Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Πέμπτη 31 Μαρτίου 2016
Weight Regain Following Intentional Weight Loss in Older Adults
Abstract
Weight gain results from an imbalance of dietary intake and energy expenditure, and rates of overweight and obesity remain high in our society. Although weight loss is achievable, most subjects who participate in weight loss studies will regain weight and consequently recidivism remains a problem. The effectiveness of maintenance therapy is a continuing area of investigation as various dietary, behavioral, and physical activity strategies are either being investigated or are recommended. This chapter will also introduce mechanisms proposed for weight regain after intentional weight loss and the influence of weight regain on metabolic risk in adults.
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The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis
Abstract
Vitamin K is an enzyme cofactor required for the carboxylation of vitamin K-dependent proteins, several of which have been implicated in diseases of aging. Inflammation is recognized as a crucial component of many chronic aging diseases, and evidence suggests vitamin K has an anti-inflammatory action that is independent of its role as an enzyme cofactor. Vitamin K-dependent proteins and inflammation have been implicated in cardiovascular disease and osteoarthritis, which are leading causes of disability and mortality in older adults. The purpose of this review is to summarize observational studies and randomized trials focused on vitamin K status and inflammation, cardiovascular disease, and osteoarthritis. Although mechanistic evidence suggests a protective role for vitamin K in these age-related conditions, the benefit of vitamin K supplementation is controversial because observational data are equivocal and the number of randomized trials is few.
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The roles of serum PDCD5 in circulating CD133 positive cells of the patients with gastric cancer
Abstract
Cancer stem cells are responsible for the development, metastasis, recurrence, and drug resistance of cancer. More and more studies exhibited that the circulating CD133+ cells is a marker for the prognosis of various malignancies. Programmed cell death protein 5 (PDCD5) can promote apoptosis in different tumor cell types in response to various stimuli. However, the impact of PDCD5 on circulating CD133+ cells of gastric cancer patients remains unclear. In this study, we detected serum PDCD5 level in blood samples of the patients with gastric cancer by using ELISA. MTT assay, sphere assay, and wound healing assay were used to test the anti-tumor effects of rhPDCD5 on CD133+ cells in vitro. Lower serum levels of PDCD5 protein were identified in the gastric cancer patients that with CD133+ fraction more than 1.6 %. No difference between healthy controls and the gastric cancer patients that with CD133+ fraction less than 1.6 %. Serum PDCD5 was correlated with the favorable prognosis of patients with gastric cancer. In the last, we confirmed that rhPDCD5 could induce apoptosis, and inhibit the proliferation, colony formation, and mobility of CD133+ cells in vitro by suppressing MEK/ERK pathway. Serum PDCD5 could be considered as a potential drug for the gastric cancer patients with circulating CD133+ cells.
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Lentivirus-mediated somatic recombination and development of a novel mouse model for sporadic colorectal cancer
Abstract
In the present study, we have developed a novel mouse model for sporadic colorectal cancer (CRC) by utilizing APC conditional knockout (ApcCKO) mouse and lentivirus encoding Cre recombinase and a reporter gene (EGFP or LacZ). Lentiviral transduction of colonic crypt stem cells allowed for the long-term expression of reporter gene as well as excision of floxed Apc alleles which resulted in tumor development. Tumors represented adenoma stages along with the nuclear accumulation of β-catenin. Loss of E-cadherin at the cellular junctions and strong expression of Vimentin suggested the sign of active epithelial-mesenchymal transition (EMT). Moreover, nuclear staining of Ki67 inside epithelial cells of aberrant crypts demonstrated their higher proliferative nature. Erratic downstream signaling of activated Wnt/β-catenin, AKT/mTOR, and Notch pathways provided strong evidence towards the higher proliferative index of epithelial cells inside the aberrant crypts. These results do recapitulate the findings of previous APC mutant mouse models. Our model represents sporadic CRC more precisely as (i) tumors result from somatic mutations but not from germline; (ii) tumors develop in colon not in small intestine; (iii) few tumors develop at the distal end of colons. Additionally, our model allows for the long-term expression of the gene(s) which get integrated into the host cell genome and provides an ability to track the tumor growth. This article is protected by copyright. All rights reserved.
