Cancer by Sfakianakis Alexandros: 08/12/17

Σάββατο 12 Αυγούστου 2017

Editorial Board

Publication date: September 2017
Source:Critical Reviews in Oncology/Hematology, Volume 117

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Advantages in Prognosis of Adult Patients with Ewing Sarcoma: 11-years Experiences and Current Treatment Management

Abstract

Ewing sarcoma (ES) is an exceptionally rare tumor in adults. Data regarding outcomes of adult patients with ES and experiences with age-adapted therapeutic strategies are very limited. The aim of this study was to evaluate prognostic factors and clinical outcome in a cohort of adult patients treated according to pediatric protocols in the Czech Republic. The records of 58 adult ES patients diagnosed between 2002 and 2013 were reviewed and factors relevant to prognosis and survival were analyzed. The median age of study cohort was 29 years (range, 18–59). The most frequent location was axial (36.2%), followed by involvement of extraskeletal tissues (34.5%) and bones of the extremities (29.3%). Twenty-eight (48.3%) patients had metastatic disease. In cases with localized ES, the 5-year overall survival (OS) was 76.5%. Using the log-rank test, the presence of metastasis at diagnosis, local treatment without surgery and a failure to achieve complete remission were associated with significantly shorter survival. In a multivariate Cox proportional hazard analysis, the achievement of complete remission was an independent predictor of patients's survival time. Outcomes of adults with localized ES treated according to multimodal pediatric protocols are similar to children. The achievement of complete remission is an independent predictor of survival time in ES patients. Severe hematological toxicity is foreseeable and manageable. Prognosis of patients with metastases or progression remains dismal.

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Advantages in Prognosis of Adult Patients with Ewing Sarcoma: 11-years Experiences and Current Treatment Management

Abstract

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CRS and HIPEC for PMP—Use of the LC-CUSUM to Determine the Number of Procedures Required to Attain a Minimal Level of Proficiency in Delivering the Combined Modality Treatment

Abstract

The learning curve for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei (PMP) which peaks at 90 procedures for the surgeon may take several years to reach. The cumulative summation (CUSUM) test of the learning curve (LC-CUSUM) was used to assess the safety of the procedure (minimal level of proficiency for the surgeon) in terms of morbidity, mortality, and completeness of cytoreduction and early oncological failure before the peak of the learning curve had been reached. The limits for h0 and h1 were set based on the results of large series of such cases published before. From 2011 to 2016, 77 patients with PMP underwent CRS and HIPEC. The mean peritoneal cancer index (PCI) was 28 and 75% of the patients had a CC-0/1 resection. The grade 3–4 morbidity was 42.6% and the mortality was 5.2%. The 5-year overall survival (OS) was 62.3% and the 3-year disease-free survival (DFS) was 71%. The LC-CUSUM analysis showed that for in-hospital mortality, acceptable limits are reached after the 57th case, after the 38th case for the grade 3–4 morbidity and CC-2/3 resections both and after the 70th case for early oncological failure. The number of cases required to attain a minimal level of proficiency for each prognostic variable is different. Using the CUSUM test, surgeons can analyze their performance and determine the areas in which they need to improve before the peak of the learning curve is reached. These outcomes reflect the performance of the multidisciplinary team and not the surgeon alone.

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The novel autophagy inhibitor elaiophylin exerts antitumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis

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Successful treatment of advanced pancreatic liposarcoma with apatinib: A case report and literature review

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Fast and robust online adaptive planning in stereotactic MR-guided adaptive radiation therapy (SMART) for pancreatic cancer

To implement a robust and fast stereotactic MR-guided adaptive radiation therapy (SMART) online strategy in locally advanced pancreatic cancer (LAPC).

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Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers

Abstract

Diminished ANK3 contributes to cell survival by inhibiting detachment-induced apoptosis. TP53BP1 that interacts with p53 and MFN1 that encodes a mitochondrial membrane protein are considered to have tumor suppressor gene (TSG) functions. HACD4 involving fatty acid synthesis and TCPL10 with transcription regulation functions are considered TSGs. Many genes involved in DNA methylations such as LCMT2, RNMT, TRMT6, METTL8 and METTL16 are often perturbed in cancer. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbored 11 (13.9%), 3 (3.8%), 0 (0%), 5 (6.3%), 1 (1.3%), 2 (2.5%), 4 (5.1%), 3 (3.8%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. There were ITH of the frameshift mutations of ANK3, MFN1 and TP53BP1 in 1 (6.3%), 1 (6.3%) and 1 (6.3%) cases, respectively. Our data exhibit that cancer-related genes ANK3, HACD4, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC.

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Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers

Abstract

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Artery of Percheron infarction: a case report

The artery of Percheron is a rare anatomic variant of arterial supply to the paramedian thalamus and rostral midbrain, and occlusion of the artery of Percheron results in bilateral paramedian thalamic infarcts...

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Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group

Abstract

Background

Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL.

Procedure

One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample.

Results

Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect.

Conclusions

Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.

