Surgical Intervention in Gastric Carcinoid is Associated With Improved Survival in Local and Regional Disease.

Introduction: Gastric carcinoid is a rare entity with complex management options. This study aims to determine if surgical intervention in patients with local, regional, and metastatic gastric carcinoid is associated with prolonged survival. Materials and Methods: The California Cancer Registry merged with the California Office of Statewide Health Planning and Development was queried for patients with a diagnosis of gastric carcinoid (2000 to 2011). Clinicopathologic characteristics, management, and outcomes were evaluated. Results: There were 1012 patients with a diagnosis of gastric carcinoid identified. The median age was 63 (range, 18 to 99) and the majority of patients were women (615, 60.7%). Most patients had localized disease (644, 64%), whereas 9.4% (95) had regional and 13.4% (133) had distant metastases at diagnosis. The majority of patients underwent gastric surgery (56.7%, n=574 vs. 43.2%, n=438). Prolonged survival was associated with gastric surgery in patients with both local (median survival not reached; P

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Efficacy of Modified Dose-dense Paclitaxel in Recurrent Cervical Cancer.

Objective: To examine survival outcomes of women with recurrent cervical cancer who received salvage chemotherapy with modified dose-dense paclitaxel (MDDP) monotherapy (paclitaxel 80 mg/m2, administered on day 1, 8, and 15 without day 22). Materials and Methods: A retrospective study was conducted to evaluate cause-specific survival after the first recurrence (SAR) of women with recurrent cervical cancer diagnosed between 2006 and 2014. Pooled analyses were performed to examine SAR in women who received MDDP monotherapy (n=17) for any treatment line, compared with those who received salvage chemotherapy with paclitaxel-doublet (n=18) and nonpaclitaxel regimens (n=52). Results: In the whole cohort, median SAR was 13.7 months including 63 (72.4%) events. MDDP monotherapy regimen was most commonly used in the second-line setting (35.3%) followed by the third/fourth lines (both, 23.5%). Among the women who received MDDP regimen, there were 6 (35.3%) women who received >=6 cycles; there was 1 (5.9%) women who discontinued the regimen due to adverse effects (grade 3 transaminitis); regimen postponement was seen in 2 (1.4%) of 140 total cycles; and the response rate after the sixth cycle of this regimen was 29.4% (1 complete and 4 partial responses). On univariate analysis, MDDP usage had the highest 2-year SAR rate (MDDP 54.1%, paclitaxel-doublet 43.6%, and nonpaclitaxel regimens 28.1%; Ptrend=0.044). On multivariate analysis, MDDP monotherapy remained an independent prognostic factor for improved SAR compared with the nonpaclitaxel regimen (adjusted-hazard ratio, 0.50; 95% confidence interval, 0.26-0.95; P=0.036). Conclusion: Our results suggested that MDDP monotherapy is a tolerable and relatively effective regimen for recurrent cervical cancer. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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A Phase I Clinical Trial of the Phosphatidylserine-targeting Antibody Bavituximab in Combination With Radiation Therapy and Capecitabine in the Preoperative Treatment of Rectal Adenocarcinoma.

Objectives: There is interest in improving the tumoricidal effects of preoperative radiotherapy for rectal carcinoma by studying new radiosensitizers. The safety and toxicity profile of these combination regimens needs rigorous clinical evaluation. The primary objective of this study was to evaluate the toxicity of combining bavituximab, an antibody that targets exposed phosphatidylserine, with capecitabine and radiation therapy. Materials and Methods: Patients with stage II or III rectal adenocarcinoma were enrolled on a phase I study combining radiation therapy, capecitabine, and bavituximab. A standard 3+3 trial designed was used. Results: In general, bavituximab was safe and well tolerated in combination with radiation therapy and capecitabine in the treatment of rectal adenocarcinoma. One patient at the highest dose level experienced a grade III infusion reaction related to the bavituximab. One tumor demonstrated a complete pathologic response to the combination treatment. Conclusions: Bavituximab is safe in combination with capecitabine and radiation therapy at the doses selected for the study. Further clinical investigation would be necessary to better define the efficacy of this combination. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Advanced Age is Not a Contraindication for Treatment With Curative Intent in Esophageal Cancer.

Objectives: The objective of this study is to compare long-term outcomes between younger and older (70 y and above) esophageal cancer patients treated with curative intent. Materials and Methods: Overall survival (OS), disease-free survival (DFS), and locoregional recurrence-free interval were compared between older (70 y and above) and younger (below 70 y) esophageal cancer patients treated between 1998 and 2013. Treatment consisted of neoadjuvant chemoradiotherapy with surgery or definitive chemoradiotherapy: 36 to 50.4 Gy in 18 to 28 fractions combined with 5-fluorouracil/cisplatin or carboplatin/paclitaxel. Results: The study comprised 253 patients, of whom 76 were 70 years and older. Median age was 64 years (range, 41 to 83). Most patients had stage II-IIIA disease (83%). Planned treatment was neoadjuvant chemoradiotherapy with surgery for 169 patients (41 patients aged 70 y and older) and definitive chemoradiotherapy for 84 patients (31 patients aged 70 y and older). The compliance to radiotherapy was 92%, with no difference between older and younger patients. In 33 patients (13 patients aged 70 y and older) planned surgery was not performed. Median follow-up was 4.9 years. Three-year OS was 42%. The multivariable analysis showed no statistical difference in OS or in DFS comparing older and younger patients: OS (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.61-1.28), DFS (HR, 0.87; 95% CI, 0.60-1.25). Elderly showed a longer locoregional recurrence-free interval; HR, 0.53 (95% CI, 0.30-0.92; P=0.02) and a higher pathologic complete response rate (50% vs. 25%; P=0.02). Conclusions: Long-term outcomes of older esophageal cancer patients (70 y and above) selected for treatment with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy were comparable with the outcomes of their younger counterparts. Advanced age alone should not be a contraindication for potentially curative chemoradiotherapy-based treatment in esophageal cancer patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The phytological future of prostate cancer staging: prostate-specific membrane antigen positron emission tomography and the dandelion theory

Future Oncology, Ahead of Print.


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Clinical significance of farnesoid X receptor expression in thyroid neoplasia

Future Oncology, Ahead of Print.


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Metabolomics analysis reveals distinct profiles of nonmuscle-invasive and muscle-invasive bladder cancer

Abstract

Urothelial carcinoma is the most common form of bladder cancer, but pathway changes that occur with stage-wise progression have not been well defined. We used a metabolomics approach to identify potential metabolic pathways uniquely altered in normal urothelium, nonmuscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC). We performed global metabolomic profiling using GC-mass spectrometry (MS) and LC-MS platforms to identify metabolite signatures between normal urothelium and high-grade urothelial carcinoma of different stages. Pathways globally dysregulated in cancer relative to normal urothelium included glucose, tricarboxylic acid (TCA) cycle, lipid, amino acid, and nucleotide pathways. Urothelial carcinoma showed elevated glucose utilization for glycolysis and increased sorbitol pathway intermediates, consistent with Warburg effect. Anaplerosis to sustain energy production suggested by increased late TCA cycle intermediates, amino acids, and dipeptides occurs in bladder cancer. Urothelial carcinoma also shows altered membrane lipid membrane metabolism and differential derivation of nucleic acid components pyrimidine and purine. In stage comparison, MIBC appears to preferentially enhance cyclooxygenase (COX) and lipoxygenase (LOX) signaling, increase heme catabolism, and alter nicotinamide adenine dinucleotide (NAD+) synthesis with a possible influence from associated inflammatory cells. We identify numerous metabolomic alterations in NMIBC and MIBC that likely reflect underlying pathway changes. Differential pathway activity may have value in designing stage-specific novel therapeutics in urothelial carcinoma.

Using a highly sensitive metabolomics approach, we identified multiple pathway changes between normal urothelium and high-grade urothelial carcinoma and between high-grade carcinomas of different stages. Several of these differential metabolite profiles suggest the potential for unique targeted therapy in NMIBC and MIBC populations.

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Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent

Abstract

The SCLC combination screen examined a 9-point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin-targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo-like kinase-1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ-27291199 produced enhanced killing in 80% of the SCLC lines. Chk-1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK-3β inhibitor LY-2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK-8628 increased the SCLC cell killing by etoposide/carboplatin in 20–25% of the SCLC lines. Only 10–15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib.

Sixty-three human small cell lung cancer cell lines were screened to search for agents which may act synergistically with etoposide/carboplatin. Most third agents were additive or antagonistic with etoposide/carboplatin. Third agents which were synergistic are highlighted.

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Identification of sentinel lymph nodes by contrast-enhanced ultrasonography with Sonazoid in patients with breast cancer: a feasibility study in three hospitals

Abstract

The aim of this prospective study was to evaluate the feasibility of periareolar injection of the contrast agent Sonazoid (SNZ) followed by ultrasonography (US) for the identification of sentinel lymph node (SLN) in breast cancer patients with clinically negative node. Patients (n = 100) with T1-2N0M0 breast cancer received a periareolar injection of SNZ followed by US to identify contrast-enhanced SLN. Each contrast-enhanced SLN underwent fine needle aspiration cytology (FNAC) followed by SLN biopsy with a conventional method using blue dye and/or radiocolloid (B/R). In almost all cases, contrast-enhanced lymphatic vessels were clearly visualized by US soon after the periareolar injection of SNZ and the SLNs were easily identified with an identification rate of 98% (98/100) for SNZ and 100% (100/100) for B/R. The number of SLNs identified by SNZ (SNZ-SLN) (mean per patient, 1.52) was significantly lower than that identified by B/R (B/R-SLN) (2.19) (P < 0.0001). Twenty-five patients with positive SLNs had at least one positive SNZ-SLN. On a node-by-node basis, sensitivity, specificity, and accuracy of FNAC for SNZ-SLNs (n = 149) were 33.3%, 99.2%, and 85.9%, respectively. Identification of SLN by periareolar injection of SNZ is a technically simple method with an identification rate as high as 98%. SNZ-SLN thus seems to be a good target for FNAC, but sensitivity of FNAC for SNZ-SLNs needs to be improved.

