal outcomes by local recurrence or metastatic disease. It is assumed that the initial radiation-induced damage to the resident cells triggers a multifaceted damage-signalling cascade in irradiated normal tissues including a multifactorial secretory program. The resulting pro-inflammatory and pro-angiogenic microenvironment triggers a cascade of events that can lead within weeks to a pronounced lung inflammation (pneumonitis) or after months to excessive deposition of extracellular matrix molecules and tissue scarring (pulmonary fibrosis).

The use of preclinical in vivo models of DNA damage-induced pneumopathy in genetically modified mice has helped to substantially advance our understanding of molecular mechanisms and signalling molecules that participate in the pathogenesis of radiation-induced adverse late effects in the lung. Herein, murine models of whole thorax irradiation or hemithorax irradiation nicely reproduce the pathogenesis of the human disease with respect to the time course and the clinical symptoms. Alternatively, treatment with the radiomimetic DNA damaging chemotherapeutic drug Bleomycin (BLM) has frequently been used as a surrogate model of radiation-induced lung disease. The advantage of the BLM model is that the symptoms of pneumonitis and fibrosis develop within 1 month.

Here we summarize and discuss published data about the role of danger signalling in the response of the lung tissue to DNA damage and its cross-talk with the innate and adaptive immune systems obtained in preclinical studies using immune-deficient inbred mouse strains and genetically modified mice. Interestingly we observed differences in the role of molecules involved in damage sensing (TOLL-like receptors), damage signalling (MyD88) and immune regulation (cytokines, CD73, lymphocytes) for the pathogenesis and progression of DNA damage-induced pneumopathy between the models of pneumopathy induced by whole thorax irradiation or treatment with the radiomimetic drug BLM. These findings underline the importance to pursue studies in the radiation model(s) if we are to unravel the mechanisms driving radiation-induced adverse late effects.

A better understanding of the cross-talk of danger perception and signalling with immune activation and repair mechanisms may allow a modulation of these processes to prevent or treat radiation-induced adverse effects. Vice-versa an improved knowledge of the normal tissue response to injury is also particularly important in view of the increasing interest in combining radiotherapy with immune checkpoint blockade or immunotherapies to avoid exacerbation of radiation-induced normal tissue toxicity.

http://ift.tt/2wreqS3

Core-needle biopsy of breast cancer is associated with a higher rate of distant metastases 5 to 15 years after diagnosis than FNA biopsy

BACKGROUND

The literature offers discordant results regarding whether diagnostic biopsy is associated with the dissemination of cancer cells, resulting in local and/or distant metastasis. The long-term outcomes of patients with breast cancer were compared between those who were diagnosed using either fine-needle aspiration biopsy (FNAB) or core-needle biopsy (CNB) during 2 decades: the 1970s and 1990s.

METHODS

In the 1970s, the only diagnostic needle biopsy method used for breast cancer in Sweden was FNAB. CNB was introduced 1989 and became established in Stockholm Gotland County in the early 1990s. The authors compared the clinical outcomes of patients diagnosed using FNAB from 1971 to 1976 (n = 354) versus those of patients diagnosed using CNB from 1991 to 1995 (n = 1729). Adjusting for differences in various treatment modalities, mammography screening, tumor size, DNA ploidy, and patient age between the 2 decades, 2 strictly matched samples representing FNAB (n = 181) and CNB (n = 203) were selected for a 15-year follow-up study.

RESULTS

In a comparison of the rates of distant metastasis in the strictly matched patient groups from the FNAB and CNB cohorts, significantly higher rates of late-appearing (5-15 years after diagnosis) distant metastasis were observed among the patients who were diagnosed on CNB compared with those who were diagnosed on FNAB. No significant difference in local metastasis was observed between the 2 groups.

CONCLUSIONS

At 5 to 15 years after diagnosis of the primary tumor, CNB-diagnosed patients had significantly higher rates of distant metastases than FNAB-diagnosed patients. [See related editorial on pages 000-000, this issue.] Cancer Cytopathol 2017. © 2017 American Cancer Society.

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Primum Non Nocere

In a 15-year follow-up study based on the presence and numbers of circulating tumor cells and tumor DNA before, immediately after, and at defined points after core-needle and fine-needle biopsy procedures, a strong case is made for revisiting and potentially changing current practice to include fine-needle biopsy as the initial biopsy procedure in patients with breast masses. See also pages 000-000.

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Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3

Abstract

In cancer cells the small compounds erastin and RSL3 promote a novel type of cell death called ferroptosis, which requires iron-dependent accumulation of lipid reactive oxygen species. Here we assessed the contribution of lipid peroxidation activity of lipoxygenases (LOXs) to ferroptosis in oncogenic Ras-expressing cancer cells. Several 12/15-LOX inhibitors prevented cell death induced by erastin and RSL3. Furthermore, siRNA-mediated silencing of ALOX15 significantly decreased both erastin- and RSL3-induced ferroptotic cell death, whereas exogenous overexpression of ALOX15 enhanced the effect of these compounds. Immunofluorescence analyses revealed that the ALOX15 protein consistently localizes to cell membrane during the course of ferroptosis. Importantly, treatments of cells with ALOX15-activating compounds accelerated cell death at low, but not high doses of erastin and RSL3. These observations suggest that tumor ferroptosis is promoted by LOX-catalyzed lipid hydroperoxide generation in cellular membranes.

This article is protected by copyright. All rights reserved.

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c-Jun N-terminal kinase in pancreatic tumor stroma augments tumor development in mice

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a life-threatening disease, and there is an urgent need to develop improved therapeutic approaches. The role of c-Jun N-terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1a^Cre/+;Kras^G12D/+ mice with JNK1^-/- mice to generate Ptf1a^Cre/+;Kras^G12D/+;JNK1^-/- (Kras;JNK1^-/-) mice. The tumor weight were significantly lower in Kras;JNK1^-/- mice than in Kras;JNK1^+/- mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 subcutaneously into wild-type (WT) and JNK1^-/- mice. The tumor diameters were significantly smaller in JNK1^-/- mice. Phosphorylated JNK (p-JNK) was activated in α-SMA-positive cells in the tumor stroma, and mPC-conditioned medium activated p-JNK in tumor-associated fibroblasts (TAFs) in vitro. The relative expression of Ccl20 was downregulated in stimulated TAFs. Ccl20 is an important chemokine that promotes CD8⁺ T-cell infiltration via recruitment of dendritic cells, and the number of CD8⁺ T cells was decreased in Kras;JNK1^+/- mice compared with Kras;JNK1^-/- mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAFs via activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8⁺ T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAFs and induce accumulation of CD8⁺ T cells, which would be expected to enhance antitumor immunity.

This article is protected by copyright. All rights reserved.