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Chilblain lupus and steroid-responsive pancytopenia precede monosomy 7-linked AML as manifestation of rasopathy

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Blockade of transforming growth factor-β signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models

Abstract

Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset of tumor cells with stem-like properties, termed GBM stem-like cells (GSCs), are considered to play a role in tumor relapse. Although oncolytic herpes simplex virus (oHSV) is a promising therapeutic for GBM, its efficacy against recurrent GBM is incompletely characterized. Transforming growth factor beta (TGF-β) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF-β inhibitors would synergistically exert anti-tumor effects for recurrent GBM. Here we established a panel of patient-derived recurrent tumor models from GBMs that relapsed after post-surgical radiation and chemotherapy, based on GSC-enriched tumor sphere cultures. These GSCs are resistant to the standard-of-care temozolomide but susceptible to oHSVs G47Δ and MG18L. Inhibition of TGF-β receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF-βR inhibitor was synergistic in killing recurrent GSCs through, in part, an inhibitor-induced JNK-MAPK blockade and increase in oHSV replication. In vivo, systemic treatment with TGF-βR inhibitor greatly enhanced the anti-tumor effects of single intratumoral oHSV injections, resulting in cures in 60% of mice bearing orthotopic recurrent GBM. These results reveal a novel synergistic interaction of oHSV therapy and TGF-β signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients. This article is protected by copyright. All rights reserved.

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How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer, treatment rates and adverse obstetric outcomes in Australia, a high vaccination coverage country

Abstract

Primary HPV screening enables earlier diagnosis of cervical lesions compared to cytology, however, its effect on the risk of treatment has not been investigated. We estimated the cumulative lifetime risk (CLR) of cervical cancer and excisional treatment; and change in adverse obstetric outcomes in HPV unvaccinated women and cohorts offered vaccination (>70% coverage in 12-13 years) for the Australian cervical screening program. 2-yearly cytology screening (ages 18-69 years) was compared to 5-yearly primary HPV screening with partial genotyping for HPV16/18 (ages 25-74 years). A dynamic model of HPV transmission, vaccination, cervical screening and treatment for precancerous lesions was coupled with an individual-based simulation of obstetric complications. For cytology screening, the CLR of cervical cancer diagnosis, death and treatment would be 0.65%, 0.20% and 13% without vaccination and 0.18%, 0.06% and 7%, in vaccinated cohorts, respectively. For HPV screening, relative reductions of 33% and 22% in cancer risk for unvaccinated and vaccinated cohorts are predicted, respectively, compared to cytology. Without vaccination, a 4% increase in treatment risk for HPV versus cytology screening is predicted, implying a possible increase in pre-term delivery (PTD) and low birthweight (LBW) events of 19-35 and 14-37, respectively, per 100,000 unvaccinated women. However, in vaccinated cohorts treatment risk will decrease by 13%, potentially leading to 4-41 fewer PTD events and from 2 more to 52 fewer LBW events per 100,000 vaccinated women. HPV screening starting at age 25 in populations with high vaccination coverage, is therefore expected to decrease the risks of cervical cancer and excisional treatment. This article is protected by copyright. All rights reserved.

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Cancer risk in different generations of Middle Eastern Immigrants to California, 1988-2013

Abstract

The objective of this study is to compare cancer risk among different generations of Middle Eastern (ME) immigrants and Non-Hispanic Whites (NHW) in California between 1988 and 2013. We used data from the California Cancer Registry to identify invasive primary incident cancer cases in three population groups: a) first generation ME immigrants, b) second or subsequent generations ME immigrants, and c) NHW. Proportional Incidence Ratio (PIR) was used to compare cancer risk of the 15 selected most common cancers in the 3 population groups taking into consideration time since immigration for first generation ME immigrants. First generation ME immigrants were more likely to be at increased risk of stomach (PIR= 3.13) and hepatobiliary (PIR=2.27) cancers in females and thyroid (PIR=2.19) and stomach (PIR=2.13) cancers in males in comparison with NHW. Second or subsequent generations ME immigrants were at increased risk of thyroid cancer (PIR=1.43 in females and 2.00 in males) in comparison with NHW, and malignant melanoma cancer (PIR=4.53 in females and 4.61 in males) in comparison with first generation ME immigrants. The risk levels of breast, thyroid, and bladder cancers in ME first generation were significantly higher compared to NHW regardless of time spent in the United States suggesting the role of genetic predisposition, and/or cultural characteristics associated with these cancers. The results suggest that differences in cancer risk between ME first generation immigrants and NHW change in second or subsequent generations, approaching the risk level of NHW and indicating the impact of acculturation in this immigrant population. This article is protected by copyright. All rights reserved.

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Familial associations of female breast cancer with other cancers

Abstract

Familial risks of breast cancer (BC) are well established but whether BC clusters with other, i.e. discordant, cancers is less certain but of interest for the identification of common genetic and possible environmental factors contributing to a general cancer susceptibility. We apply a novel approach to search for familial associations of BC with other (discordant) cancers based on the Swedish Family-Cancer Database. Relative risks (RRs) were calculated for BC in families with increasing numbers of patients with discordant cancer X, and conversely, familial RRs for cancer X in families with increasing numbers of BC patients. Joint p-values were calculated from independent analyses.