Patients (n = 100) received periareolar injection of Sonazoid followed by ultrasonography of the axilla for identification of contrast-enhanced sentinel lymph node (SLN). This method is technically simple with a high success rate (98%) and comparable to the conventional method using blue dye and/or radiocolloid.

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Patterns of failure in limited-stage small cell lung cancer: Implications of TNM stage for prophylactic cranial irradiation

The relationship between tumor-node-metastasis (TNM) stage and patterns of failure in limited-stage small cell lung cancer (LS-SCLC) remains unclear. We hypothesized that TNM stage predicts brain metastasis risk, and could inform the use of prophylactic cranial irradiation.

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Early assessment of dosimetric and biological differences of total marrow irradiation versus total body irradiation in rodents

To develop a murine total marrow irradiation (TMI) model in comparison with the total body irradiation (TBI) model.

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Benefit from the inclusion of radiation therapy in the treatment of patients with stage III classical Hodgkin lymphoma: A propensity matched analysis of the Surveillance, Epidemiology, and End Results database

While stage III and IV classical Hodgkin lymphoma (HL) patients are often combined and defined as "advanced stage," there are significant differences in disease distribution and burden between the two stages. This may obscure advantages of radiotherapy (RT) in a combined modality therapy strategy in stage III disease due to the relative lack of benefit in stage IV patients.

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Overall survival advantage of chemotherapy and radiotherapy in the perioperative management of large extremity and trunk soft tissue sarcoma; a large database analysis

Intergroup 9514 reported promising outcomes with neoadjuvant chemoradiotherapy for large extremity/trunk soft tissue sarcoma (ESTS). One decade later, optimum integration of chemotherapy and radiotherapy into the perioperative management of ESTS remains to be defined.

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Relationship between mammographic calcifications and the clinicopathologic characteristics of breast cancer in Western China: a retrospective multi-center study of 7317 female patients

Abstract

Background and purpose

Limited information is available regarding the correlations between mammographic calcifications and the epidemiological features of patients with breast cancer living different lifestyles in Western China. Thus, this study aimed to investigate the relationship between mammographic calcifications and the epidemiological characteristics of female patients with breast cancer in Western China.

Methods

This was a hospital-based, retrospective, multi-center epidemiological study of patients with breast cancer. Using the Western China Clinical Cooperation Group (WCCCG) database, we obtained the records of 7317 patients (with mammographic data) diagnosed with breast cancer between March 2011 and June 2016. These patients were divided into Groups I (mass alone) and II (mass combined with calcification), and their clinical and pathological data were compared.

Results

A total of 4211 patients were enrolled in Group I, and 3106 patients were enrolled in Group II. The tumors in Group II were more likely to be larger (P < 0.0001), higher grade (P = 0.0029), estrogen receptor (ER)+/progesterone receptor (PR)− (P = 0.0319), and human epidermal growth factor receptor 2 (HER-2)-positive (P < 0.0001), and to have axillary lymph node metastasis (P = 0.0033) than those in Group I. Regarding treatment, patients in Group II were more likely to have undergone chemotherapy (P = 0.0108) and anti-HER2 therapy (P = 0.0102), whereas patients in Group I were more likely to have undergone endocrine therapy (P < 0.0001).

Conclusions

In conclusion, mammographic calcifications in tumors were associated with distinct clinicopathologic characteristics and aggressive treatments.

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Outcome of Azacitidine Therapy in Acute Myeloid Leukemia is not Improved by Concurrent Vorinostat Therapy but is Predicted by a Diagnostic Molecular Signature

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML) but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA but this has not been prospectively studied in AML. Experimental Design: We compared outcomes in 259 adults with AML (n=217) and MDS (n=42) randomized to receive either AZA monotherapy (75 mg/m²x seven days every 28 days) or AZA combined with VOR 300 mg bd on days 3-9 po. Next generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate (P=0.84) or overall survival (OS) (P=0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P=0.0001), IDH1 (P=0.004) and TP53 (P=0.003) was associated with reduced OS. Lymphoid multi-potential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusion: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell cycle arrest as a mechanism by which AZA exerts its clinical activity.

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Phase 1 dose-escalation study of the anti-CD70 antibody ARGX-110 in Advanced Malignancies

Purpose: The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies. <br /><br />Experimental Design: <p>Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N=26). ARGX-110 was administered intravenously every three weeks until progression or intolerable toxicity. Dose limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.</p> <br /><br />Results: <p>Dose limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRRs). Of the 20 SAEs reported, 5 events, all IRRs, were considered related to ARGX-110.</p> <p>ARGX-110 demonstrates dose proportionality over the dose range 1-10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10-13 days.</p> <p>The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related anti-tumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematological malignancies.</p> <br /><br />Conclusions:This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics and preliminary anti-tumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies.

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Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-Mediated Resistance to Type I MET Inhibitors in Nonclinical Models

Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non-small cell lung cancer (NSCLC) driver mutations.  We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del-positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET Inhibitors.<br /><br />Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.<br /><br />Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA. <br /><br />Conclusions: Together, these data demonstrate glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors.

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Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer

Purpose: Resistance to platinum-based chemotherapy or PARP inhibition in germline BRCA1 or BRCA2 mutation carriers may occur through somatic reversion mutations or intragenic deletions that restore BRCA1 or BRCA2 function. We assessed whether BRCA1/2 reversion mutations could be identified in circulating cell-free DNA (cfDNA) of ovarian or breast cancer patients previously treated with platinum and/or PARP inhibitors. <p>Experimental Design: cfDNA from 24 prospectively accrued BRCA1- or BRCA2-germline mutant patients, including 19 platinum-resistant/refractory ovarian cancer and five platinum and/or PARP inhibitor pre-treated metastatic breast cancer patients, was subjected to massively parallel sequencing targeting all exons of 141 genes and all exons and introns of BRCA1 and BRCA2. Functional studies were performed to assess the impact of the putative BRCA1/2 reversion mutations on BRCA1/2 function.</p> <p>Results: Diverse and often polyclonal putative BRCA1 or BRCA2 reversion mutations were identified in cfDNA from four ovarian cancer patients (21%) and from two breast cancer patients (40%). BRCA2 reversion mutations were detected in cfDNA prior to PARP inhibitor treatment in a breast cancer patient who did not respond to treatment, and were enriched in plasma samples after PARP inhibitor therapy. Foci formation and immunoprecipitation assays suggest that a subset of the putative reversion mutations restored BRCA1/2 function.</p> <p>Conclusions: Putative BRCA1/2 reversion mutations can be detected by cfDNA sequencing analysis in ovarian and breast cancer patients. Our findings warrant further investigation of cfDNA sequencing to identify putative BRCA1/2 reversion mutations and to aid the selection of patients for PARP inhibition therapy.

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Overcoming acquired resistance to AZD9291, a third generation EGFR inhibitor, through modulation of MEK/ERK-dependent Bim and Mcl-1 degradation

Purpose: <p>The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO™), an approved third generation EGFR inhibitor, in EGFR-mutant non-small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.</p> <br /><br />Experimental Design: <p>AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytomentry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenogtaft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA.</p> <br /><br />Results: <p>AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo.</p> <br /><br />Conclusions: <p>Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291.

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Tumor Treating Fields: A Fourth Modality in Cancer Treatment

Despite major advances in therapy, cancer continues to be a leading cause of mortality. Additionally, toxicities of traditional therapies pose a significant challenge to tolerability and adherence. TTFields, a noninvasive anticancer treatment modality, utilizes alternating electric fields at specific frequencies and intensities to selectively disrupt mitosis in cancerous cells. TTFields target proteins crucial to the cell cycle, leading to mitotic arrest and apoptosis. TTFields also facilitate an antitumor immune response. Clinical trials of TTFields have proven safe and efficacious in patients with GBM, and are FDA-approved for use in newly-diagnosed and recurrent GBM. Trials in other localized solid tumors are ongoing.

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Association between MPO-463G > A polymorphism and cancer risk: evidence from 60 case-control studies

Abstract

Background

Though a number of studies have been conducted to explore the association between myeloperoxidase (MPO)-463G > A polymorphism and cancer risk, the results remain inconsistent. Therefore, we performed a meta-analysis to derive a more systematic estimation of this relationship.

Method

Relevant studies were searched by PubMed, EMBASE, CNKI, Google Scholar, Ovid, and Cochrane library prior to December 2015. The strength of the association between MPO-463G > A polymorphism and cancer risk was estimated by odds ratios (OR) with 95% confidence interval (95%CI). Cumulative analysis was used to evaluate the stability of results through time.

Results

The current analysis consisted of 16,858 cases and 21,756 controls from 60 studies. Pooled results showed that MPO-463G > A polymorphism were associated with the overall decreased cancer susceptibility in all the genetic models included in this study (additive model: OR = 0.84, 95%CI = 0.76–0.94; allele genetic model: OR = 0.90, 95%CI = 0.840–0.954; recessive genetic model: OR = 0.89, 95%CI = 0.83–0.95). However, in the stratified analysis of cancer type, the significant results were only found in lung cancer (dominant model: OR = 0.93, 95%CI = 0.87–0.99) and digestive system cancer groups (dominant model: OR = 0.67 0.53–0.84; allele frequency model = 0.71, 95%CI = 0.57–0.87), but not in the blood system cancer or breast cancer group. When we further stratified the digestive system cancer group into digestive tract and digestive gland cancer groups, results showed a significant association between allele A of MPO-463G > A and digestive gland cancer in all the genetic models (allele frequency model: OR = 0.63, 95%CI = 0.40–0.99; additive model: OR = 0.41, 95%CI = 0.23–0.73; recessive model: OR = 0.51, 95%CI = 0.29–0.89; dominant model: OR = 0.58, 95%CI = 0.35–0.96), digestive tract cancers in allele frequency model (OR = 0.75, 95%CI = 0.59–0.95), and dominant model (OR = 0.72, 95%CI = 0.56–0.92). When stratified by ethnicity, results demonstrated that the genotype A might be a protect factor for both Caucasians and Asians. In group analysis according to source of controls, significant results were found in population from hospital in all the genetic models. In cumulative analysis, result of allele contrast showed a declining trend and increasingly narrower 95% overall, while the inclination toward non-significant association with lung cancer risk.