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CBX8 is a predictor of muscle invasive bladder cancer and promotes cell proliferation by repressing the p53 pathway

Abstract

CBX8, also known as human polycomb 3, is a repressor that maintains the transcriptionally repressive state in various cellular genes, and has been reported to promote tumorigenesis. In the present study we examined the CBX8 expression in 8 pairs of muscle invasive bladder cancer tissues and adjacent non-tumor tissues, and found that CBX8 was frequently upregulated in muscle invasive bladder cancer tissues when compared to adjacent non-tumor tissues. Analysis showed that high expression of CBX8 in 152 muscle invasive bladder cancer specimens was associated with progression of the T-, N-, and M stage (P = 0.004, 0.005, <0.001, respectively). Furthermore, Kaplan-Meier survival analysis and log-rank test showed that muscle invasive bladder cancer patients with high CBX8 expression had a poor rate of overall survival (P <0.001) and 5-year recurrence-free survival (P <0.001) compared to patients with low CBX8 expression. High CBX8 expression predicted poor overall survival and 5-year recurrence-free survival in T- and N- stages of muscle invasive bladder cancer patients. Moreover, knockdown of CBX8 inhibited cells proliferation of urothelial carcinoma of the bladder both in vitro and in vivo. In addition, CBX8 depletion resulted in cell cycle delay of urothelial carcinoma cells of the bladder at the G2/M phase via the p53 pathway. The data suggests that high expression of CBX8 plays a critical oncogenic role in aggressiveness of urothelial carcinoma cells of the bladder through promoting cancer cell proliferation by repressing the p53 pathway, and CBX8 could be employed as a novel predictor for muscle invasive bladder cancer patients.

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Diagnostic and prognostic role of urinary collagens in primary human bladder cancer

Abstract

Collagen type 4 alpha 1 (COL4A1) and collagen type 13 alpha 1 (COL13A1) produced by urothelial cancer cells support the vital oncogenic property of tumor invasion. We investigated the diagnostic and prognostic capability of COL4A1 and COL13A1 in voided urine and compared the observed values with those of CYFRA21-1, NMP-22, and voided urine cytology in bladder cancer (BCa). We collected voided urine samples from 154 patients newly diagnosed with BCa, before surgery and from 61 control subjects. Protein levels of COL4A1, COL13A1, CYFRA21-1, and NMP-22 in urine supernatants were measured using enzyme-linked immunosorbent assays. The diagnostic performance and optimal cutoff values were determined by receiver operating characteristic analysis. Urine levels of COL4A1, COL13A1, the combined values of COL4A1 and COL13A1 (COL4A1+COL13A1), and CYFRA21-1 were significantly elevated in urine from patients with BCa compared to the controls. Among these biomarkers, the optimal cutoff value of COL4A1+COL13A1 at 1.33 ng/mL resulted in 57.4%, 83.7%, 56.1%, 80.7%, and 91.7% sensitivity for low-grade tumors, high-grade tumors, Ta, T1, and muscle invasive disease, respectively. We evaluated the prognostic value of preoperative urine levels in 130 non-muscle invasive BCa samples after the initial transurethral surgery. A high urinary COL4A1+COL13A1 was found to be an independent risk factor of intravesical recurrence. Although these data need to be externally validated, urinary COL4A1 and COL13A1 could be a potential diagnostic and prognostic biomarker for BCa. This easy-to-use urinary signature identifies a subgroup of patients with high probability of recurrence and progression in non-muscle invasive and muscle invasive BCa.

This article is protected by copyright. All rights reserved.

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Elevated expression of JAM-A promotes neoplastic properties of lung adenocarcinoma

Abstract

A cell-cell adhesion protein, junctional adhesion molecule-A (JAM-A), has been shown to be involved in neoplasia of various organs. However, the fundamental role of JAM-A in tumorigenesis is still controversial because dysregulated expression of this protein has distinct effects, playing opposite roles in carcinogenesis depending on the target tissues. In the present study, we found elevated levels of JAM-A expression in lung adenocarcinoma and its preinvasive lesions, including atypical adenomatous hyperplasia and adenocarcinoma in situ by immunohistochemistry. We also showed that suppression of constitutive JAM-A expression conferred target cells with increased susceptibility to apoptosis in lung adenocarcinoma cells. Consequently, inhibition of JAM-A activity decreased colony-forming capability in vitro and tumorigenicity in vivo. The transformed phenotype following suppression of JAM-A expression was sufficient to reduce motile and invasive capacities. Importantly, knockout of JAM-A had striking effects on cells. Our observations suggested that increased expression of JAM-A promotes neoplasia of lung adenocarcinoma. In addition, an anti-JAM-A antibody efficiently reduced cell proliferation and provoked apoptosis, indicating the potential feasibility of JAM-A-inhibitory cancer therapy.

This article is protected by copyright. All rights reserved.

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A phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer

Abstract

This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics, and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg twice daily on days 1–21 with carboplatin (area under the concentration–time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m² on days 1, 8, and 15 every 3 weeks for up to 6 21-day cycles. Dose escalation followed a 3+3 design to determine dose-limiting toxicities, maximum tolerated dose, and the recommended phase 2 dose. Nine patients (median age 62 [range 27–72] years) received a median of 5 (range 3–6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose-limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea, and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in 5 patients, was partial in 4 and complete in 1 (objective response rate 100%). Response could not be assessed in 4 patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg twice daily. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer.

This article is protected by copyright. All rights reserved.

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Anti-CD19 CAR T Cells in CNS Diffuse Large-B-Cell Lymphoma

To the Editor: We report the case of a 68-year-old woman with refractory diffuse large-B-cell lymphoma (DLBCL), germinal-center subtype, with a BCL2 rearrangement and multiple copies of MYC and BCL6. Her disease was refractory to intensive infusional chemotherapy, dose-adjusted etoposide,…

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Concurrent chemoradiotherapy with or without cetuximab for stage II to IVb nasopharyngeal carcinoma: a case–control study

Abstract

Background

This study aimed to evaluate the long-term outcome and toxicities in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated by concurrent chemoradiotherapy (CCRT) with/without adding cetuximab.

Methods

A total of 62 patients treated with CCRT plus cetuximab were matched with 124 patients treated with CCRT alone by age, sex, pathological type, T category, N category, disease stage, radiotherapy (RT) technique, Epstein-Barr virus (EBV) DNA levels, and Eastern Cooperative Oncology Group (ECOG). Overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method and log-rank test. Treatment toxicities were clarified and compared between two groups.