The total number of familial BCs was 12,266, 14.9% with one first-degree relative with BC and 1.2% with at least 2 affected relatives. Ovarian and prostate cancers showed the strongest associations with BC (p-value <10⁻¹¹). The p-value for melanoma was <10⁻⁶, for stomach and male colorectal cancer <2.5x10⁻⁶, for cancer of unknown primary <2.5x10⁻⁵, and for lung cancer <5x10⁻⁵. Significance level <5x10⁻⁴ was reached with pancreatic cancer. The remaining associations (p<0.0025) included thyroid, endometrial, testicular, eye cancers (uveal melanoma), nervous system and endocrine tumors and non-Hodgkin lymphoma. The RR for BC increased by increasing numbers of patients with any cancer in family members and it reached 1.62 when three or more family members were affected. The results suggest that BC shares susceptibility with a number of other cancers. This might alert genetic counselors and challenge approaches for gene and gene-environment identification. This article is protected by copyright. All rights reserved.

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Malignant pleural mesothelioma – Pleural cavity irradiation after decortication with helical tomotherapy

Publication date: September–October 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 5
Author(s): Semi B. Harrabi, Stefan A. Koerber, Sebastian Adeberg, Sonja Katayama, Klaus Herfarth, Juergen Debus, Florian Sterzing
BackgroundMalignant pleural mesothelioma (MPM) is a rare and aggressive disease that poses a treatment challenge in spite of recent technical developments. The aim of this retrospective analysis is to assess the feasibility of administering intensity-modulated radiotherapy (IMRT) to the pleural cavity using helical tomotherapy in patients who had undergone pleurectomy/decortication (P/D) and also the resulting toxicity levels.Patients and methodsTen patients who had MPM and had undergone P/D were treated with pleural cavity irradiation that included a median dose of 52.2Gy using helical tomotherapy. The median age of the patients was 53 years (31–74). In addition to clinical and diagnostic findings from regular follow-up examinations, we evaluated the dose distribution for other organs at risk to assess treatment in relation to toxicity, with special regard for the underlying intact lung.ResultsThe mean lung dose on the treatment site was 32.8Gy (±6.8). The V20Gy was 71.7% (±17.2). No treatment-related toxicity that exceeded grade III according to common toxicity criteria (CTC) was observed. Median progression-free survival (PFS) was 13 months with a median overall survival (OAS) of 19 months.ConclusionThe findings of this analysis provide data indicating that sparing the underlying lung in patients with MPM after P/D is not only feasible with helical tomotherapy, but that this treatment also causes reasonably few side effects.

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Improving radiation oncology through clinical audits: Introducing the IROCA project

Publication date: September–October 2017
Source:Reports of Practical Oncology & Radiotherapy, Volume 22, Issue 5
Author(s): Maria Glòria Torras, Magdalena Fundowicz, Luisa Aliste, Esther Asensio, Anna Maria Boladeras, Josep Maria Borràs, Luísa Carvalho, Carla Castro, Letizia Deantonio, Ewelina Konstanty, Marco Krengli, Marta Kruszyna, Joana Lencart, Miquel Macià, Susanna Marín, Carles Muñoz-Montplet, Carla Pisani, Diana Pinto, Montserrat Puigdemont, Ferran Guedea, Artur Aguiar, Piotr Milecki, Julian Malicki
As radiotherapy practice and processes become more complex, the need to assure quality control becomes ever greater. At present, no international consensus exists with regards to the optimal quality control indicators for radiotherapy; moreover, few clinical audits have been conducted in the field of radiotherapy. The present article describes the aims and current status of the international IROCA "Improving Radiation Oncology Through Clinical Audits" project. The project has several important aims, including the selection of key quality indicators, the design and implementation of an international audit, and the harmonization of key aspects of radiotherapy processes among participating institutions. The primary aim is to improve the processes that directly impact clinical outcomes for patients. The experience gained from this initiative may serve as the basis for an internationally accepted clinical audit model for radiotherapy.

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MicroRNA-492 overexpression involves in cell proliferation, migration and radiotherapy response of cervical squamous cell carcinomas