Conclusions

This meta-analysis suggested that MPO-463G > A polymorphism was associated with the overall reduced cancer susceptibility significantly. It might be a more reliable predictor of digestive system cancer instead of lung cancer, blood system cancer, and breast cancer. In cumulative analysis, the stable trend indicated that evidence was sufficient to show the association between MPO-463G > A polymorphism and cancer risk.

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Association of calcium sensing receptor polymorphisms at rs1801725 with circulating calcium in breast cancer patients

Abstract

Background

Breast cancer (BC) patients with late-stage and/or rapidly growing tumors are prone to develop high serum calcium levels which have been shown to be associated with larger and aggressive breast tumors in post and premenopausal women respectively. Given the pivotal role of the calcium sensing receptor (CaSR) in calcium homeostasis, we evaluated whether polymorphisms of the CASR gene at rs1801725 and rs1801726 SNPs in exon 7, are associated with circulating calcium levels in African American and Caucasian control subjects and BC cases.

Methods

In this retrospective case-control study, we assessed the mean circulating calcium levels, the distribution of two inactivating CaSR SNPs at rs1801725 and rs1801726 in 199 cases and 384 age-matched controls, and used multivariable regression analysis to determine whether these SNPs are associated with circulating calcium in control subjects and BC cases.

Results

We found that the mean circulating calcium levels in African American subjects were higher than those in Caucasian subjects (p < 0.001). As expected, the mean calcium levels were higher in BC cases compared to control subjects (p < 0.001), but the calcium levels in BC patients were independent of race. We also show that in BC cases and control subjects, the major alleles at rs1801725 (G/T, A986S) and at rs1801726 (C/G, Q1011E) were common among Caucasians and African Americans respectively. Compared to the wild type alleles, polymorphisms at the rs1801725 SNP were associated with higher calcium levels (p = 0.006) while those at rs1801726 were not. Using multivariable linear mixed-effects models and adjusting for age and race, we show that circulating calcium levels in BC cases were associated with tumor grade (p = 0.009), clinical stage (p = 0.003) and more importantly, with inactivating mutations of the CASR at the rs1801725 SNP (p = 0.038).

Conclusions

These data suggest that decreased sensitivity of the CaSR to calcium due to inactivating polymorphisms at rs1801725, may predispose up to 20% of BC cases to high circulating calcium-associated larger and/or aggressive breast tumors.

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Gemcitabine-induced TIMP1 attenuates therapy response and promotes tumor growth and liver metastasis in pancreatic cancer

Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC), but patients often respond poorly to this agent. Molecular markers downstream of gemcitabine treatment in pre-clinical models may provide an insight into resistance mechanisms. Using cytokine arrays, we identified potential secretory biomarkers of gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC. We verified the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP1) in primary pancreatic tumors and metastases using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increased inflammatory cytokines including TIMP1 in the KPC mouse model. TIMP1 was upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. Additionally, TIMP1 played a role in tumor clonogenic survival and vascular density, while TIMP1 inhibition resensitized tumors to gemcitabine and radiotherapy. We observed a linear relationship between TIMP-1 expression, liver metastatic burden, and infiltration by CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs, whereas the presence of tumor cells was required for immune cell infiltration. Overall, our results identify TIMP1 upregulation as a resistance mechanism to gemcitabine and provide a rationale for combining chemo/radiotherapy with TIMP1 inhibitors in PDAC.

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Mitochondrial superoxide increases age-associated susceptibility of human dermal fibroblasts to radiation and chemotherapy

Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR, (~70-80% killing) relative to young fibroblasts (5 months and 1 year; ~10-20% killing) and adult fibroblasts (20 years old; ~10-30% killing). Old fibroblasts also displayed significantly increased (2-4 fold) steady-state levels of O2·-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7 fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2·- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase (SOD) mimetic (GC4419; 0.25 µM), significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2·- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy and can be mitigated by GC4419.

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Clinical Outcomes in pT4 Tongue Carcinoma are Worse Than in pT3 Disease: How Extrinsic Muscle Invasion Should be Considered?

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Clinical Outcomes in pT4 Tongue Carcinoma are Worse than in pT3 Disease: How Extrinsic Muscle Invasion Should be Considered?

Abstract

Background

The identification of extrinsic tongue muscle invasion in oral cavity cancer remains challenging. Notably, the most recent American Joint Committee on Cancer (AJCC 2017, 8th edition) staging manual indicates that extrinsic muscle invasion does not lead to the diagnosis of a T4 tumor. Because this approach carries the risk of tumor downstaging, we compared the clinical outcomes of patients with oral tongue squamous cell carcinoma (SCC) staged as pT3 vs. pT4 according to the AJCC 2010, 7th edition criteria.

Methods

We retrospectively examined the records of consecutive patients with pT3 (n = 135) and pT4 (n = 68) tongue SCC who underwent radical surgery. Of the 68 pT4 tongue SCC, 63 (93%) had extrinsic muscle involvement alone. The 5-year locoregional control (LRC), distant metastasis (DM), and disease-free survival (DFS) rates served as outcome measures.

Results

Compared with pT3 tongue SCC, pT4 patients presented significantly more frequently with pN2 disease, extranodal extension, poor tumor differentiation, tumor depth >15 and >20 mm, margin status ≤4 mm, perineural invasion, vascular invasion, and were more frequently treated with surgery plus concurrent chemoradiotherapy. Less favorable 5-year outcomes were observed in patients with pT4 than pT3 tumors (LRC 50 vs. 75%, p < 0.001; DM 27 vs. 14%, p = 0.013; DFS 43 vs. 69%, respectively, p < 0.001). We identified pT4 disease (vs. pT3) as an independent adverse prognostic factor for LRC and DFS.

Conclusions

We suggest classifying patients with tongue SCC and extrinsic muscle invasion as having pT4 disease.

http://ift.tt/2vripOv

Impact of Bilateral Prophylactic Mastectomy and Immediate Reconstruction on Health-Related Quality of Life in Women at High Risk for Breast Carcinoma: Results of the Mastectomy Reconstruction Outcomes Consortium Study

Abstract

Background

Although bilateral prophylactic mastectomy (BPM) can reduce the risk of breast cancer, the decision to proceed surgically can have significant consequences and requires careful deliberation. To facilitate decision making for women at high risk for breast carcinoma, the risks and benefits of BPM should be well-elucidated. We sought to determine the effects of BPM and immediate reconstruction on health-related quality-of-life outcomes among a multisite cohort of women at high risk for breast carcinoma.

Methods

Patient-reported outcome data were prospectively collected as part of the Mastectomy Reconstruction Outcomes Consortium Study, and data on a subgroup of 204 high-risk women who elected to have BPM and immediate reconstruction were evaluated. Baseline scores were compared with scores at 1 or 2 years after reconstruction.

Results

Satisfaction with breasts and psychosocial well-being were significantly higher at both 1 and 2 years (p < 0.01); however, anxiety was significantly lower at 1 or 2 years (p < 0.01) and physical well-being of the chest and upper body was significantly worse at 1 year (p < 0.01).

Conclusion

Our results highlight the impact of BPM and immediate reconstruction on health-related quality-of-life outcomes in this setting. BPM and reconstruction can result in significant, positive, lasting changes in a woman's satisfaction with her breasts, as well as her psychosocial well-being. Furthermore, presurgery anxiety was significantly reduced by 1 year post-reconstruction and remained reduced at 2 years. With this knowledge, women at high risk for breast carcinoma, and their providers, will be better equipped to make the best individualized treatment decisions.

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Radical Lymph Node Dissection Along the Proximal Splenic Artery During Laparoscopic Gastrectomy for Gastric Cancer Using the Left Lateral Approach

Abstract

Background

Recent technical improvements allow safe laparoscopic lymph node dissection (LND) in gastric cancer.1 ^,2 In suprapancreatic LND, careful LND around the celiac artery (CA) is essential. From a patient's right side, deep LND is performed around the right side of the CA after dissecting around the common hepatic artery (CHA). For LND around the left side of the CA on the same operative axis as the right side, we developed a new procedure for LND along the proximal splenic artery (SA), performed from the patient's left side.

Methods

After LND around the CHA and right side of the CA from the patient's right side, the surgeon then moves to the patient's left side. The anterior pancreatic fascia is cut at the middle point of the SA to discern the dorsal layer of the LN along the SA, such as the splenic vein. LND is performed by preserving the posterior pancreatic fascia around the SA in a left-to-right direction. Finally, the LNs around the left side of the CA are deeply dissected.

Results

We performed this procedure on ten patients between April 2016 and January 2017; no operative complications were reported in grade II or higher cancer patients.3 After exposing the dorsal landmark, LNs around the proximal SA and left side of the CA were removed in all patients.

Conclusion

This procedure enables early identification of the dorsal layer and deep LND around the left side of the CA, keeping this layer. The left lateral approach is useful for radical LND along the proximal SA.

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Pertuzumab/Trastuzumab/CT Versus Trastuzumab/CT Therapy for HER2+ Breast Cancer: Results from the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST)

Abstract

Background

Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping.

Methods

Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment.

Results

In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%).

Conclusions

The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.

http://ift.tt/2wjEieN

Time to Initiation of Adjuvant Chemotherapy in Pancreas Cancer: A Multi-Institutional Experience

Abstract

Background

Despite randomized trials addressing adjuvant therapy (AT) for pancreas cancer, the ideal time to initiate therapy remains undefined. Retrospective analyses of the ESPAC-3 trial demonstrated that time to initiation of AT did not impact overall survival (OS). Given the absence of confirmatory data outside of a clinical trial, we sought to determine if AT timing in routine clinical practice is associated with OS differences.