Results

A total of 186 well-balanced stage II to IV NPC patients were retrospectively analyzed (median follow-up, 76 months). Compared to CCRT alone, adding cetuximab resulted in more grade 3 to 4 radiation mucositis (51.6% vs. 23.4%; P < 0.001). No differences were found between the CCRT + cetuximab group and the CCRT group in 5-year OS (89.7% vs. 90.7%, P = 0.386), 3-year PFS (83.9% vs. 88.7%, P = 0.115), the 3-year LRFS (95.0% vs. 96.7%, P = 0.695), and the 3-year DMFS (88.4% vs 91.9%, P = 0.068). Advanced disease stage was the independent prognostic factor predicting poorer OS and PFS.

Conclusion

Adding cetuximab to CCRT did not significantly improve benefits in survival in stage II to IV NPC and exacerbated acute mucositis and acneiform rash. Further investigations are warranted.

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Country and regional variations in purchase prices for essential cancer medications

Abstract

Background

Accessibility to essential cancer medications in low- and middle-income countries is threatened by insufficient availability and affordability. The objective of this study is to characterize variation in transactional prices for essential cancer medications across geographies, medication type, and time.

Methods

Drug purchase prices for 19 national and international buyers (representing 29 total countries) between 2010 and 2014 were obtained from Management Sciences for Health. Median values for drug pricing were computed, to address outliers in the data. For comparing purchase prices across geographic units, medications, and over time; Mann-Whitney U tests were used to compare two groups, Kruskal Wallis H tests were used to compare more than two groups, and linear regression was used to compare across continuous independent variables.

Results

During the five-year data period examined, the median price paid for a package of essential cancer medication was $12.63. No significant differences in prices were found based on country-level wealth, country-level disease burden, drug formulation, or year when medication was purchased. Statistical tests found significant differences in prices paid across countries, regions, individual medications, and medication categories. Specifically, countries in the Africa region appeared to pay more for a package of essential cancer medication than countries in the Latin America region, and cancer medications tended to be more expensive than anti-infective medications and cardiovascular medications.

Conclusions

Though preliminary, our study found evidence of variation in prices paid by health systems to acquire essential cancer medications. Primarily, variations in pricing based on geographic location and cancer medication type (including when comparing to essential medicines that treat cardiovascular and infectious diseases) indicate that these factors may impact availability, affordability and access to essential cancer drugs. These factors should be taken into consideration when countries assess formulary decisions, negotiate drug procurement terms, and when formulating health and cancer policy.

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Case 26-2017: A 63-Year-Old Woman with Fever, Hypotension, and Hypoxemia

Presentation of Case. Dr. Robert H. Goldstein (Medicine): A 63-year-old woman was admitted to the intensive care unit (ICU) of this hospital because of fever, hypotension, and hypoxemia. Five months before the current admission, weakness of the proximal muscles of the arms and dyspnea on exertion…

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Ptosis, miosis and cats

Horner's syndrome (HS) is caused by a disruption in the oculosympathetic pathway. Both congenital and acquired HS are unusual in children. Acquired HS can be caused by trauma, surgical intervention, tumours, vascular malformations or infection.

We describe the case of a 6-year-old boy who was brought to our emergency department with ptosis, miosis, painful cervical lymphadenopathy and a cat scratch on a hand. The diagnosis of a cat scratch disease was confirmed by serology. A full recovery was observed on antibiotic treatment and cervical lymphadenomegaly reduction 3 weeks later.

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Augmented-pressure distal colostogram: the most important diagnostic tool for planning definitive surgical repair of anorectal malformations in boys

Abstract

There is little current literature on the augmented-pressure distal colostogram, the single most important diagnostic study performed in boys with imperforate anus prior to definitive repair. Accurate understanding of the anatomy of the anorectal malformation including an associated fistulous communication between the rectum and the urogenital tract is essential for optimal surgical management. Specifically, the position of the rectal pouch and recto-urinary fistula relative to posterior sagittal structures of the perineum, especially the sacral spine, dictates the operative approach. This pictorial essay is a guide for those who encounter such children with relative infrequency to become more comfortable with the technique. We report how to perform this radiologic exam and the potential pitfalls from our experience of performing the technique in our large pediatric colorectal practice.

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Anti-CD19 CAR T Cells in CNS Diffuse Large-B-Cell Lymphoma

To the Editor: We report the case of a 68-year-old woman with refractory diffuse large-B-cell lymphoma (DLBCL), germinal-center subtype, with a BCL2 rearrangement and multiple copies of MYC and BCL6. Her disease was refractory to intensive infusional chemotherapy, dose-adjusted etoposide,…

http://ift.tt/2vj1Y39

Is there a socioeconomic variation in survival from renal tumours in children and young people resident in northern England (1968–2012)?

Publication date: October 2017
Source:Cancer Epidemiology, Volume 50, Part A
Author(s): Ugonna T. Offor, Nermine O. Basta, Peter W. James, Richard J.Q. McNally
BackgroundDespite strong evidence of a social gradient in cancer survival among UK adults, studies in children and young people remain inconclusive and have not included renal tumours. This study investigated the relationship between socioeconomic status and survival from renal tumours among children and young people.ProcedureKaplan-Meier estimation and Cox regression were used to analyse survival for all 209 renal tumours in children and young people (0–24 years) diagnosed 1968–2012 and registered by a specialist population-based registry. Sociodemographic and clinicopathologic variables, including paternal occupation at birth, were also analysed.ResultsNo significant disparity in overall renal tumour and Wilms tumour (WT) survival was observed according to paternal social class [p=0.988 and 0.808, respectively]. The strongest predictor of survival was stage, with late stage (III–IV) disease having a 4-fold higher risk of death compared to early stage (I–II) disease [p<0.001]. Similarly, high mortality-risk was seen for late stage WT in children aged 0–14 years (Hazard Ratio=6.37; 95% CI=2.60–15.59).ConclusionsThis study did not detect a significant social gradient in renal tumour survival. The identification of tumour stage as a strong predictor of survival irrespective of age, necessitates the development of appropriate public health interventions that target early diagnosis and treatment.



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The feasibility and benefit of a brief psychosocial intervention in addition to early palliative care in patients with advanced cancer to reduce depressive symptoms: a pilot randomized controlled clinical trial

Abstract

Background

The aim of this study was to assess the feasibility and potential benefit of a brief psychosocial intervention based on cognitive-behavioral therapy performed in addition to early palliative care (PC) in the reduction of depressive symptoms among patients with advanced cancer.

Methods

An open-label randomized phase II clinical trial with two intervention arms and one control group. Patients with advanced cancer starting palliative chemotherapy and who met the selection criteria were included. The participants were randomly allocated to three arms: arm A, five weekly sessions of psychosocial intervention combined with early PC; arm B, early PC only; and arm C, standard cancer treatment. Feasibility was investigated by calculating rates (%) of inclusion, attrition, and contamination (% of patients from Arm C that received PC). Scores of depression (primary aim), anxiety, and quality of life were measured at baseline and 45, 90, 120, and 180 days after randomization.