Abstract

MicroRNAs (miRNAs) are small non-coding RNA that target protein-coding mRNAs at the post-transcriptional level. The aim of this study was to define the role of miR-492 in cervical squamous cell carcinomas. After microRNA profiling and comparison, we firstly detected miR-492 expression in 104 tumor tissues biopsies derived from advanced staged (FIGO IIB-IIIB) cervical squamous cell carcinoma patients before receiving concomitant chemoradiotherapy and found miR-492 expression was significantly higher in the specimens that were sensitive to concomitant chemoradiotherapy, as compared with insensitive cancer specimens (p < 0.05). Moreover, higher expression of miR-492 was associated with pelvic lymph node metastasis (LNM) (p < 0.05). Further studies illustrated ectopic miR-492 overexpression in SiHa cells promoted cell proliferation, migration and enhanced the sensitivity of cervical cancer cells to irradiation by promoting apoptosis. In addition, we identified TIMP2 as a direct miR-492 target, which has been shown to be critical in modulating cancer cell migration and invasion. We also confirmed that miR-492 expression levels in positive pelvic LNM were much higher than negative LNM and miR-492 played a vital role in pelvic lymph node metastasis via regulating miR-492/TIMP2/MMP10 axis. In particular, miR-492 was correlated with prognosis in the subgroup of patients with negative pelvic LNM (p < 0.05) and had a promising value in predicting treatment response in the subgroup of patients with positive pelvic LNM (an AUC of 85%, 75.00% specificity and 95.24% sensitivity). Taken together, the results suggested that miR-492 may serve as a potential biomarker for cervical cancer treatment and prognosis. This article is protected by copyright. All rights reserved

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Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response

Abstract

Treatment with tyrosine kinase inhibitors (TKIs) may sequentially induce TKI-resistant BCR-ABL mutants in chronic myeloid leukemia (CML). Conventional polymerase chain reaction (PCR) monitoring of BCR-ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot quantify separately amounts of BCR-ABL and its mutants, including alternatively spliced BCR-ABL with an insertion of 35 intronic nucleotides (BCR-ABL^I^ns35bp) between ABL exons 8 and 9 which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR-ABL mutants, we performed deep sequencing analysis of BCR-ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched into nilotinib. At baseline, TKI-resistant mutations were documented in 3 patients, whereas BCR-ABL^I^ns35bp was detected in all patients. After switching to nilotinib, both BCR-ABL and BCR-ABL^I^ns35bp became undetectable in 3 patients who attained complete molecular response (CMR), whereas in remaining all 34 patients, BCR-ABL^I^ns35bp was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated MR in 5 patients whose BCR-ABL^I^ns35bp was persisted, although BCR-ABL^I^ns35bp does not inevitably mark TKI-resistance. Therefore, quantification of BCR-ABL^I^ns35bp is useful for evaluating "functional" MRD and determining effectiveness of TKIs with accuracy.

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A Long-Standing Primary Vaginal Paraganglioma—Coexisting with Esophageal Carcinoma

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Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes

Abstract

Background

Children with inherited bone marrow failure syndromes (IBMFSs) may be symptomatic in utero, resulting in maternal and fetal problems during the pregnancy. Subsequent pregnancies by their mothers should be considered "high risk".

Methods

We retrospectively analyzed outcomes of 575 pregnancies in 165 unaffected mothers of offspring with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), and Shwachman–Diamond syndrome (SDS) for events noted during pregnancy, labor, and delivery. We compared outcomes of pregnancies with affected and unaffected offspring within each group of mothers and with the general population.

Results

The rates of miscarriage (12–20%), elective abortion (5–10%), and live birth (68–78%) among mothers of all IBMFS groups were similar and comparable with general population rates but recurrent miscarriages (≥2) were significantly more common in mothers of offspring with DBA and SDS. Offspring with FA were more frequently born small for gestational age (SGA) than unaffected babies (39% vs. 4%) and had fetal malformations (46%) with 18% having three or more, often necessitating early delivery and surgery; offspring with DC had higher rates of SGA (39% vs. 8%) and fetal distress (26% vs. 3%); and offspring with DBA had fetal hypoxia (19% vs. 1%) leading to preterm and emergency cesarean deliveries (26% vs. 6%). Offspring with early-onset severe phenotypes had the most prenatal and peripartum adverse events.

Conclusion

We identified the high-risk nature of pregnancies in mothers with IBMFS-affected fetuses, suggesting the need for prepregnancy counseling and monitoring of subsequent pregnancies by high-risk fetal–maternal specialists.

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Prevalence of low bone mass among adolescents with nontransfusion-dependent hemoglobin E/β-thalassemia and its relationship with anemia severity

Abstract

Background

Low bone mass is common among adolescents with transfusion-dependent β-thalassemia despite adequate transfusion and iron chelation. However, there are few reports regarding bone mineral density (BMD) among adolescents with nontransfusion-dependent thalassemia (NTDT). Indeed, only BMD data in patients with nontransfusion-dependent (NTD) β-thalassemia intermedia have been reported. No previous study has investigated BMD among adolescents with NTD hemoglobin (Hb) E/β-thalassemia.

Objective

To determine the prevalence of low bone mass among adolescents with NTD Hb E/β-thalassemia and factors relating to low bone mass.

Methods

We investigated BMD of lumbar spine (L2–L4; BMDLS) and total body (BMDTB), as measured by dual-energy X-ray absorptiometry, in 22 adolescents (aged 13.2–20 years) with NTD Hb E/β-thalassemia.

Results

Low bone mass was found to be 18.2% and 22.7% at the lumbar spine (BMDLS Z-score adjusted for bone age and height age) and 13.6% and 9.1% at the total body (BMDTB Z-score adjusted for bone age and height age). Patients with mean Hb level <8 g/dl were more likely to have low bone mass (BMDLS and BMDTB Z-scores adjusted for bone age) compared to those with Hb level ≥ 8 g/dl. Mean Hb level correlated with BMDLS and BMDTB Z-scores adjusted for bone age.