Methods

Perioperative data of pancreatectomies for ductal adenocarcinoma from five institutions (2005–2015) were assessed. Delay in AT was defined as initiation >12 weeks after surgery. Multivariate analysis was performed to identify predictors of mortality.

Results

Of 867 patients, 172 (19.8%) experienced omission of AT. Improved OS was observed in patients who received AT compared with patients who did not (24.8 vs. 19.1 months, p < 0.01). Information on time to initiation of AT was available in 488 patients, of whom 407 (83.4%) and 81 (16.6%) received chemotherapy ≤12 and >12 weeks after surgery, respectively. There were no differences in recurrence-free survival or OS (all p > 0.05) between the timely and delayed AT groups. After controlling for perioperative characteristics and tumor pathology, patients who initiated AT ≤ 12 or > 12 weeks after surgery had a 50% lower odds of mortality than patients who only underwent resection (p < 0.01).

Conclusions

In a multi-institutional experience of resected pancreas cancer, delayed initiation of AT was not associated with poorer survival. Patients who do not receive AT within 12 weeks after surgery are still appropriate candidates for multimodal therapy and its associated survival benefit.

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Sentinel Lymph Node Biopsy for Recurrent Melanoma: A Multicenter Study

Abstract

Background

Sentinel lymph node biopsy (SLNB) is routinely performed for primary cutaneous melanomas; however, limited data exist for SLNB after locally recurrent (LR) or in-transit (IT) melanoma.

Methods

Data from three centers performing SLNB for LR/IT melanoma (1997 to the present) were reviewed, with the aim of assessing (1) success rate; (2) SLNB positivity; and (3) prognostic value of SLNB in this population.

Results

The study cohort included 107 patients. Management of the primary melanoma included prior SLNB for 56 patients (52%), of whom 10 (18%) were positive and 12 had complete lymph node dissections (CLNDs). In the present study, SLNB was performed for IT disease (48/107, 45%) or LR melanoma (59/107, 55%). A sentinel lymph node (SLN) was removed in 96% (103/107) of cases. Nodes were not removed for four patients due to lymphoscintigraphy failures (2) or nodes not found during surgery (2). SLNB was positive in 41 patients (40%, 95% confidence interval (CI) 31.5–50.5), of whom 35 (88%) had CLND, with 13 (37%) having positive nonsentinel nodes. Median time to disease progression after LR/IT metastasis was 1.4 years (95% CI 0.75–2.0) for patients with a positive SLNB, and 5.9 years (95% CI 1.7–10.2) in SLNB-negative patients (p = 0.18). There was a trend towards improved overall survival for patients with a negative SLNB (p = 0.06).

Conclusion

SLNB can be successful in patients with LR/IT melanoma, even if prior SLNB was performed. In this population, the rates of SLNB positivity and nonsentinel node metastases were 40% and 37%, respectively. SLNB may guide management and prognosis after LR/IT disease.

http://ift.tt/2wjxlL5

Cosmetic Outcome and Chronic Breast Toxicity After Intraoperative Radiation Therapy (IORT) as a Single Modality or as a Boost Using the Intrabeam ® Device: A Prospective Study

Abstract

Purpose

We aim to report our results in terms of chronic toxicities and cosmetic outcomes after intraoperative radiotherapy (IORT) using kV X-rays in women treated for early breast cancer at our institution.

Methods

Patients with early breast carcinoma were recruited between April 2011 and November 2014. After breast-conserving surgery, patients were treated with IORT using the Intrabeam^® device. IORT was completed by whole-breast radiotherapy (WBRT) at a dose of 46–50.4 Gy in 23–28 fractions in case of adverse pathologic criteria on the final specimen examination. Skin toxicity was graded using the Late Effects in Normal Tissues—Subjective, Objective, Management and Analytic (LENT-SOMA) scale every 6 months, and cosmetic outcomes were evaluated at 36 months by patient self-evaluation and by two radiation oncologists, on a 1–10 scale.

Results

Forty-one women received IORT only and 30 patients received IORT followed by WBRT (IORT + WBRT group). After a median follow-up of 38.9 months, no locoregional or distant recurrence occurred. After IORT only, 2.4% of grade 2 or higher breast fibrosis, and no other grade 2 or higher disease, was observed. In the IORT + WBRT group, grade 2 or higher fibrosis and grade 2 or higher breast retraction were observed in 43.3 and 23.3% of patients, respectively. Objective cosmetic outcomes were very good and significantly better in the IORT-only group compared with the IORT + WBRT group (8.87 vs. 6.96) (p < 0.001).

Conclusion

IORT using the Intrabeam^® is well-tolerated, with very little chronic toxicity and good cosmetic outcome. However, a high rate of grade 2 or higher chronic breast toxicity was observed when IORT had to be completed by WBRT.

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The Impact of Residual Disease After Preoperative Systemic Therapy on Clinical Outcomes in Patients with Inflammatory Breast Cancer

Abstract

Background

Inflammatory breast cancer (IBC) is a rare and aggressive disease treated with multimodality therapy: preoperative systemic therapy (PST) followed by modified radical mastectomy (MRM), chest wall and regional nodal radiotherapy, and adjuvant biologic therapy and/or endocrine therapy when appropriate. In non-IBC, the degree of pathologic response to PST has been shown to correlate with time to recurrence (TTR) and overall survival (OS). We sought to determine if pathologic response correlates with oncologic outcomes of IBC patients.

Methods

Following review of IBC patients' records (1997–2014), we identified 258 stage III IBC patients; 181 received PST followed by MRM and radiotherapy and were subsequently analyzed. Pathologic complete response (pCR) to PST, hormone receptor and human epidermal growth factor receptor 2 (HER2) status, grade, and histology were evaluated as predictors of TTR and OS by Cox model.

Results

Overall, 95/181 (52%) patients experienced recurrence; 93/95 (98%) were distant metastases (median TTR 3.2 years). Seventy-three patients (40%) died (median OS 6.9 years). pCR was associated with improved TTR (hazard ratio [HR] 0.20, 95% confidence interval [CI] 0.09–0.46, p < 0.01, univariate; HR 0.17, 95% CI 0.07–0.41, p < 0.0001, multivariate) and improved OS (HR 0.26, 95% CI 0.11–0.65, p < 0.01, univariate). In patients with pCR, grade III (HR 1.91, 95% CI 1.16–3.13, p = 0.01), and triple-negative phenotype (HR 3.54, 95% CI 1.79–6.98, p = 0.0003) were associated with shorter TTR, while residual ductal carcinoma in situ was not (HR 0.85, 95% CI 0.53–1.35, p = 0.48, multivariate).

Conclusions

In stage III IBC, pCR was associated with prognosis, further influenced by grade, hormone receptor, and HER2 status. Investigating mechanisms that contribute to better response to PST could help improve oncologic outcomes in IBC.

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Analysis of Perioperative Chemotherapy in Resected Pancreatic Cancer: Identifying the Number and Sequence of Chemotherapy Cycles Needed to Optimize Survival

Abstract

Purpose

Receipt of 6 cycles of adjuvant chemotherapy (AC) is standard of care in pancreatic cancer (PC). Neoadjuvant chemotherapy (NAC) is increasingly utilized; however, optimal number of cycles needed alone or in combination with AC remains unknown. We sought to determine the optimal number and sequence of perioperative chemotherapy cycles in PC.

Methods

Single institutional review of all resected PCs from 2008 to 2015. The impact of cumulative number of chemotherapy cycles received (0, 1–5, and ≥6 cycles) and their sequence (NAC, AC, or NAC + AC) on overall survival was evaluated Cox-proportional hazard modeling, using 6 cycles of AC as reference.

Results

A total of 522 patients were analyzed. Based on sample size distribution, four combinations were evaluated: 0 cycles = 12.1%, 1–5 cycles of combined NAC + AC = 29%, 6 cycles of AC = 25%, and ≥6 cycles of combined NAC + AC = 34%, with corresponding survival. 13.1, 18.5, 37, and 36.8 months. On MVA (P < 0.0001), tumor stage [hazard ratio (HR) 1.35], LNR (HR 4.3), and R1 margins (HR 1.77) were associated with increased hazard of death. Compared with 6 cycles AC, receipt of 0 cycles [HR 3.57, confidence interval (CI) 2.47–5.18] or 1–5 cycles in any combination (HR 2.37, CI 1.73–3.23) was associated with increased hazard of death, whereas receipt of ≥6 cycles in any sequence was associated with optimal and comparable survival (HR 1.07, CI 0.78–1.47).

Conclusions

Receipt of 6 or more perioperative cycles of chemotherapy either as combined neoadjuvant and adjuvant or adjuvant alone may be associated with optimal and comparable survival in resected PC.

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Immaturity of Bile Canalicular–Ductule Networks in the Future Liver Remnant While Associating Liver Partition and Portal Vein Occlusion for Staged Hepatectomy (ALPPS)

Abstract

Background

We studied histologic changes of bile canalicular–ductule networks in the future liver remnant (FLR) while associating liver partition and portal vein occlusion for staged hepatectomy (ALPPS), since little is known about regeneration of these networks during the relatively short interval between procedures in ALPPS.

Methods

Bile canalicular–ductule networks were examined in specimens from eight patients treated with ALPPS and six patients undergoing hepatectomy following portal vein embolization (PVE). Expression of multidrug resistance-1 (MDR1), a membrane transporter in bile canaliculi (BC), was analyzed immunohistochemistcally. Morphologic changes of BC and tight junctions (TJs) adjoining BC were also assessed electron microscopically.