Results

From the total of 613 screened patients (10.3% inclusion rate), 19, 22, and 22 patients were allocated to arms A, B, and C, respectively. Contamination and attrition rates (180 days) were 31.8% and 38.0%, respectively. No interaction between the arms and treatments were found. Regarding effect sizes, there was a moderate benefit in arm A over arms B and C in emotional functioning (−0.66 and −0.61, respectively) but a negative effect of arm A over arm C in depression (−0.74).

Conclusions

Future studies to be conducted with this population group need to revise the eligibility criteria and make them less restrictive. In addition, the need for arm C is questioned due to high contamination rate. The designed psychosocial intervention was not able to reduce depressive symptoms when combined with early PC. Further studies are warrant to evaluate the intervention on-demand and in subgroups of high risk of anxiety/depression.

Trial registration

Clinical Trials identifier NCT02133274. Registered May 6, 2014.

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Novel histone deacetylase 8-selective inhibitor 1,3,4-oxadiazole-alanine hybrid induces apoptosis in breast cancer cells

Abstract

Identification of isoform-specific histone deacetylase inhibitors (HDACi) is a significant advantage to overcome the adverse side effects of pan-HDACi for the treatment of various diseases, including cancer. We have designed, and synthesized novel 1,3,4 oxadiazole with glycine/alanine hybrids as HDAC8-specific inhibitors and preliminary evaluation has indicated that 1,3,4 oxadiazole with alanine hybrid [(R)-2-amino-N-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)propanamide (10b)] to be a potent HDAC8 inhibitor. In the present study, the in vitro efficacy of the molecule in inhibiting the cancer cell proliferation and the underlying molecular mechanism was studied. 10b inhibited the growth of MDA-MB-231 and MCF7 breast cancer cells, with a lower IC₅₀ of 230 and 1000 nM, respectively, compared to K562, COLO-205 and HepG2 cells and was not cytotoxic to normal breast epithelial cells, MCF10A. 10b was specific to HDAC8 and did not affect the expression of other class I HDACs. Further, a dose-dependent increase in H3K9 acetylation levels demonstrated the HDAC-inhibitory activity of 10b in MDA-MB-231 cells. Flow cytometric analysis indicated a dose-dependent increase and decrease in the percent apoptotic cells and mitochondrial membrane potential, respectively, when treated with 10b. Immunoblot analysis showed a modulation of Bax/Bcl2 ratio with a decrease in Bcl2 expression and no change in Bax expression. 10b treatment resulted in induction of p21 and inhibition of CDK1 proteins along with cytochrome c release from mitochondria, activation of caspases-3 and -9 and cleavage of poly ADP-ribose polymerase leading to apoptotic death of MDA-MB-231 and MCF7 cells. In conclusion, our results clearly demonstrated the efficacy of 10b as an anticancer agent against breast cancer.

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Response to crizotinib in a lung adenocarcinoma patient harboring a novel SLC34A2-ROS1 fusion variant

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Survival significance of epidermal growth factor receptor tyrosine kinase inhibitors and current staging system for survival after recurrence in patients with completely resected lung adenocarcinoma

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Immunotherapy in Gynecologic Cancers: Are We There Yet?

Opinion statement

Immune-targeted therapies have demonstrated durable responses in many tumor types with limited treatment options and poor overall prognosis. This has led to enthusiasm for expanding such therapies to other tumor types including gynecologic malignancies. The use of immunotherapy in gynecologic malignancies is in the early stages and is an active area of ongoing clinical research. Both cancer vaccines and immune checkpoint inhibitor therapy continue to be extensively studied in gynecologic malignancies. Immune checkpoint inhibitors, in particular, hold promising potential in specific subsets of endometrial cancer that express microsatellite instability. The key to successful treatment with immunotherapy involves identification of the subgroup of patients that will derive benefit. The number of ongoing trials in cervical, ovarian, and endometrial cancer will help to recognize these patients and make treatment more directed. Additionally, a number of studies are combining immunotherapy with standard treatment options and will help to determine combinations that will enhance responses to standard therapy. Overall, there is much enthusiasm for immunotherapy approaches in gynecologic malignancies. However, the emerging data shows that with the exception of microsatellite unstable tumors, the use of single-agent immune checkpoint inhibitors is associated with response rates of 10–15%. More effective and likely combinatorial approaches are needed and will be informed by the findings of ongoing trials.

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Fertility Sparing Strategies in Patients Affected by Placental Site Trophoblastic Tumor

Opinion statement

Placental site trophoblastic tumor (PSTT) is the least common and the most ambiguous gestational trophoblastic tumor. Presentation of PSTT may occur in the course of gestation or from 1 week to 14 years after a normal or an abnormal pregnancy (mole, ectopic pregnancy, abortion). The indicators of aggressive behavior for this tumor are not well established. Due to the rarity of this disease that usually affects women of childbearing potential, we aimed to review the current literature, to identify risk factors and the best conservative therapeutic choices among the cases described. We performed a systematic literature search of articles in English language, published from 1996 to 2017 and indexed in PubMed and Scopus. Based on selective inclusion/exclusion criteria, we considered eight papers eligible for the review. Five were case reports and three were retrospective studies. We extracted and organized data into three different categories depending on the main treatment used. A total of 12 cases were treated with laparotomy; in 5 cases, the treatment was not curative. Therefore, a total abdominal hysterectomy was needed. Five cases were treated successfully with a minimally invasive approach, 2 with uterine evacuation, 2 with hysteroscopic resection, and 1 with a combined hysteroscopic/laparoscopic resection. Only 1 case treated with exclusive chemotherapy proved curative for the patient. Preservation of fertility in PSTT patients of childbearing age should be considered and as showed by the abovementioned studies, is a possible and safe therapeutic choice. Laparotomy for local uterine resection with the modified Strassman approach could be offered in patients at clinical stage 1 that are very motivated to retain fertility, extensively informing the patient of the risks and benefits related to this choice.

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Role of magnetic resonance urography in pediatric renal fusion anomalies

Abstract

Renal fusion is on a spectrum of congenital abnormalities that occur due to disruption of the migration process of the embryonic kidneys from the pelvis to the retroperitoneal renal fossae. Clinically, renal fusion anomalies are often found incidentally and associated with increased risk for complications, such as urinary tract obstruction, infection and urolithiasis. These anomalies are most commonly imaged using ultrasound for anatomical definition and less frequently using renal scintigraphy to quantify differential renal function and assess urinary tract drainage. Functional magnetic resonance urography (fMRU) is an advanced imaging technique that combines the excellent soft-tissue contrast of conventional magnetic resonance (MR) images with the quantitative assessment based on contrast medium uptake and excretion kinetics to provide information on renal function and drainage. fMRU has been shown to be clinically useful in evaluating a number of urological conditions. A highly sensitive and radiation-free imaging modality, fMRU can provide detailed morphological and functional information that can facilitate conservative and/or surgical management of children with renal fusion anomalies. This paper reviews the embryological basis of the different types of renal fusion anomalies, their imaging appearances at fMRU, complications associated with fusion anomalies, and the important role of fMRU in diagnosing and managing children with these anomalies.