Conclusion

We demonstrated that a low Hb level was associated with low bone mass among adolescents with NTD Hb E/β-thalassemia. A significant proportion of low bone mass among these patients highlights the importance of appropriate management, including red cell transfusion, vitamin D and calcium supplementation for improved long-term bone health.

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An analysis of inpatient pediatric sickle cell disease: Incidence, costs, and outcomes

Abstract

Objective

To identify characteristics of pediatric sickle cell disease (SCD) hospitalizations and to examine admission demographics and medical expenditures.

Methods

Admissions with SCD were identified from the 2009 and 2012 releases of the Healthcare and Cost Utilization Project's Kids Inpatient Database. Disease-specific secondary diagnoses including acute chest syndrome (ACS), vaso-occlusive pain crisis (VOC), splenic sequestration, and stroke/transient ischemic attack were analyzed for patient and hospital demographics. Analytical endpoints included total healthcare expenditures and mortality.

Results

We reviewed 75,234 inpatient hospitalizations with a diagnosis of SCD. Over $900,000,000 was spent annually in associated healthcare expenditure. The median length of hospitalization stay (LOS) for all admissions was 3 days (interquartile range [IQR] 2–5 days). VOC was the most frequent secondary diagnosis, recording 48,698 total hospitalizations and a median LOS of 3 days (IQR 2–6 days). Of the 8,490 hospitalizations with ACS, the infant population had a significantly higher mortality rate compared to other age groups (2% vs. 0.3%, P < 0.001). Cerebral vascular accidents incurred the second highest median hospitalization cost ($18,956), behind ACS ($22,631). A high proportion of Caucasian patients died during hospitalization for VOC (0.4% vs. 0.1%, P = 0.014) and ACS (4% vs. 0.2%, P < 0.001) when compared to non-Caucasians.

Conclusion

Inpatient hospitalizations for secondary manifestations of pediatric SCD were associated with significant healthcare expenditures. Patients with an increased statistical risk for death during hospitalization included Caucasians with SCD complications of ACS and VOC, and patients <1-year-old with ACS. Further research is needed to substantiate the associated clinical significance of these findings.

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Cancers, Vol. 9, Pages 107: ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice

Cancers, Vol. 9, Pages 107: ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice

Cancers doi: 10.3390/cancers9080107

Authors: Paul Hofman

Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to treatment, in most cases relapse or progression occurs due to resistance mechanisms mainly caused by mutations in the tyrosine kinase domain of ALK. The detection of an ALK rearrangement is pivotal and can be done using different methods, which have variable sensitivity and specificity depending, in particular, on the quality and quantity of the patient's sample. This review will first highlight briefly some information regarding the pathobiology of an ALK rearrangement and the epidemiology of patients harboring this genomic alteration. The different methods used to detect an ALK rearrangement as well as their advantages and disadvantages will then be examined and algorithms proposed for detection in daily routine practice.

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Cancers, Vol. 9, Pages 106: ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients

Cancers, Vol. 9, Pages 106: ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients

Cancers doi: 10.3390/cancers9080106

Authors: Paul Hofman

Patients with advanced stage non-small cell lung carcinoma (NSCLC) harboring an anaplastic lymphoma kinase ALK gene rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. However, while treatment is initially effective in most cases, relapse or progression occurs due to different resistance mechanisms including mutations in the tyrosine kinase domain of echinoderm microtubule-associated protein-like 4 (EML44)-ALK. The liquid biopsy concept has recently radically changed the clinical care of NSCLC patients, in particular for those harboring an epidermal growth factor receptor (EGFR) gene mutation. Therefore, liquid biopsy is an alternative or complementary method to tissue biopsy for the detection of some resistance mutations in EGFR arising during tyrosine kinase inhibitor treatment. Moreover, in some frail patients, or if the tumor lesion is not accessible to a tissue biopsy, a liquid biopsy can also detect some activating mutations in EGFR on initial assessment. Recent studies have evaluated the possibility of also using a liquid biopsy approach to detect an ALK rearrangement and/or the emergence during inhibitor treatment of some resistance mutations in ALK. These assessments can be performed by studying circulating tumor cells by fluorescent in situ hybridization and by immunocytochemistry and/or after the isolation of RNA from plasma samples, free or associated with platelets. Thus, the liquid biopsy may be a complementary or sometimes alternative method for the assessment of the ALK status in certain NSCLC patients, as well as a non-invasive approach for early detection of ALK mutations. In this review, we highlight the current data concerning the role of the liquid biopsy for the ALK status assessment for NSCLC patients, and we compare the different approaches for this evaluation from blood samples.

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Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses

Abstract

Background

The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study.

Objective

The objective of this study was to quantitatively characterize the benefit–risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule.

Methods

We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule.

Results

Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity.

Conclusions

These analyses support a favorable benefit–risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program.