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Inter-regulation of IGFBP1 and FOXO3a unveils novel mechanism in ursolic acid-inhibited growth of hepatocellular carcinoma cells
Ursolic acid (UA), a natural pentacyclic triterpenoid, exerts anti-tumor effects in various cancer types including hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying this remain large...
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Characterization of DNA topoisomerase I in three SN-38 resistant human colon cancer cell lines reveals a new pair of resistance-associated mutations
DNA topoisomerase I (Top1) is a DNA unwinding protein and the specific target of the camptothecin class of chemotherapeutic drugs. One of these, irinotecan, acting through its active metabolite SN-38, is used ...
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Sustained delivery of siRNA/PEI complex from in situ forming hydrogels potently inhibits the proliferation of gastric cancer
Gastric cancer remains a major cause of mortality and morbidity worldwide. In recent years, gene-based therapeutic strategies were confirmed promising in cancer inhibition and attracted great attention. RNA in...
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Targeting of tubulin polymerization and induction of mitotic blockage by Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) in human cervical cancer HeLa cell
Microtubule Targeting Agents (MTAs) including paclitaxel, colchicine and vinca alkaloids are widely used in the treatment of various cancers. As with most chemotherapeutic agents, adverse effects and drug resi...
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Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice
Abstract
Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, and melanoma CSCs were capable of forming large tumors in humanized bone marrow, liver, thymus (hu-BLT) mice with fully reconstituted human immune system. In addition, major human immune subsets including NK cells, T cells, B cells, and monocytes were present in the spleen, bone marrow, peripheral blood, and tumor microenvironment. Similar to our previously published in vitro data, CSCs differentiated with split anergized NK cells prior to implantation in mice formed smaller tumors. Intravenous injection of functionally potent osteoclast-expanded NK cells inhibited tumor growth through differentiation of CSCs in humanized mice. In this review, we present current approaches, advances, and existing limitations in studying interactions of the immune system with the tumor, in particular NK cells with CSCs, using in vivo preclinical hu-BLT mouse model. In addition, we discuss the use of osteoclast-expanded NK cells in targeting cancer stem-like tumors in humanized mice—a strategy that provides a much-needed platform to develop effective cancer immunotherapies.
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DNA cytophotometric and histological analysis of N -butyl- N -(4-hydroxybutyl)nitrosamine-induced precancerous lesions of the bladder urothelium
Abstract
Purpose
The morphology of experimentally induced urinary bladder precancerous lesions has been differentially interpreted in the literature. Here, we aimed to describe the development of precancerous lesions of the urothelium histologically and by DNA cytophotometric analysis.
Methods
We induced precancerous lesions of the urothelium in 60 Wistar rats with 0.05 % N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) solution as drinking water. After exposure for 2–20 weeks, each animal received tap water for 2 weeks. Subsequently, six animals were killed every 2 weeks, and urothelia of three urinary bladders per time point were examined by DNA cytophotometry of smear preparations. An additional three urinary bladders were processed for histological analysis.
Results
Over 20 weeks, BBN exposure led to a significant difference between the control group and most of the BBN-exposed 2-week groups and to differences between most of these time point groups. After week 4, this difference included a higher proportion of cells with increased nuclear DNA content. At the end of the experiment, DNA cytophotometric values of the urothelium in experimental rats corresponded to those of poorly differentiated urothelial carcinomas.
Conclusions
Biologically significant stages of precancerous lesions were already detectable after 4 weeks of BBN exposure, considerably earlier than previously described in the literature.
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Totally laparoscopic versus laparoscopic-assisted total gastrectomy for upper and middle gastric cancer: a single-unit experience of 253 cases with meta-analysis
Abstract
Background
Laparoscopic-assisted total gastrectomy (LATG) is the most commonly used methods of laparoscopic gastrectomy for upper and middle gastric cancer. However, totally laparoscopic total gastrectomy (TLTG) is unpopular because reconstruction is difficult, especially for the intracorporeal esophagojejunostomy. We adopted TLTG with various types of intracorporeal esophagojejunostomy. In this study, we compared LATG and TLTG to evaluate their outcomes.