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Endothelial progenitor cells in multiple myeloma neovascularization: a brick to the wall

Abstract

Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow that leads to events such as bone destruction, anaemia and renal failure. Despite the several therapeutic options available, there is still no effective cure, and the standard survival is up to 4 years. The evolution from the asymptomatic stage of monoclonal gammopathy of undetermined significance to MM and the progression of the disease itself are related to cellular and molecular alterations in the bone marrow microenvironment, including the development of the vasculature. Post-natal vasculogenesis is characterized by the recruitment to the tumour vasculature of bone marrow progenitors, known as endothelial progenitor cells (EPCs), which incorporate newly forming blood vessels and differentiate into endothelial cells. Several processes related to EPCs, such as recruitment, mobilization, adhesion and differentiation, are tightly controlled by cells and molecules in the bone marrow microenvironment. In this review, the bone marrow microenvironment and the mechanisms associated to the development of the neovasculature promoted by EPCs are discussed in detail in both a non-pathological scenario and in MM. The latest developments in therapy targeting the vasculature and EPCs in MM are also highlighted. The identification and characterization of the pathways relevant to the complex setting of MM are of utter importance to identify not only biomarkers for an early diagnosis and disease progression monitoring, but also to reveal intervention targets for more effective therapy directed to cancer cells and the endothelial mediators relevant to neovasculature development.

http://ift.tt/2w0XVLw

Frizzled-5: a high affinity receptor for secreted frizzled-related protein-2 activation of nuclear factor of activated T-cells c3 signaling to promote angiogenesis

Abstract

Secreted frizzled-related protein 2 (SFRP2) is a pro-angiogenic factor expressed in the vasculature of a wide variety of human tumors, and modulates angiogenesis via the calcineurin-dependent nuclear factor of activated T-cells cytoplasmic 3 (NFATc3) pathway in endothelial cells. However, until now, SFRP2 receptor for this pathway was unknown. In the present study, we first used amino acid alignments and molecular modeling to demonstrate that SFRP2 interaction with frizzled-5 (FZD5) is typical of Wnt/FZD family members. To confirm this interaction, we performed co-immunofluorescence, co-immunoprecipitation, and ELISA binding assays, which demonstrated SFRP2/FZD5 binding. Functional knock-down studies further revealed that FZD5 is necessary for SFRP2-induced tube formation and intracellular calcium flux in endothelial cells. Using protein analysis on endothelial cell nuclear extracts, we also discovered that FZD5 is required for SFRP2-induced activation of NFATc3. Our novel findings reveal that FZD5 is a receptor for SFRP2 and mediates SFRP2-induced angiogenesis via calcineurin/NFATc3 pathway in endothelial cells.

http://ift.tt/2xf4atC

Religiousness and health in Europe

Abstract

Recent research suggests that epidemiological forces in religion and health can have opposed effects. Using longitudinal data of people aged 50+ included in wave 1 (2004–2005) of the Survey of Health, Ageing and Retirement in Europe (SHARE), and followed up through waves 2 (2006–2007), 4 (2011) and 5 (2013), we examined two forms of religious internalization and their association with health. Multivariate logistic regressions were used to examine all associations. Taking part in a religious organization was associated with lower odds of GALI (global activity limitation index) (OR = 0.86, 95% CI 0.75, 0.98) and depressive symptoms 0.80 (95% CI 0.69, 0.93), whereas being religiously educated lowered odds of poor self-rated health (SRH) 0.81 (95% CI 0.70, 0.93) and long-term health problems 0.84 (95% CI 0.74, 0.95). The more religious had lower odds of limitations with activities of daily living 0.76 (95% CI 0.58, 0.99) and depressive symptoms 0.77 (95% CI 0.64, 0.92) than other respondents, and compared to people who only prayed and did not have organizational involvement, they had lower odds of poor SRH 0.71 (95% CI 0.52, 0.97) and depressive symptoms 0.66 (95% CI 0.50, 0.87). Conversely, people who only prayed had higher odds of depressive symptoms than non-religious people 1.46 (95% CI 1.15, 1.86). Our findings suggest two types of religiousness: 1. Restful religiousness (praying, taking part in a religious organization and being religiously educated), which is associated with good health, and 2. Crisis religiousness (praying without other religious activities), which is associated with poor health.

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Primary renal echinococcosis with gross hydatiduria

Renal echinococcosis is a rare disease. It is usually asymptomatic but may present with pain, lump or in rare cases hydatiduria. Diagnosis is mainly by imaging but serology is usually false negative. We present a patient of renal echinococcosis who presented with passing of grape skin like structures in urine and was diagnosed to be a case of renal echinococcosis on the basis of positive serology, ultrasonographic and CT findings. The patient underwent a nephroureterectomy and was given albendazole preoperatively and postoperatively.

http://ift.tt/2w78v1O

Case of steroid-responsive encephalopathy from hypoglycaemia

Hypoglycaemic encephalopathy is a feared complication in the management of patients with diabetes mellitus. We report on a 73-year-old woman with type 1 diabetes managed with an insulin pump who presented unresponsive after an inappropriate insulin bolus. The patient had minimal improvement in her neurological status over 8 days. After administration of 1 g intravenous methylprednisolone, she had dramatic neurological improvement including successful extubation and discharge from the intensive care unit. Steroid responsive encephalopathy is increasingly recognised in practice and literature. However, to the best of our knowledge, this is the first case of hypoglycaemic encephalopathy that responded to high-dose steroids.

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Hepatic artery aneurysm: an unusual cause of upper gastrointestinal bleed

An 86-year-old woman presented to hospital with melaena. This was her third presentation with the same symptom. There was no obvious source of bleeding on her oesophagogastroduodenoscopy; however, it did show a previously clipped Dieulafoy lesion. CT angiography showed an aneurysm arising from the hepatic artery. Selective coeliac artery angiogram showed aneurysmal dilatation of the distal part of the coeliac trunk and confirmed the presence of the common hepatic artery aneurysm. The aneurysm was coiled by the interventional radiologist. Final angiogram showed good flow through the hepatic artery with obliteration of the inferior patch. The procedure was uncomplicated and the patient was discharged shortly afterwards.

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Elephantiasis nostras verrucosa secondary to recurrent erysipelas

Description

A 79-year-old man presented with worsening lower leg oedema, nausea, prostration, fever and chills. He had history of several episodes of erysipelas during 10 years, chronic venous insufficiency and type 2 diabetes mellitus. Physical examination revealed lesions of a mossy and verrucose appearance, with exophytic and agglomerated lesions on the left lower limb (figure 1). The dermatological findings of epidermal thickening, lymphoedema and fibrosis of the dermis and subcutaneous tissue were consistent with the final stage of erysipelas in the rare form of elephantiasis nostras verrucosa (ENV). The patient received intravenous furosemide and heparin to control oedema and to prevent deep vein thrombosis and antibiotic therapy.