Trial Registration Numbers

ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537

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Radiotherapy induces cell cycle arrest and cell apoptosis in nasopharyngeal carcinoma via the ATM and Smad pathways.

Radiotherapy induces cell cycle arrest and cell apoptosis in nasopharyngeal carcinoma via the ATM and Smad pathways.

Cancer Biol Ther. 2017 Aug 11;:0

Authors: Li MY, Liu JQ, Chen DP, Li ZY, Qi B, He L, Yu Y, Yin WJ, Wang MY, Lin L

Abstract
Nasopharyngeal carcinoma (NPC) is a common malignant neoplasm of the head and neck which is harmful to human's health. Radiotherapy is commonly used in the treatment of NPC and it induces immediate cell cycle arrest and cell apoptosis. However, the mechanism remains unknown. Evidences suggested the activation of Ataxia telangiectasia mutated (ATM) pathway and Smad pathway are two of the important crucial mediators in the function of radiotherapy. In this study, we carried out in vitro assays with human nasopharyngeal carcinoma CNE-2 cells and in vivo assays with nude mice to investigate the role of the ATM and Smad pathways in the treatment of nasopharyngeal carcinoma with radiotherapy. The results suggested that radiation induced activation of ATM pathway by inducing expression of p-ATM, p-CHK1, p-CHK2, p15 and inhibiting expression of p-Smad3. In addition, Caspase3 expression was increased while CDC25A was decreased, leading to cell cycle arrest and cell apoptosis. On the other hand, activation of Smad3 can inhibited the ATM pathway and attenuated the efficacy of radiation. In summary, we suggest that both ATM and Smad pathways contribute to the cell cycle arrest and cell apoptosis during nasopharyngeal carcinoma cells treated with radiation.

PMID: 28799829 [PubMed - as supplied by publisher]

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Geometric image biomarker changes of the parotid gland are associated with late xerostomia

Publication date: Available online 12 August 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Lisanne V. van Dijk, Charlotte L. Brouwer, Hans Paul van der Laan, Johannes G.M. Burgerhof, Johannes A. Langendijk, Roel J.H.M. Steenbakkers, Nanna M. Sijtsema
Backgroundand purpose: The aim of this study was to identify a surrogate marker for late xerostomia 12 months after radiotherapy (Xer12m) based on information obtained shortly after treatment.Materials and methodsDifferences in parotid gland (PG) were quantified in image biomarkers (ΔIBMs) before and 6 weeks after radiotherapy of 107 patients. By performing step-wise forward selection, ΔIBMs that were associated with Xer12m were selected. Subsequently, other variables, such as PG dose and acute xerostomia scores were added to improve the prediction performance. All models were internally validated.ResultsPrediction of Xer12m based on PG surface reduction (ΔPG-surface) was good (AUC=0.82). PG dose was related to ΔPG-surface (p<0.001, R²=0.27). The addition of acute xerostomia scores to the ΔPG-surface improved the prediction of Xer12m significantly and vice versa. The final model including ΔPG-surface and acute xerostomia had outstanding performance in predicting Xer12m early after radiotherapy (AUC=0.90).ConclusionPG surface reduction was associated with late xerostomia. The early post-treatment model with ΔPG-surface and acute xerostomia scores can be considered as surrogate marker for late xerostomia.

Teaser

The aim of this study was to identify a surrogate marker for late xerostomia 12 months after radiotherapy based on information obtained shortly after treatment. Differences in parotid gland (PG) were quantified in image biomarkers (ΔIBMs) before and 6 weeks after radiotherapy of 107 patients. The early post-treatment model with parotid gland surface reduction and acute xerostomia scores is a good candidate surrogate marker for late xerostomia.

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Current status and future direction in the management of malignant melanoma.

The incidence of malignant melanoma is increasing rapidly on a global scale. Although some types of melanoma, for example primary cutaneous melanoma, can be managed by surgery, metastatic melanoma cannot and it has a high mortality rate. Both oncogene and immune-targeted strategies have shown marked efficacy in some patients, but their effect on overall survival is still variable. Therefore, newer therapeutic approaches are needed. Fortunately, new advances in molecular medicine have led to an understanding of an individual patient's cancer at the genomic level. This information is now being used in all stages of cancer treatment including diagnosis, treatment selection, and treatment monitoring. This new strategy of personalized medicine may lead to marked shifts in immunotherapeutic treatment approaches such as individualized cancer vaccines and adoptive transfer of genetically modified T cells. This review provides an overview of recent approaches in cancer research and expected impact on the future of treatment for metastatic melanoma. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The role of depression and personality traits in patients with melanoma: a South-European study.