Results

Extrapolated kinetic growth of the FLR was greater during ALPPS (17.2 ± 6.8 mL/day) than after PVE (6.3 ± 3.4 mL/day; p = 0.005), and continuity of the MDR1-positive bile canalicular networks was less evident in ALPPS than PVE (p < 0.001). Electron microscopically, no significant difference was evident in numbers of BC or BC lumen size between the two groups; however, development of microvilli in BC was poorer in the ALPPS group than in the PVE group (p < 0.001). TJ/desmosome complexes were shorter in the ALPPS group (0.69 ± 0.52 μm) than in the PVE group (1.09 ± 0.50 μm; p < 0.001), and leaky TJs were seen more frequently in the ALPPS group (64.9 vs. 23.6%; p = 0.001).

Conclusions

Regeneration of bile canalicular–ductule networks in the FLR was poorer in ALPPS than PVE, which may be associated with prolonged cholestasis following final hepatectomy in ALPPS.

http://ift.tt/2wjSFQy

Standard Pathologic Features Can Be Used to Identify a Subset of Estrogen Receptor-Positive, HER2 Negative Patients Likely to Benefit from Neoadjuvant Chemotherapy

Abstract

Background

The benefit of neoadjuvant chemotherapy (NAC) in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancers and in invasive lobular carcinoma (ILC) is uncertain due to the low rates of pathologic complete response (pCR).

Objective

The aim of this study was to determine if pathologic features can identify subsets likely to benefit from NAC.

Methods

Patients with stage I–III ER+, HER2− breast cancer receiving NAC were retrospectively reviewed. Endpoints were downstaging to breast-conserving surgery (BCS) and nodal pCR after NAC. Patients were grouped by progesterone receptor (PR) status and grade/differentiation (high grade or poor [HP] vs. non-HP).

Results

From 2007 to 2016, 402 ER+/HER2− cancers in patients receiving NAC were identified. Median age was 50 years, 98% were clinical stage II–III, and 75% were cN+. Overall pCR rate was 5%; breast pCR in 7% and nodal pCR in 15% of cN+ patients (p < 0.0001). Patients with ILC initially ineligible for BCS (n = 56) were less likely to downstage than those with invasive ductal carcinoma (IDC; n = 183, 16 vs. 48%, p ≤ 0.0001), with a similar trend in the axilla (p = 0.086). The rates of BCS eligibility after NAC were highest in PR−/HP patients (62%) and lowest in PR+/non-HP patients (29%) [p = 0.005]. In the axilla, nodal pCR among cN+ patients (n = 301) ranged from 0 to 35% (p < 0.0001) within these groups, and was most frequent in PR−/HP patients.

Conclusions

ER+/HER2− patients most likely to benefit from NAC are those with PR− and HP tumors. Patients with ILC are unlikely to downstage in the breast or axilla compared with IDC. The use of these criteria can assist in defining the initial treatment approach.

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Clinicopathological Determinants of an Elevated Systemic Inflammatory Response Following Elective Potentially Curative Resection for Colorectal Cancer

Abstract

Introduction

The postoperative systemic inflammatory response (SIR) is related to both long- and short-term outcomes following surgery for colorectal cancer. However, it is not clear which clinicopathological factors are associated with the magnitude of the postoperative SIR. The present study was designed to determine the clinicopathological determinants of the postoperative systemic inflammatory response following colorectal cancer resection.

Methods

Patients with a histologically proven diagnosis of colorectal cancer who underwent elective, potentially curative resection during a period from 1999 to 2013 were included in the study (n = 752). Clinicopathological data and the postoperative SIR, as evidenced by postoperative Glasgow Prognostic Score (poGPS), were recorded in a prospectively maintained database.

Results

The majority of patients were aged 65 years or older, male, were overweight or obese, and had an open resection. After adjustment for year of operation, a high day 3 poGPS was independently associated with American Society of Anesthesiologists (ASA) grade (hazard ratio [HR] 1.96; confidence interval [CI] 1.25–3.09; p = 0.003), body mass index (BMI) (HR 1.60; CI 1.07–2.38; p = 0.001), mGPS (HR 2.03; CI 1.35–3.03; p = 0.001), and tumour site (HR 2.99; CI 1.56–5.71; p < 0.001). After adjustment for year of operation, a high day 4 poGPS was independently associated with ASA grade (HR 1.65; CI 1.06–2.57; p = 0.028), mGPS (HR 1.81; CI 1.22–2.68; p = 0.003), NLR (HR 0.50; CI 0.26–0.95; p = 0.034), and tumour site (HR 2.90; CI 1.49–5.65; p = 0.002).

Conclusions

ASA grade, BMI, mGPS, and tumour site were consistently associated with the magnitude of the postoperative systemic inflammatory response, evidenced by a high poGPS on days 3 and 4, in patients undergoing elective potentially curative resection for colorectal cancer.

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Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Moderately and Poorly Differentiated Appendiceal Adenocarcinoma: Survival Outcomes and Patient Selection

Abstract

Background

Moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death.

Methods

Overall, 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database. Clinical, pathologic, and treatment factors were analyzed for outcomes.

Results

Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42%) patients. These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease. Twenty-seven (41%) patients were excluded from cytoreductive surgery (CRS) because of findings on DL, while 116 (65%) patients underwent CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), with a median disease-free survival (DFS) of 23 months. Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS. The median OS following CRS and HIPEC was 48 months. Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with OS. Eight-five (73.3%) patients received neoadjuvant chemotherapy, and 40 (47.1%) patients achieved a radiographic response; 36 (42.3%) had stable disease, while 9 (10.6%) had progressive disease. Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011).

Conclusions

In selected patients, long-term survival can be obtained. Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI ≤ 20, and response/stable disease after neoadjuvant chemotherapy are important selection criteria for CRS and HIPEC.

http://ift.tt/2vrdKMA

Oncologic Outcome of Metastasectomy for Urothelial Carcinoma: Who Is the Best Candidate?

Abstract

Background

Resection of metastatic lesions (metastasectomy) is performed for highly selected patients with metastatic urothelial carcinoma (mUC). This study aimed to identify the clinicopathologic factors associated with oncologic outcome for patients who underwent metastasectomy for mUC.

Methods

This analysis included 37 UC patients who underwent metastasectomy with curative intent at nine Japanese hospitals. The primary end point was cancer-specific survival. The Kaplan–Meier method with the log-rank test and the multivariable Cox proportional hazards model addressed the relationship between clinical characteristics and survival.

Results

Metastasectomy was performed for pulmonary (n = 23), nodal (n = 7), and other (n = 7) metastases. The median survival time was 35.4 months (interquartile range [IQR] 15.5, not reached) from the detection of metastasis and 34.3 months (IQR 13.1, not reached) from metastasectomy. The 5-year cancer-specific survival rate after detection of metastasis was 39.7%. In the multivariate analysis, the time from primary surgery to detection of metastasis (time-to-recurrence [TTR]) of 15 months or longer (hazard ratio [HR] 0.23; p = 0.0063), no symptoms of recurrence (HR 0.23; p = 0.0126), and serum C-reactive protein (CRP) levels lower than than 0.5 mg/dl (HR 0.24; p = 0.0052) were significantly associated with better survival.

Conclusions

Long-term survival could be achieved for some patients with mUC who underwent metastasectomy. Lung and lymph nodes were predominant sites for metastasectomy. Symptoms, TTR, and CRP value were identified as associated with survival and should be taken into account when metastasectomy is considered.

http://ift.tt/2wjSAfI

Patterns of Initial Recurrence in Gastric Adenocarcinoma in the Era of Preoperative Therapy

Abstract

Background

We sought to determine the sites of recurrence and identify predicting factors for recurrence and survival in patients who underwent gastrectomy for adenocarcinoma at an institution where preoperative therapy is commonly used for advanced gastric cancer.

Methods

We collected clinicopathologic data and sites of recurrence from a prospectively maintained database of patients who underwent potentially curative resection of gastric or gastroesophageal adenocarcinoma at our institution in 1995–2014, and we assessed associations between these characteristics and recurrence patterns and survival.

Results

We identified 488 patients who underwent R0 resection of localized gastric cancer. The median age was 63 years (interquartile range 53–71 years), and 60% were male. The most common T and N categories, per endoscopic ultrasonography, were T3 (58%) and N0 (61%). Preoperative treatment was used in 61% of patients. A total of 125 (26%) patients experienced recurrence during follow-up. Recurrences were locoregional in 19 patients (15%), peritoneal in 61 (49%), and nonperitoneal distant in 67 (54%). The peritoneum also was the most common organ of recurrence (49%), followed by the liver (21%). The median time from primary resection to recurrence was 2.7 years for locoregional, 1.3 years for peritoneal, and 0.6 years for nonperitoneal distant recurrence (p = 0.01). Median overall survival was markedly shorter after peritoneal and nonperitoneal distant recurrences than after locoregional recurrences.

Conclusions

The peritoneum was a common site of recurrence after curative resection of gastric cancer and was associated with poor survival. Prophylactic treatment targeting the peritoneal cavity might improve survival of advanced gastric cancer.

http://ift.tt/2vqWGpK

Lack of Efficacy of Radioiodine Remnant Ablation for Papillary Thyroid Microcarcinoma: Verification Using Inverse Probability of Treatment Weighting

Abstract

Background

Most of the increase in thyroid cancer in recent decades has been due to papillary thyroid microcarcinoma (PTMC). We evaluated the efficacy of radioiodine remnant ablation (RRA) in patients with PTMC.

Methods

This historical cohort study included 1932 PTMC patients without lateral cervical lymph node (LN) or distant metastasis who underwent total thyroidectomy (TT) during the median 8.3 years of follow-up. The clinical outcomes of patients with or without RRA were compared using weighted logistic regression models with the inverse probability of treatment weighting (IPTW) method and considering risk factors, including age, sex, primary tumor size, extrathyroidal extension, multifocality, and central cervical LN metastasis.

Results

The median primary tumor size of the RRA group was significantly larger than that of the no-RRA group (0.7 vs. 0.5 cm, P < 0.001). There were significantly more patients with multifocality, extrathyroidal extension, and cervical LN metastasis in the RRA group compared with the no-RRA group. There was no significant difference in recurrence-free survival between the two groups (P = 0.11). Cox proportional–hazard analysis with IPTW by adjusting for clinicopathological risk factors demonstrated no significant difference in recurrence of PTMC according to RRA treatment (hazard ratio [HR] 2.02; 95% confidence interval [CI] 0.65–6.25; P = 0.2).