Figure 1

Detailed view of verrucose and exophytic lesions on the left lower limb of the patient.

ENV is a serious complication of chronic lymphoedema that causes progressive cutaneous hypertrophy.1 Lymphoedema, if left untreated,...

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Prevalence of Anal Human Papillomavirus Infection in Hungarian Men Who Have Sex with Men

Abstract

Anal cancer is one of the leading causes of death in non-AIDS defining cancers. Most of these cancers are associated with high risk HPV infection. So far, the prevalence and the significance of anal HPV infection have not been studied in the Hungarian MSM population. The main objective of our study was to determine the prevalence and associated risk factors of HPV-infection in the Hungarian MSM community, particularly in HIV-infected MSM. Out of 109 examinations 92 samples (80 HIV-infected and 12 HIV-negative MSM) were evaluated for both cytological abnormalities and HPV genotyping PCR. Using a questionnaire all enrolled individuals were interviewed about their sexual behavior, socioeconomic factors, drug use and other known or suspected risk factors. In the HIV-infected cohort 97.5% of the examined individuals were positive for any HPV type. In this group we detected high risk (HR) HPV in 88.8%, low risk (LR) HPV in 75.0% and probably high risk (PHR) HPV in 47.5% and multiple HPV infection was absolutely common (82.5%). In the HIV-negative MSM group the incidence of HPV-infection was 58.3%. The respective rate of HR-HPV, LR-HPV and PHR-HPV genotypes were 33.3%, 58.4%, and 16.7%. In the HIV-negative group both HPV infection frequency and the prevalence of the pertinent genotypes were much lower. The Hungarian MSM population is severely infected with HPV and HR-HPV. High-risk sexual behaviors are strong predictors for acquiring HR-HPV co-infections. Our results underline the necessity of anal cancer screening and the introduction of the vaccination program in the high-risk population.

http://ift.tt/2w7jo3W

Prevalence of Anal Human Papillomavirus Infection in Hungarian Men Who Have Sex with Men

Abstract

Anal cancer is one of the leading causes of death in non-AIDS defining cancers. Most of these cancers are associated with high risk HPV infection. So far, the prevalence and the significance of anal HPV infection have not been studied in the Hungarian MSM population. The main objective of our study was to determine the prevalence and associated risk factors of HPV-infection in the Hungarian MSM community, particularly in HIV-infected MSM. Out of 109 examinations 92 samples (80 HIV-infected and 12 HIV-negative MSM) were evaluated for both cytological abnormalities and HPV genotyping PCR. Using a questionnaire all enrolled individuals were interviewed about their sexual behavior, socioeconomic factors, drug use and other known or suspected risk factors. In the HIV-infected cohort 97.5% of the examined individuals were positive for any HPV type. In this group we detected high risk (HR) HPV in 88.8%, low risk (LR) HPV in 75.0% and probably high risk (PHR) HPV in 47.5% and multiple HPV infection was absolutely common (82.5%). In the HIV-negative MSM group the incidence of HPV-infection was 58.3%. The respective rate of HR-HPV, LR-HPV and PHR-HPV genotypes were 33.3%, 58.4%, and 16.7%. In the HIV-negative group both HPV infection frequency and the prevalence of the pertinent genotypes were much lower. The Hungarian MSM population is severely infected with HPV and HR-HPV. High-risk sexual behaviors are strong predictors for acquiring HR-HPV co-infections. Our results underline the necessity of anal cancer screening and the introduction of the vaccination program in the high-risk population.

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Human leukemia antigen-A*0201-restricted epitopes of human endogenous retrovirus W family envelope (HERV-W env) induce strong cytotoxic T lymphocyte responses

Abstract

Human endogenous retrovirus W family (HERV-W) envelope (env) has been reported to be related to several human diseases, including autoimmune disorders, and it could activate innate immunity. However, there are no reports investigating whether human leukemia antigen (HLA)-A*0201⁺ restriction is involved in the immune response caused by HERV-W env in neuropsychiatric diseases. In the present study, HERV-W env-derived epitopes presented by HLA-A*0201 are described with the potential for use in adoptive immunotherapy. Five peptides displaying HLA-A* 0201-binding motifs were predicted using SYFEPITHI and BIMAS, and synthesized. A CCK-8 assay showed peptides W, Q and T promoted lymphocyte proliferation. Stimulation of peripheral blood mononuclear cells from HLA-A*0201⁺ donors with each of these peptides induced peptide-specific CD8⁺ T cells. High numbers of IFN-γ-secreting T cells were also detectable after several weekly stimulations with W, Q and T. Besides lysis of HERV-W env-loaded target cells, specific apoptosis was also observed. These data demonstrate that human T cells can be sensitized toward HERV-W env peptides (W, Q and T) and, moreover, pose a high killing potential toward HERV-W env-expressing U251 cells. In conclusion, peptides W Q and T, which are HERV-W env antigenic epitopes, have both antigenicity and immunogenicity, and can cause strong T cell immune responses. Our data strengthen the view that HERV-W env should be considered as an autoantigen that can induce autoimmunity in neuropsychiatric diseases, such as multiple sclerosis and schizophrenia. These data might provide an experimental foundation for a HERV-W env peptide vaccine and new insight into the treatment of neuropsychiatric diseases.

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Interplay between hepatitis C virus and ARF4

Abstract

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Mevastatin promotes neuronal survival against Aβ-induced neurotoxicity through AMPK activation

Abstract

Statins or HMG-CoA reductase inhibitors have been shown to be effective at lowering cholesterol levels, and the application of these molecules has gradually emerged as an attractive therapeutic strategy for neurodegenerative diseases. Epidemiological studies suggest that statin use is associated with a decreased incidence of Alzheimer's disease (AD). Thus, statins may play a beneficial role in reducing amyloid β (Aβ) toxicity, the most relevant pathological feature and pathogenesis of AD. However, the precise mechanisms involved in statin-inhibited Aβ toxicity remain unclear. In the present study, we report that mevastatin significantly protects against Aβ-induced neurotoxicity in SK-N-MC neuronal cells by restoring impaired insulin signaling. This protection appears to be associated with the activation of AMP-activated protein kinase (AMPK), which has long been known to increase insulin sensitivity. Our results also indicate that high levels of cholesterol likely underlie Aβ-induced neurotoxicity and that activation of AMPK by mevastatin alleviates insulin resistance. Signaling through the insulin receptor substrate-1/Akt pathway appears to lead to cell survival. These findings demonstrate that mevastatin plays a potential therapeutic role in targeting Aβ-mediated neurotoxicity. The molecule presents a novel therapeutic strategy for further studies in AD prevention and therapeutics.