We explored the potential association of depression history and personality, evaluated through a robust questionnaire tool, namely the Eysenck Personality Scale, with disease risk and progression among Greek patients. A total of 106 melanoma patients and their 1 : 1 sex-matched controls were interviewed on the basis of a questionnaire comprising phenotypic, sociodemographic, lifestyle and medical history variables, as well as information on history of lifetime major depression. The Eysenck Personality Questionnaire, measuring the four personality dimensions (extraversion, neuroticism, psychoticism, lie), was thereafter completed. Adjusted odds ratios (ORs) for melanoma risk were derived through multiple logistic regression analyses, whereas potential predictors of survival were explored using Cox proportional hazards models. Sun sensitivity score [OR: 1.55, 95% confidence interval (CI): 1.16-2.06] and major depression history (OR: 5.72, 95% CI: 1.38-23.73) were significantly associated with melanoma, whereas inverse associations of extraversion (OR: 0.90, 95% CI: 0.83-0.97) and psychoticism score (OR: 0.88, 95% CI: 0.78-1.00) were noted. These associations were more pronounced and remained solely among female patients; notably, decreased extraversion (OR: 0.86, 95% CI: 0.76-0.98) and psychoticism score (OR: 0.63, 95% CI: 0.43-0.91), as well as increased depression history (OR: 10.69, 95% CI: 1.43-80.03) were evident. Cox-derived hazard ratios showed nonsignificant associations of depression history and personality with disease outcome. Our data support the hypotheses that depression history and personality are associated with melanoma risk. No effect on survival after cancer diagnosis was observed. If confirmed in future studies, these associations may contribute toward better understanding the etiology of melanoma, enhancing health-related quality of life. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Economic burden of advanced melanoma in France, Germany and the UK: a retrospective observational study (Melanoma Burden-of-Illness Study).

The aim of this study was to estimate the cost-of-illness associated with completely resected stage IIIB/IIIC melanoma with macroscopic lymph node involvement, overall and by disease phase, in France, Germany and the UK. This retrospective observational study included patients aged older than or equal to 18 years first diagnosed with stage IIIB/IIIC cutaneous melanoma between 1 January 2009 and 31 December 2011. Data were obtained from medical records and a patient survey. Direct costs, indirect costs and patient out-of-pocket expenses were estimated in euros ([Euro sign]) (and British pounds, [pounds]) by collecting resource use and multiplying by country-specific unit costs. National annual costs were estimated using national disease prevalence from the European cancer registry and other published data. Forty-nine centres provided data on 558 patients (58.2% aged

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Response to targeted therapy in two patients with metastatic melanoma carrying rare BRAF exon 15 mutations: A598_T599insV and V600_K601delinsE.

Concurrent BRAF-MEK inhibition improves clinical outcomes in patients with advanced BRAF V600E/K-mutant melanoma. There is currently less evidence for the efficacy of this treatment in patients with rare BRAF non-V600E/K genotypes. We report on two patients with rare BRAF exon 15 mutations - BRAF A598_T599insV and V600_K601delinsE - obtaining clinical benefit and a radiological response to inhibitors directed against the mitogen-activated protein kinase pathway. This highlights the importance of using tests that detect both V600E/K and non-V600E/K BRAF mutations to keep open the possibility of treatment with targeted therapy in patients with uncommon, yet potentially actionable, BRAF exon 15 mutations. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Risk factors for development of melanoma brain metastasis and disease progression: a single-center retrospective analysis.

Melanoma metastasis to the brain is associated with a poor prognosis. We sought to determine patient demographics and primary tumor factors associated with the development of brain metastasis (BM) and survival. We also investigated whether the BM detection setting (routine screening vs. symptomatic presentation) affected clinical outcomes. A database of melanoma patients seen from 1999 to 2015 at our institution was reviewed to identify patients who developed BM. Patients with BM were matched by initial stage with patients who did not develop BM as a control group. Patient demographics, primary tumor characteristics, and clinical outcomes were analyzed. A total of 123 patients with BM were matched by initial presenting stage to 237 patients without BM. The characteristics of the primary melanoma tumor associated with BM development included location on the scalp (P=0.030), nodular histologic type (P=0.020), and Breslow depth more than 4 mm (P=0.048), whereas location on the leg was associated with decreased BM risk (P=0.006). In patients with BM, time to first recurrence for melanomas of the scalp was significantly shorter (10.8 vs. 24.8 months, P=0.007) than nonscalp head and neck tumors. Patient stage, tumor depth, nodular type, and ulceration were also associated with worse clinical outcomes. There were no differences in the clinical outcomes between patients whose BM were detected upon routine screening versus those detected upon symptomatic presentation. In summary, factors predictive of development of BM included primary scalp location, nodular type, and depth. In BM patients, scalp location, stage, tumor depth, nodular type, and ulceration, but not detection setting, were associated with worse clinical outcomes. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Malignant melanoma incidence trends in a Mediterranean population following socioeconomic transition and war: results of age-period-cohort analysis in Croatia, 1989-2013.