Conclusions

RRA had no therapeutic effect on the clinical outcomes of patients with PTMC who underwent TT. Surgical treatment without RRA could be applicable for patients with PTMC if there is no evidence of lateral cervical LN metastasis or distant metastasis.

http://ift.tt/2wjH5EQ

Expression of Programmed Cell Death Protein 1 by Tumor-Infiltrating Lymphocytes and Tumor Cells is Associated with Advanced Tumor Stage in Patients with Esophageal Adenocarcinoma

Abstract

Background

Despite recent advances in the therapy for adenocarcinoma of the esophagogastric junction (AEG), overall prognosis remains poor. Programmed cell death protein 1 (PD1) is a co-inhibitory receptor primarily expressed by T-cells. Tumor cells can escape anticancer immune responses by triggering the PD1 pathway. Moreover, PD1 receptor engagement on cancer cells may trigger tumor-intrinsic growth signals. This study aimed to evaluate the potential clinical relevance of PD1 expression by tumor-infiltrating lymphocytes (TILs) and cancer cells in the AEG.

Methods

Patients with AEG who underwent esophagectomy from 1992 to 2011 were included in the study. Expression of PD1was evaluated by immunohistochemistry and correlated with long-term overall survival (OS), disease-free survival (DFS), and various clinicopathologic parameters.

Results

Tumor biospecimens from 168 patients were analyzed. In the analysis, 81% of the patients showed high tumoral frequencies (>5%) of PD1-expressing TILs (TIL-PD1⁺), and 77% of patient tumors harbored high levels (>5%) of PD1⁺ cancer cells (cancer-PD1⁺). Expression of PD1 by TILs and cancer cells correlated significantly (p < 0.05) with patients' tumor stage and lymph node involvement. Compared with the patients who had low tumoral frequencies of PD1⁺ TILs or cancer cells, the TIL-PD1⁺ and cancer-PD1⁺ patients demonstrated significantly reduced DFS in the univariate analysis (5-year DFS: 73.3 vs. 41.9%, log-rank 0.008 and 71.3 vs. 41.6%, p = 0.008, respectively). Additionally, the cancer-PD1⁺ patients showed significantly decreased OS in the univariate analysis compared with the cancer-PD1⁻ patients (5-year OS: 68.8 vs. 43.5%; p = 0.047). However, these correlations did not reach significance in the multivariate analysis.

Conclusions

The PD1 receptor is expressed by both TILs and cancer cells in AEG. High expression of PD1 is associated with advanced tumor stage and lymph node involvement, but not with survival.

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Refining the Role of Lymph Node Biopsy in Survival for Patients with Nasopharyngeal Carcinoma: Population-Based Study from the Surveillance Epidemiology and End-Results Registry

Abstract

Background

The updated version of the National Comprehensive Cancer Network (NCCN) guidelines revised pretreatment workup for nasopharyngeal carcinoma (NPC) into "biopsy of the primary site or neck." Despite provision of important diagnostic information, concerns regarding tumor cell dissemination limit the application of lymph node biopsy. This study aimed to investigate whether biopsy of the neck is associated with impaired survival in NPC.

Methods

A propensity score-matched, population-based cohort identified from the Surveillance, Epidemiology, and End Results database was used to compare overall survival (OS) and disease-specific survival (DSS) of patients who underwent pretreatment cervical lymph node biopsy without subsequent neck dissection or removal of node compared with patients who did not undergo node biopsy.

Results

Of 2910 eligible patients, 416 (14.3%) underwent pretreatment lymph node biopsy. After use of control for patient, tumor, and demographic characteristics, biopsy was not associated with impaired OS (hazard ratio [HR], 1.15; 95% confidence interval [CI] 0.89–1.47; P = 0.29) or DSS (HR, 1.07; 95% CI 0.81–1.40; P = 0.63). Interestingly, in the subgroup analysis, the unfavorable effect of biopsy was observed for patients with differentiated non-keratinizing squamous cell carcinoma (but not other histologic types). Race did not positively alter the survival outcomes.

Conclusions

The findings provide reference for clinical practice, showing that pretreatment cervical lymph node biopsy is not associated with impaired survival in NPC, except for patients with differentiated non-keratinizing squamous cell carcinoma. The recommended NCCN guidelines would be more specific by adding details to the general recommendation that neck biopsy is safe for all patients. Future prospective studies are needed to verify the study findings.

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Bilateral Prophylactic Mastectomy and Immediate Breast Reconstruction in High-Risk Women: The Importance of Health-Related Quality of Life in Decision Making

http://ift.tt/2vrhYDB

Abstract

http://ift.tt/2vratgd

The psychological impact of prostate biopsy: prevalence and predictors of procedure-related distress

ABSTRACT

Background

Many men undergo prostate biopsies each year. Most data on consequences of prostate biopsy for men pertain to physical after-effects and/or come from clinical trial populations. We quantified prevalence of, and identified factors associated with, procedure-related distress in men having prostate biopsies in routine clinical practice.

Methods

Men who had undergone prostate biopsy for follow-up of a raised prostate specific antigen test result and/or abnormal digital rectal examination in six centres in Ireland completed questionnaires. Biopsy-related psychological distress was measured using the Impact of Event Scale (IES). An IES score ≥9 was considered significant biopsy-related distress. Logistic regression was used to identify predictors of significant distress.

Results

335 men completed questionnaires. Overall 49% had significant biopsy-related distress; this was higher in men whose biopsy result indicated cancer (59%) and those who did not have a definitive result (54%) than those with a negative result (35%; p<0.001). In multivariable analyses, the odds of significant distress were three-times higher in men with cancer (OR=3.33, 95%CI 1.83-6.04) and more than twice as high in men without a definitive result (OR= 2.61, 95%CI 1.43-4.78) compared to men with a negative result. Men with intermediate (OR=3.19, 95%CI 1.85-5.53) or high (OR=7.10, 95%CI 3.45-14.57) health anxiety (propensity to worry about one's health) also had significantly increased odds of biopsy-related distress.

Conclusions

Significant distress is common after prostatic biopsy. Some men, including those who are highly health anxious and those awaiting definitive results, may benefit from additional support around the time of and/or following prostate biopsy.

http://ift.tt/2uWGHNd

Effects of Vacuolar H + -ATPase Inhibition on Activation of Cathepsin B and Cathepsin L Secreted from MDA-MB231 Breast Cancer Cells

Abstract

Studies indicate secreted cathepsins are involved in metastasis. V-ATPases, which are necessary for activating intracellular cathepsins, also play a role in metastasis and are targeted to the plasma membrane of metastatic breast cancer cells. We are interested in a connection between cell surface V-ATPases, activation of secreted cathepsins and the metastatic phenotype of MDA-MB231 cells. We investigated whether V-ATPase inhibition would reduce the activity of secreted cathepsin B and cathepsin L. Using cell lysates and conditioned media, we measured cathepsin B and L activity within and outside of the cells. We found different forms of cathepsin B and L were secreted representing the pre-pro, pro and active forms of the proteases. Cathepsin B activity was higher than cathepsin L in conditioned media and in cell lysates. V-ATPase inhibition by concanamycin A decreased cathepsin B activity in conditioned media and significantly decreased cathepsin B activity in cell lysates. Cathepsin L activity showed a slight decrease in cell lysates. Changes in the activity of secreted and intracellular cathepsins following V-ATPase inhibition were supported by changes in the amounts of pro and active forms of cathepsin B in conditioned media and cathepsins B and L in cell lysates. Overall, our data shows that inactive forms of cathepsins B and L are secreted from the MB231 cells and V-ATPase activity is important for the activation of secreted cathepsin B. This indicates a connection between cell surface V-ATPases in metastatic breast cancer cells and the function of secreted cathepsin B.

http://ift.tt/2f6zKVS

Abstract

http://ift.tt/2vratgd

ABO genotype-phenotype discrepancy due to chimerism resolved by clonal separation

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Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia

Abstract

Telomere shortening represents an established mechanism connecting aging and cancer development. We sequentially analyzed telomere length (TL) of 49 acute myeloid leukemia (AML) patients at diagnosis (n = 24), once they achieved complete cytological remission (CCR) and/or during refractory disease or relapse and after 1-year follow-up, with all patients having at least two sequential samples. TL was analyzed by monochrome multiplex quantitative polymerase chain reaction. We have observed substantially shortened TL in the cells of patients at diagnosis compared to age-adjusted controls. In patients reaching CCR after chemotherapy, telomere shortening was less pronounced than in persistence or relapse but still significantly shortened compared to controls. We estimate patients harboring approximately 20 years of premature telomere loss compared to healthy aged-matched subjects at the time of AML onset. Our data indicate a pre-existing telomere deficit in non-clonal hematopoiesis of AML patients providing a link between age and AML development.

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Treatment of refractory autoimmune hemolytic anemia with venetoclax in relapsed chronic lymphocytic leukemia with del(17p)

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Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation

Abstract

Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2 weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (<2), intermediate (2, 3), and high (>3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p = 0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p = 0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p < 0.01) and a lower tendency for Bacteroidetes (p = 0.106) than non-aGVHD patients. Maintenance of Bacteroidetes throughout allo-HSCT may be a strategy to prevent aGVHD.