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Identification of pathogenic retrotransposon insertions in cancer predisposition genes

Publication date: Available online 24 August 2017
Source:Cancer Genetics
Author(s): Yaping Qian, Debora Mancini-DiNardo, Thaddeus Judkins, Hannah C. Cox, Krystal Brown, Maria Elias, Nanda Singh, Courtney Daniels, Jayson Holladay, Bradford Coffee, Karla R. Bowles, Benjamin B. Roa
Cancer risks have been previously reported for some retrotransposon element (RE) insertions; however, detection of these insertions is technically challenging and very few oncogenic RE insertions have been reported. Here we evaluate RE insertions identified during hereditary cancer genetic testing using a comprehensive testing strategy. Individuals who had single-syndrome or pan-cancer hereditary cancer genetic testing from February 2004 to March 2017 were included. RE insertions were identified using Sanger sequencing, Next Generation Sequencing, or multiplex quantitative PCR, and further characterized using targeted PCR and sequencing analysis. Personal cancer history, ancestry, and haplotype were evaluated. A total of 37 unique RE insertions were identified in 10 genes, affecting 211 individuals. BRCA2 accounted for 45.9% (17/37) of all unique RE insertions. Several RE insertions were detected with high frequency in populations of conserved ancestry wherein up to 100% of carriers share a high degree of haplotype conservation, suggesting founder effects. Our comprehensive testing strategy resulted in a substantial increase in the number of reported oncogenic RE insertions, several of which may have possible founder effects. Collectively, these data show that the detection of RE insertions is an important component of hereditary cancer genetic testing and may be more prevalent than previously reported.



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Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy-induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy

Publication date: Available online 24 August 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Raafat Abdel-Malek, Noha Abbas, Kyrillus S. Shohdy, Mohamed Ismail, Radwa Fawzy, Dalal S. Salem, Ezzat Safwat
BackgroundNeurokinin-1 receptor antagonists, such as aprepitant are currently emerging as powerful prophylactic agents for chemotherapy-induced nausea and vomiting (CINV). Therefore, it is important to adjust the anti-emetic regimens based on personal risk factors of the patient, duration of the chemotherapy regimen and cost-effectiveness.PurposeTo determine the efficacy of the 3-day aprepitant along with ondansetron and dexamethasone in controlling CINV in patients with large B cell lymphoma receiving multiday-cisplatin regimen chemotherapy.MethodsThis is a pilot prospective cross-over trial. Patients were allocated to either aprepitant 125mg on day 1 and 80mg on days 2 & 3 or placebo in the first 2 cycles, with crossover to the opposite treatment in the 3rd and 4th cycles. The primary end point was complete response (CR) of both acute (days 1–5) and delayed (days 6–8) CINV. CR means neither to develop emetic episodes nor to use rescue anti-emetics medication.ResultsTwelve of the 15 patients recruited for the study were fully evaluable and completed 4 cycles of ESHAP regimen with a total of 48 cycles given. In the cycles with aprepitant and those without the CR were 83.3% and 0% respectively (p<0.05). Patients receiving aprepitant in the first 2 cycles recorded less nausea in subsequent cycles that were given without aprepitant. This was not statistically significant.ConclusionThis triple anti-emetic regimen showed efficacy in controlling the multi-day cisplatin-induced nausea and vomiting. Further randomized controlled trials are needed to compare between 3-day and 7-day aprepitant for multi-day cisplatin regimens.



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Alveolar soft part sarcoma of orbit: A rare diagnosis

Publication date: Available online 23 August 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Pritee B. Chaudhari, Sushmita Pathy, Suryanarayana S.V. Deo, Bhavna Chawla, Asit Ranjan Mridha
ObjectiveAlveolar soft part sarcoma (ASPS) is an aggressive, rare tumour with unique morphological and histopathological features.MethodsWe report a rare case of orbital ASPS and its management in a young male who presented with painless proptosis and progressive loss of vision.ResultTwenty-two year male presented with a history of gradually increasing proptosis with loss of vision since 12months. He underwent radical re-excision of mass with right orbital exenteration and reconstruction using temporalis muscle flap. Adjuvant radiotherapy to a dose of 64Gy in 32 fractions over 6.5weeks was planned in view of positive surgical margins. Patient is free of disease and currently under follow up in multidisciplinary clinic.ConclusionFunction preserving surgery remains the standard treatment approach in localised disease however the complex anatomy and locally aggressive nature makes it difficult to achieve clear surgical margin. Adjuvant radiotherapy has shown to improve local control in patients with positive surgical margins.



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Impact of CYP1A1, GSTP1 and XRCC1 genes polymorphisms on toxicity and response to chemotherapy in childhood acute lymphoblastic leukemia

Publication date: Available online 24 August 2017
Source:Journal of the Egyptian National Cancer Institute
Author(s): Asmaa Abo-Bakr, Ghada Mossallam, Nevin El Azhary, Hanafy Hafez, Ragia Badawy
BackgroundAcute lymphoblastic leukemia (ALL) is the most common childhood malignancy. The interindividual genetic variations in drug metabolizing enzymes and DNA repair genes influence the efficacy and toxicity of numerous chemotherapeutic drugs affecting the treatment outcome.Aim of the workThe aim of the study was to investigate the impact of drug metabolizing CYP1, GSTP1 and DNA repair (XRCC1) genes polymorphisms on the toxicity and response to chemotherapy in childhood ALL.Patients and methodologyNinety seven ALL pediatric patients were genotyped for CYP1A1, GSTP1 ILe105Val and XRCC1 Arg194Tryp single nucleotide polymorphisms (SNPs) using PCR-RFLP.ResultsNo statistically significant differences were observed between the wild and variant (homozygous and heterozygous) genotypes of the polymorphisms studied in CYP1A1, GSTP1 or XRCC1 genes regarding age, total leukocyte count, immunophenotyping, cytogenetic or risk group. The SNPs in CYP1A1, GSTP1 and XRCC1 genes did not show significant association with complete remission (CR) rate, overall survival (OS) or event free survival (EFS). However, XRCC1 Arg194Trp SNP was associated with higher drug toxicity; carriers of variant genotypes (CT and TT) had a significantly higher frequency of myelosuppression compared to those with the wild CC genotype (21/43[48.8%]) compared to (14/54[25.9%]) (p=0.020). The analysis of the combined effect of studied SNPs did not show any significant association with patient outcome.ConclusionOur study reported a significant association between the DNA repair gene polymorphism and myelosuppression in childhood ALL patients. Adjustment of the dose of chemotherapeutic agents according to XRCC1 Arg194Trp polymorphism may improve outcome in cases with risk of toxicity.