The aim of this study was to analyse trends of malignant melanoma incidence in Croatia for men and women of different age groups by birth cohorts and time periods, and to interpret them in the context of national socioeconomic changes over time and the possible implications for future prevention in South-Eastern European postcommunist countries with high mortality rates. We used the Croatian National Cancer Registry data to analyse incidence trends of malignant melanoma of the skin (ICD-9 code 172 and ICD-10 code C43) in men and women aged 25-79 years by age-period-cohort modelling. Over the 25-year period, the incidence was increasing by 5.0% annually in men and 4.6% in women. The age-period model provided the best fit for data in both sexes, with steeply increasing incidence rates, followed by a stabilization after the 2000s. On the cohort scale, incidence rates increased in successive generations of men, whereas in women, the risk of malignant melanoma attenuated in recent cohorts. Even if some progress has been achieved in recent years, the increasing melanoma incidence without concomitant declines in mortality would indicate a need to rekindle prevention efforts in the country taking the specific socioeconomic context into account. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The Effect of Ondansetron on Acute Opioid Tolerance in Patients Receiving Intrathecal Opioids Prior to Cesarean Delivery.

Background: Multiple animal studies suggest that ondansetron ameliorates opioid-induced hyperalgesia and tolerance. In this study, we aimed to determine if the administration of ondansetron prior to spinal anesthesia would have an effect on intrathecal opioid-induced acute opioid tolerance, postoperative pain, and analgesic requirements in patients undergoing cesarean delivery with spinal anesthesia. Methods: Eighty-six patients undergoing elective cesarean delivery were recruited and randomly allocated to receive either 8 mg intravenous ondansetron (n = 44) or placebo (n = 42) in a prospective, double-blind design. All patients received spinal anesthesia consisting of 15 mg bupivacaine, 20 [mu]g of fentanyl, and 100 [mu]g of preservative-free morphine. We used linear mixed-effects models to assess the difference in pain and opioid consumption in the first 24 hours after surgery between the 2 groups. Results: No differences between the 2 groups were found in age, body mass index, American Society of Anesthesiologists physical status scores, duration of surgery, or sensory and motor block characteristics. There was no difference between the 2 groups in postoperative pain scores (P = 0.95) or opioid consumption (P = 0.68). Conclusions: In patients undergoing cesarean delivery under spinal anesthesia with intrathecal opioids, the administration of ondansetron prior to spinal anesthesia did not significantly affect postoperative pain scores or opioid consumption. Thus, the administration of ondansetron did not have an effect on acute opioid tolerance in our study. Copyright (C) 2017 by American Society of Regional Anesthesia and Pain Medicine.

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Psoas Versus Femoral Blocks: A Registry Analysis of Risks and Benefits.

Background and Objectives: Psoas blocks are an alternative to femoral nerve blocks and have the potential advantage of blocking the entire lumbar plexus. However, the psoas muscle is located deeply, making psoas blocks more difficult than femoral blocks. In contrast, while femoral blocks are generally easy to perform, the inguinal region is prone to infection. We thus tested the hypothesis that psoas blocks are associated with more insertion-related complications than femoral blocks but have fewer catheter-related infections. Methods: We extracted 22,434 surgical cases from the German Network for Regional Anesthesia registry (2007-2014) and grouped cases as psoas (n = 7593) and femoral (n = 14,841) blocks. Insertion-related complications (including single-shot blocks and catheter) and infectious complications (including only catheter) in each group were compared with [chi]2 tests. The groups were compared with multivariable logistic models, adjusted for potential confounding factors. Results: After adjustment for potential confounding factors, psoas blocks were associated with more complications than femoral blocks including vascular puncture 6.3% versus 1.1%, with an adjusted odds ratio (aOR) of 3.6 (95% confidence interval [CI], 2.9-4.6; P

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Cancer Clonal Theory, Immune Escape, and Their Evolving Roles in Cancer Multi-Agent Therapeutics

Abstract

Purpose of Review

The knowledge base of malignant cell growth and resulting targets is rapidly increasing every day. Clonal theory is essential to understand the changes required for a cell to become malignant. These changes are then clues to therapeutic intervention strategies. Immune system optimization is a critical piece to find, recognize, and eliminate all cancer cells from the host. Only by administering (1) multiple therapies that counteract the cancer cell's mutational and externally induced survival traits and (2) by augmenting the immune system to combat immune suppression processes and by enhancing specific tumor trait recognition can cancer begin to be treated with a truly targeted focus.

Recent findings

Since the sequencing of the human genome during the 1990s, steady progress in understanding genetic alterations and gene product functions are being unraveled. In cancer, this is proceeding very fast and demonstrates that genetic mutations occur very rapidly to allow for selection of survival traits within various cancer clones. Hundreds of mutations have been identified in single individual cancers, but spread across many clones in the patient's body. Precision oncology will require accurate measurement of these cancer survival-benefiting mutations to develop strategies for effective therapy. Inhibiting these cellular mechanisms is a first step, but these malignant cells need to be eliminated by the host's mechanisms, which we are learning to direct more specifically.

Summary

Cancer is one of the most complicated cellular aberrations humans have encountered. Rapidly developing significant survival traits require prompt, repeated, and total body measurements of these attributes to effectively develop multi-agent treatment of the individual's malignancy. Focused drug development to inhibit these beneficial mutations is critical to slowing cancer cell growth and, perhaps, triggering apoptosis. In many cases, activation and targeting of the immune system to kill the remaining malignant cells is essential to a cure.

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