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Transcranial color Doppler in stroke-free adult patients with sickle cell disease

Abstract

The threshold velocity ≥200 cm/s at transcranial Doppler (TCD) evaluation is a useful cut-off for preventing the stroke (STOP trial) in pediatric patients with sickle cell disease (SCD), term including different types of sickle genotypes. Scanty data are available for adult SCD patients. We compared intracranial blood flow velocities between adult SCD patients and controls using transcranial color Doppler (TCCD), measuring the peak of systolic velocity (PSV) with the insonation angle correction and the pulsatility index (PI), an indicator of endothelial elasticity. Fifty-three adult SCD patients (aged >18 years) were enrolled (15 sickle cell anemia, 26 sickle cell thalassemia, and 12 HbS/HbC). None of the patients presented neurological signs. PSVs in middle cerebral artery (MCA) were higher in SCD patients than in controls (p = 0.001). In sickle cell anemia patients, PSVs were higher when compared to HbS/βThal (p < 0.0060) and HbS/HbC patients (p < 0.0139). PI was within the lower range of normality in SCD patients compared to controls. Moreover, MCA-PSV was higher with lower Hb levels and higher HbS%; PI did not change with variation of Hb levels and HbS%.

PSV and PI in SCD adult patients could be a relevant index to indicate the abnormal cerebral blood flow and to detect the sickle endothelial damage, in order to prevent cerebrovascular accidents.

http://ift.tt/2u1A1Ai

PD-1 signaling and inhibition in AML and MDS

Abstract

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.

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Calcineurin inhibitor-free GVHD prophylaxis with sirolimus and mycophenolate mofetil combination

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High KIF2A expression predicts unfavorable prognosis in diffuse large B cell lymphoma

Abstract

Kinesin family member 2A (KIF2A), a conserved motor protein, plays a critical role in the pathogenesis and prognosis of several malignant tumors. The aim of the present study was to investigate KIF2A expression in diffuse large B cell lymphoma (DLBCL), evaluate the association between KIF2A expression and the clinical parameters of the disease, and determine its prognostic value. KIF2A expression was evaluated in 134 DLBCL and 57 reactive hyperplasia samples using immunohistochemistry on a tissue microarray. The correlations between KIF2A expression with clinical parameters and prognosis were estimated using univariate and multivariate analyses. The expression of KIF2A was significantly higher in DLBCL tissue samples compared with those from subjects with reactive hyperplasia (P=0.002). Furthermore, increased expression of KIF2A protein in DLBCL was related to Ann Arbor stage (P=0.027) and international prognostic index (IPI) score (P=0.01). The survival analysis showed that KIF2A expression (P=0.016), serum LDH level (P=0.049), and IPI score (P<0.001) were independent prognostic markers for DLBCL. Our findings also confirmed that downregulating KIF2A expression decreased tumor cell viability, accompanied by downregulation of pAKT levels. Taken together, these data provide the first evidence that increased KIF2A expression predicts poor prognosis in patients with DLBCL, and a rationale for treatment of DLBCL by targeting KIF2A.

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In Burkitt lymphoma patients who relapse after induction with a short-intensive chemoimmunotherapy protocol, aggressive salvage chemotherapy therapy is ineffective: a single-center retrospective study

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Clinical-associated characteristics and microbiological features of bloodstream nontyphoidal salmonella infection in adult patients receiving allogeneic hematopoietic stem cell transplantation

Abstract

Bloodstream nontyphoidal salmonella (NTS) infection is rare, but its associated characteristics and microbiological features in immunocompromised patients are worth paying attention to, particularly for those receiving allogeneic hematopoietic stem cell transplantation (SCT). No studies so far have analyzed post-transplant bloodstream NTS infection. Therefore, we reviewed 423 adult patients undergoing allogeneic hematopoietic SCT from 2003 to 2014. Nine out of four hundred twenty-three patients (2.13%) developed post-transplant bloodstream NTS infection, including two patients who had subsequent or combined metastatic infections. The median age at SCT was 35 years (interquartile range, 29–46) among the nine patients with bloodstream NTS infection. Male patients were predominant (78%). The median onset of bloodstream NTS infection was at 315 days after SCT (range, 207–629). Multivariate analysis revealed that extensive chronic graft-versus-host disease (GVHD) (OR 8.054, p = 0.003) and nonmyeloablative transplant conditioning (OR 4.604, p = 0.037) were significant associated characteristics for NTS infection. Currently, there are no published data analyzing and exploring post-transplant bloodstream NTS infections in adult allogeneic hematopoietic SCT. Our study determined the associated characteristics and microbiological features for this infection.

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Detection of human T-cell lymphotropic virus type I-specific cytotoxic T-cells may predict treatment responses in adult T-cell leukemia/lymphoma patients

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Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy

Abstract

Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3–8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all-trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 × 10⁹/L) (P < 0.001) and high PB blast (>30 × 10⁹/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index ≥95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established.

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Soluble form of transferrin receptor-1 level is associated with the age at first diagnosis and the risk of therapeutic intervention and iron overloading in patients with non-transfusion-dependent thalassemia

Abstract

We retrospectively evaluated the relationship between serum transferrin receptor-1 (sTfR1) and some fundamental events in the life and the management (the age at diagnosis, the age at the first red blood cells transfusion, the age at splenectomy, and the overall need of chelation therapy) of 111 patients with non-transfusion-dependent thalassemia (NTDT) subdivided in four genetic entities: patients with homozygous or compound heterozygous state for β-thalassemia, patients with triplicated α genotype associated with β heterozygosity, patients with deletional HbH, and patients with the combination of a β defect plus a β chain variant. We found that the group with homozygous or compound heterozygous state for β-thalassemia had the highest sTfR1 levels and that the presence of increased sTfR1 levels (>5 times normal) was associated with a complex and severe history of disease requiring splenectomy, occasional red blood cells transfusions, and early start and continuous iron chelation therapy.

The complexity in the management of NTDT patients is an emerging issue due to the wide heterogeneity of clinical behavior. Our data indicate that the measurement of sTfR1 levels, a common laboratory test, could contribute to correctly stratify disease history and the iron chelation strategy in NTDT patients.

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Detection of the circulating tumor DNAs in angioimmunoblastic T- cell lymphoma

Abstract

Recent genetic studies identified that the disease-specific G17V RHOA mutation, together with mutations in TET2, DNMT3A, and IDH2, is a hallmark of angioimmunoblastic T cell lymphomas (AITL). The diagnostic value of these mutations is now being investigated. Circulating tumor DNAs (ctDNAs) may offer a non-invasive testing for diagnosis and disease monitoring of cancers. To investigate whether these mutations are useful markers for ctDNAs in AITL and its related lymphomas, we performed targeted sequencing for TET2, RHOA, DNMT3A, and IDH2 in paired tumors and cell-free DNAs from 14 patients at diagnosis. Eighty-three percent of mutations detected in tumors were also observed in cell-free DNAs. During the disease course, mutations were detectable in cell-free DNAs in a refractory case, while they disappeared in a chemosensitive case. These data suggest that the disease-specific gene mutations serve as sensitive indicators for ctDNAs and may also be applicable for non-invasive monitoring of minimal residual diseases in AITL.

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Telomere shortening, TP53 mutations and deletions in chronic lymphocytic leukemia result in increased chromosomal instability and breakpoint clustering in heterochromatic regions

Abstract

Complex karyotypes are associated with a poor prognosis in chronic lymphocytic leukemia (CLL). Using mFISH, iFISH, and T/C-FISH, we thoroughly characterized 59 CLL patients regarding parameters known to be involved in chromosomal instability: status of the genes ATM and TP53 and telomere length. Interestingly, a deletion of the ATM locus in 11q, independent of the cytogenetic context, was associated with significantly diminished risk (p<0.05) of carrying a mutation in TP53. In patients with loss or mutation of TP53, chromosomal breakage occurred more frequently (p<0.01) in (near-) heterochromatic regions. Median telomere length in patients with complex karyotypes was significantly shorter than that of healthy controls and shorter than in all other cytogenetic cohorts. Furthermore, the median telomere length of patients carrying a TP53 mutation was significantly shorter than without mutation. We conclude that telomere shortening in combination with loss of TP53 induces increased chromosomal instability with preferential involvement of (near-) heterochromatic regions.

http://ift.tt/2u2lJ27

Palliative home care for patients with advanced haematological malignancies—a multicenter survey

Abstract

Patients with advanced haematological malignancies in non-curative settings suffer from complex physical symptoms and psychosocial distress, comparable to patients with solid tumour entities. Nevertheless, numerous problems at the interface between haematology and palliative home care have been described. From January 2011 until October 2014, we performed a retrospective, multicenter analysis of all patients with haematological malignancies (ICD 10: C81-C95) being treated by the respective specialized palliative home care (SAPV) team. Three SAPV teams were surveyed. Disease entity, physical symptoms, psychosocial distress, number of hospital admissions, therapeutic interventions and other items were analysed descriptively. Of 3,955 SAPV patients, 1.8% (n = 73) suffered from haematological malignancies. Main problems were deterioration of general condition, pain or psychological problems. Thirty-seven percent developed new symptoms during SAPV, mainly pain, psychological distress or deterioration of general status. In 33%, patients were referred to hospital, mainly due to deterioration of general condition or pain. Seventy percent died within 3 months after beginning SAPV care; 83% died at home or in a nursing home. Patients suffering from advanced haematological malignancies were statistically underrepresented in SAPV, and SAPV was installed rather at the very last days of life. By far, more patients were able to die outside a hospital as compared to reference cohorts of haematological patients not being treated in SAPV. The spectrum of documented problems is comparable to other patient cohorts being treated in SAPV; therefore, the options and benefits of palliative home care should be incorporated in palliative haematological treatment concepts more vigorously and consequently.