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Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review

Publication date: Available online 24 August 2017
Source:Cancer Treatment Reviews
Author(s): Markus V. Heppt, Theresa Steeb, J. Gabriel Schlager, Stefanie Rosumeck, Corinna Dressler, Thomas Ruzicka, Alexander Nast, Carola Berking
BackgroundThe use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM.MethodsWe performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies.ResultsOut of 1,327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3 mg/kg in 5 trials (n=186) with a response rate of 0-5%. Two reports investigated ipilimumab at 10 mg/kg (n=45) with radiological responses observed in 0-6.5%. The median progression-free survival (PFS) was below 3 months and the median overall survival was 5.2-9.8 months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6-36%). Two studies investigated pembrolizumab (2 mg/kg) and nivolumab (3 mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9 months.ConclusionsUM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.



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Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: does age really matter?

Publication date: Available online 24 August 2017
Source:Cancer Treatment Reviews
Author(s): Roberto Ferrara, Laura Mezquita, Edouard Auclin, Nathalie Chaput, Benjamin Besse
Immunotherapy has dramatically changed the therapeutic scenario in non-small cell lung cancer (NSCLC), extending overall survival, with a favorable safety profile. However, there is still a gap of knowledge about the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. Data from randomized clinical trials testing ICIs are conflicting and often lack adequate statistical power. Although two large meta-analyses suggested an absence of a significant survival benefit in patients older than 75 years, expanded access programs and retrospective cohort studies of ICIs in the real-life setting, showed comparable survival outcomes and safety profiles between older and younger patients. In this complex scenario, a further unresolved issue is the potential correlation between older age and immunotherapy primary resistance, a phenomenon probably linked to the continuous and progressive remodeling of immune functions with ageing, known as immunosenescence. Defining the role of ICIs in elderly NSCLC patients and exploring the molecular mechanisms underlying a possible lack of benefit or even accelerated tumor growth during immunotherapy are two major challenges for future research in this field of cancer treatment. In this review, we describe the major hallmarks of immunosenescence and we summarize the existing clinical data of ICIs in elderly NSCLC patients.



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Healthcare cost of HER2-positive and negative breast tumors in the United States (2012−2035)

Publication date: Available online 24 August 2017
Source:Cancer Treatment Reviews
Author(s): Francesca Tartari, Matteo Santoni, Mirco Pistelli, Rossana Berardi
BackgroundIn this study, we estimated the current and future costs related to the use of targeted agents in patients with HER2-positive and negative advanced breast cancer (BC), aimed at identifying the subgroup associated with the higher cost in the coming years.MethodsWe calculated the patient cost considering an ideal patient who received therapeutic sequences including all approved agents for HER2-positive or negative BC. The duration of treatment was estimated by the median Progression-Free Survival (PFS) reported in the phase III trials which have led to the approval of these drugs by the US Food and Drug Administration. The estimated number of BC patients in the US from 2012 to 2035 refers to data published by the World Health Organization.ResultsThe per patient cost was $292,155 for HER2-positive and $224,955 for negative tumors, respectively. The total cost for HER2-positive patients was estimated for 2012 at $2,719,542,347, with an annual increase ranged from 4.3 (for 2035) to 7.7% (for 2020), leading to a total expense of $3,648,232,975 in 2035. Otherwise, the total cost for HER2-negative patients in 2012 was estimated as $8,376,028,459, with an increase of more than $2.5 billion from 2012 to 2035. The estimated cost for HER2-negative patients was $5.6 billion higher that for HER2-positive tumors, raising to $7.6 billion to 2035.ConclusionsOur data strongly suggest that cost-analyses should be carefully evaluated in the coming years, in particular in patients with HER2-negative tumors.



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Pancreatic Ductal Adenocarcinoma: State-of-the-Art 2017 and New Therapeutic Strategies

Publication date: Available online 23 August 2017
Source:Cancer Treatment Reviews
Author(s): Marta Chiaravalli, Michele Reni, Eileen M. O'Reilly
Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an overall 5-year survival of 8% for all stages combined. The majority of patients present with stage IV disease at diagnosis and these patients have an overall 5-year survival of 3%. Currently, the standard of care for metastatic pancreas adenocarcinoma is combination cytotoxic therapy, namely FOLFIRINOX or gemcitabine plus nab-paclitaxel for good performance status patients. Given the challenges and the rising incidence of PDAC expected to become the second leading cause of cancer-related death by 2030, there is a major unmet need to develop more effective therapies. In this setting, the molecular and genomic characterization of PDAC have underpinned the use of targeted therapies. To date, the results from targeted agent evaluation have been disappointing with some exceptions. Novel promising strategies depend on biomarker identification and patient selection e.g. germline mutations in DNA repair or mismatch repair genes, where the addition of a platinum agent or checkpoint inhibitor can have a positive impact on survival. This article will review the state-of-the-art treatment of metastatic pancreatic cancer with an emphasis on novel promising therapeutic strategies and an overview on emerging biomarkers.



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Roadmap for Investigating Epigenome Deregulation and Environmental Origins of Cancer

Abstract

The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene-environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor-specific ("fingerprints") that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed as well as advances in epigenomics that may help an understanding of the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed as well as how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment. This article is protected by copyright. All rights reserved.

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The risk of preterm birth and growth restriction in pregnancy after cancer

It is unclear whether cancer and its treatments increase the risk of adverse pregnancy outcomes. Our aim was to examine whether cancer survivors have higher risks of poor outcomes in pregnancies conceived after diagnosis than women without cancer, and whether these risks differ by cancer type and race. Diagnoses from cancer registries were linked to pregnancy outcomes from birth certificates in three U.S. states. Analyses were limited to the first, live singleton birth conceived after diagnosis. Births to women without a previous cancer diagnosis in the registry were matched to cancer survivors on age at delivery, parity, race/ethnicity and education. Log-binomial regression was used to estimate risk ratios. Cervical cancer survivors had higher risks of preterm birth (Risk ratio = 2.8, 95% Confidence interval: 2.1, 3.7), as did survivors of invasive breast cancer (RR = 1.3, 95% CI: 1.1, 1.7) and leukemia (RR = 2.1, 95% CI: 1.3, 3.5). We observed a higher risk of small for gestational age (SGA) infants (<10% of weight for age based on a national distribution) in survivors of brain cancer (RR = 1.7, 95% CI: 1.1, 2.8) and extranodal non-Hodgkin lymphoma (RR = 2.3, 95% CI: 1.5, 3.6). We did not see an increased risk of infants born preterm, low birth weight, or SGA in pregnancies conceived after ductal carcinoma in situ, thyroid cancer, melanoma, or Hodgkin lymphoma. While our results are reassuring for survivors of many cancers, some will need closer monitoring during pregnancy.

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