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Interim 18 F-FGD PET/CT may not predict the outcome in primary central nervous system lymphoma patients treated with sequential treatment with methotrexate and cytarabine

Abstract

¹⁸F-fluoro-2-dexoy-D-glucose-positron emission tomography (PET)/computed tomography (CT) is a useful imaging technique for monitoring the treatment response in lymphoma cases. We investigated the value of interim brain PET/CT (I-PET/CT) for monitoring the response to intensive methotrexate-based chemotherapy in primary central nervous system lymphoma (PCNSL) patients with diffuse large B cell lymphoma (DLBCL). Of the 76 PCNSL patients treated with intensive methotrexate and cytarabine chemotherapy between September 2006 and December 2012, 66 patients with DLBCL were included in this study. The patient cohort of 66 individuals comprised 43 men and 23 women with a median age of 59 years (range, 17–75 years). During chemotherapy, 36 patients (54.5%) showed a negative metabolism on I-PET/CT, and 47 (71.2%) were negative on final (F) PET/CT. The baseline characteristics were similar between I-PET/CT-negative (n = 36) and I-PET/CT-positive patients (n = 30) except ECOG performance status. After a median follow-up of 27.5 months, there was no difference in the progression-free survival (PFS; P = 0.701) or overall survival (OS; P = 0.620) between the I-PET/CT-negative and I-PET/CT-positive groups. However, PFS in the F-PET/CT-negative group was significantly longer than that in the F-PET/CT-positive group (P < 0.001) without a significant difference in OS (P = 0.892). I-PET/CT may not predict the survival outcome of PCNSL patients with DLBCL treated with intensive methotrexate and cytarabine chemotherapy. Prospective trials are required to fully evaluate the role of I-PET/CT.

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Advanced chronic myelomonocytic leukemia in elderly and frail patients managed by azacitidine in the field of clinical practice

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Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase

Abstract

We evaluated clinical characteristics and outcome on imatinib of 22 patients with myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB. Median age was 49 years (range 20–80), 91% were male. Fifteen different PDGFRB fusion genes were identified. Eosinophilia was absent in 4/19 (21%) cases and only 11/19 (58%) cases had eosinophils ≥1.5×10⁹/L. On imatinib, 17/17 (100%) patients in chronic phase achieved complete hematologic remission after median 2 months (range 0–13)​. Complete cytogenetic remission and/or complete molecular remission by RT-PCR were achieved in 12/13 (92%) and 12/14 patients (86%) after median 10 (range 3–34) and 19 months (range 7–110), respectively. In patients with blast phase (myeloid, n = 2; lymphoid, n = 3), treatment included combinations of imatinib (n = 5), intensive chemotherapy (n = 3), and/or allogeneic stem cell transplantation (n = 3). All 3 transplanted patients (complex karyotype, n = 2) experienced early relapse. Initially, patients were treated with imatinib 400 mg/day (n = 15) or 100 mg/day (n = 7), the dose was reduced from 400 mg/day to 100 mg/day during follow-up in 9 patients. After a median treatment of 71 months (range 1–135), the 5-year survival rate was 83%; 4/22 (18%) patients died (chronic phase; n = 2; blast phase, n = 2) due to progression (n = 3) or comorbidity while in remission (n = 1). Of note, 3/4 patients had a complex karyotype. In summary, the most important characteristics of myeloid/lymphoid neoplasms with rearrangement of PDGFRB include (a) male predominance, (b) frequent lack of hypereosinophilia, (c) presentation in chronic or blast phase, (d) rapid responses and long-term remission on low-dose imatinib, and (e) possible adverse prognostic impact of a complex karyotype.

http://ift.tt/2u28Nta

Exploring the Histogenesis and Diagnostic Strategy Using Immunoassay and RT-PCR in Alveolar Soft Part Sarcoma

Abstract

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma, but it's easily misdiagnosed in rare locations. The derivation of ASPS is still uncertain, therefore we conducted this study to explore the histogenesis of ASPS by analyzing stem cell markers (ALDH1, CD29, CD133 and Nestin). Protein TFE3 and fusion gene ASPS-TFE3 were tested in paraffin to explore diagnostic strategy and molecular pathological features. In this study, nine cases of ASPS were immunostained with stem cell surface markers (ALDH1, CD29, CD133 and Nestin) and protein TFE3. Seven cases of ASPS mRNA were successfully extracted from nine paraffin-embedded tissues. The expression of fusion gene ASPL-TFE3 was examined by reverse transcriptase-polymerase chain reaction. The immunohistochemical staining of nine patients showed that CD29 and Nestin were negative in all nine cases (0/9). CD133 was weakly positive in one cases (1/9) and ALDH1 was weakly positive in one cases (1/9). TFE3 was positive in nine cases (9/9). Seven paraffin tissues could be successfully extracted with mRNA in nine cases. The results of Reverse Transcription Polymerase Chain Reaction (RT-PCR) showed that ASPL-TFE3 fusion transcripts could be tested in the seven cases (four cases being type 2 and three cases being type 1). The positive rate of CD133 and ALDH1 were less than 1% and the expression of CD29 and Nestin were negative in ASPS. Immunohistochemistry results indicated that the histogenesis of ASPS maybe not derive from mesenchymal stem cells. Immunohistochemistry staining showed that TFE3 protein expression was highly sensitive in ASPS. Furthermore, RT-PCR results showed that fusion gene ASPL-TFE3 (ASPL-TFE3 type 1 and ASPL-TFE3 type 2) was expressed in ASPS, which could provide information for clinical molecular pathological diagnosis and improve the diagnosis rate of rare atypical ASPS.

http://ift.tt/2vqEaOx

Clinicopathological characteristics and experience in the treatment of giant retroperitoneal liposarcoma: a case report and review of the literature.

Related Articles

Clinicopathological characteristics and experience in the treatment of giant retroperitoneal liposarcoma: a case report and review of the literature.

Cancer Biol Ther. 2017 Jul 31;:0

Authors: Zeng X, Liu W, Wu X, Gao J, Zhang P, Shuai X, Tao K

Abstract
Retroperitoneal liposarcoma (RPLS) is a rare tumor, especailly those over 20 kg that are called "giant liposarcoma", whose characteristics and treatments remain relatively unknown. Herein, we report a giant RPLS measuring 65 × 45 × 30 cm in diameter and 31 kg in weight, which we successfully performed complete excision through interdisciplinary cooperation. The patient had an uneventful postoperative course and was discharged without complications. Afterwards he underwent radiotherapy and had no evidence of tumor recurrence or symptoms of metastasis at 3-month CT scan and 8-month follow-up. We also firstly review the thirteen cases reported in literature published in PubMed regarding giant RPLS. Giant RPLS commonly occurs in adults aged 40-60 years and presents atypical clinical manifestations. CT scan is the most useful examination and preoperative biopsy is controversial. Complete surgical resection still remains the principal treatment. Giant RPLS can also be removed, even reach to R0 excision, by a multidisciplinary team in a specialized center after meticulous planning even though its gigantic tumor size. Local radiotherapy following surgery may improve the rate of recurrence. Besides, closely follow-up and routine examinations are required.

PMID: 28758856 [PubMed - as supplied by publisher]

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Bilateral pheochromocytoma with ganglioneuroma component associated with multiple neuroendocrine neoplasia type 2A: a case report

Composite pheochromocytoma/paragangliomas are very rare tumors composed of ordinary pheochromocytoma paragangliomas associated with neurogenic tumors. Several hereditary susceptibility disorders are known to b...

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Sclerosing mesenteritis mimicking metachronous peritoneal metastases from descending colon adenocarcinoma

Abstract

Background

Sclerosing mesenteritis is a non-neoplastic inflammatory disease that occurs in the bowel mesentery. Distinguishing sclerosing mesenteritis from neoplasms may be difficult because of the clinical and radiographic similarities between the two disease entities.

Case presentation

We report a case of sclerosing mesenteritis mimicking peritoneal metastases of colorectal carcinoma. A 73-year-old man with stage II descending colon adenocarcinoma with poor prognostic features was found to have developed left lower abdominal quadrant masses on computed tomography (CT) 9 months after undergoing radical surgery. These masses were diagnosed as peritoneal metastases because they grew in size and displayed fluorodeoxyglucose (FDG) uptake 3 months later; thus, a laparotomy was performed. The masses, which were localized in the jejunal mesentery, were excised completely via segmental jejunal resection. Histopathological analysis confirmed that the masses were sclerosing mesenteritis. The patient showed no signs of sclerosing mesenteritis or colorectal carcinoma recurrence during follow-up.

Conclusions

In patients suspected of having localized peritoneal metastasis from malignancies, any masses must be sampled by surgical excisional biopsy and subsequently examined to rule out alternative diagnoses, such as sclerosing mesenteritis.

http://ift.tt/2uShHs0

Regulation of human glioma cell apoptosis and invasion by miR-152-3p through targeting DNMT1 and regulating NF2

Abstract

Background

MiRNAs are involved in aberrant DNA methylation through regulation of DNA methyltransferases (DNMTs) in the pathogenesis and progression of glioblastomas (GBM). MiR-152-3p was down-expressed in human malignancies, and served as a tumor suppressor. Neurofibromatosis type 2 (NF2) was significantly decreased in GBM tissues with a high level of methylation. However, the link between miR-152-3p, DNMT1 and methylation of NF2 in GBM is not clearly established. This study was conducted to detect the mechanism between miR-152-3p, DNMT1 and NF2 in GBM.

Methods

The levels of DNMT1 and NF2 expression were studied by qRT-PCR, Western blot, immunofluorescence, and immumohistochemical staining. Methylation in the promoter region of NF2 was detected by methylation-specific PCR and bisulfate genomic sequencing PCR. Cell proliferation was examined by Cell-Counting Kit-8 and 5-ethynyl-2′-deoxyuridine assay, and cell invasion was evaluated by transwell assay. Flow cytomery and Hoechst staining were used to analyze cell apoptosis. A dual luciferase system was used to confirm the relationship between miR-152-3p and DNMT1.

Results

Methylation of NF2 and DNMT1 was markedly increased, and miR-152-3p was downregulated in GBM tissues and glioma cells. Both knockdown of DNMT1 and overexpression miR-152-3p showed that demethylation activated the expression of NF2. Furthermore, miR-152-3p directly targeted DNMT1. Both miR-152-3p overexpression and DNMT1 knockdown significantly induced cell apoptosis and inhibited invasive activity. This was also observed after NF2 overexpression.

Conclusions

These results indicated that miR-152-3p can inhibit glioma cell proliferation and invasion activities by decreasing DNMT1. The restoration of miR-152-3p may have therapeutic application in the treatment of GBM.

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