Methods
From March 2006 to September 2015, 253 patients with upper and middle gastric cancer underwent laparoscopic total gastrectomy (LTG), 145 patients underwent LATG, and 108 patients underwent TLTG. The clinicopathological characteristics and postoperative outcomes were retrospectively compared between the two groups. Furthermore, a systematic review and meta-analysis were conducted.
Results
The operation time and estimated blood loss were similar between the groups. There were no significant differences in first flatus, diet initiation, and postoperative hospital stay. The surgical complication rates were 17.2 % (25/145) and 13.9 % (15/108) in the LATG and TLTG groups, respectively. The meta-analysis also revealed no significant differences in the operation time, estimated blood loss, time to first flatus, length of hospital stay, overall, and anastomosis-related complications among the groups.
Conclusions
TLTG is a feasible choice for gastric cancer patients, with comparable results to the LATG approach.
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Survival prognostic factors in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment: analysis from a single oncological center
Abstract
Background
The aim of our study is to analyze survival, treatment-related morbidity, and safety in our experience of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Methods
Sixty-four patients were treated. Survival curves were calculated according to the Kaplan-Meier method. Univariate and multivariate analyses were done, and Cox's proportional hazard model was used to identify significant factors.
Results
Global 5-year overall survival was 55 %. Overall survival was also evaluated according to neutrophils to lymphocytes ratio and neutrophils to platelets ratio. Overall survival according to pre-operative serum albumin level shows a difference in the two groups (P < 0.05). We observed minor or no adverse events in 53 cases (89.8 %), while 3 patients (5.1 %) showed a grade III–IV complication and 3 post-operative deaths (5.1 %). Post-operative complication also influenced overall survival; patients in whom a minor complication occurred had a 3-year overall survival (OS) of 62 % vs. a 3-year OS of 28 % in patients who underwent a major complication (P < 0.1).
Conclusions
Hyperthermic intraperitoneal chemotherapy (HIPEC) could be a valid and feasible option for selected patients affected by gastrointestinal malignancies' peritoneal carcinomatosis.
Pre-operative parameters could be evaluated to choose patient who could benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
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Primary ectopic substernal thyroid cancer with trachea relapse: a case report and opinions of management
Abstract
Background
Ectopic substernal thyroid is a rare symptom of thyroid disease that entirely results from the developmental defects at early stages of thyroid embryogenesis and during its descent. Cases were seldom reported as primary ectopic substernal thyroid cancer, especially those with severe local invasion and tracheal relapse.
Case Presentation
In this report, the patient presented odynophagia and a sense of progressing swallowing obstruction. She underwent total thyroidectomy and lump resection. However, she refused to use postoperative radioactive iodine or take adjuvant external-beam radiotherapy, except for thyroid hormone replacement therapy. Tracheal relapse was observed after 6 months. Tracheal stent was used to reconstruct the airway twice.
Conclusions
Trachea invasion might be a worse independent predictor of prognosis than any others and should be given particular attention. Furthermore, tracheal stent might be a palliative option for patients with tracheal relapse.
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Efficacy of transanal tube placement after anterior resection for rectal cancer: a systematic review and meta-analysis
Abstract
Background
Anastomotic leakage is a serious complication that can occur after anterior resection of the rectum. There is a question regarding whether the placement of a transanal tube can decrease the rate of anastomotic leakage. The aim of this systematic review and meta-analysis was to evaluate the efficacy of transanal tube placement after anterior resection.
Methods
We searched three major databases (PubMed, Embase, and the Cochrane Library) up until January 2015 for studies evaluating the benefit of transanal tubes after anterior resection for rectal cancer. The primary outcome measure was the rate of clinical anastomotic leakage. Secondary outcome was the rate of reoperation. Pooled risk ratios (RR) with 95 % confidence intervals (CI) were obtained using random effects models.
Results
One randomized controlled trial and three observational studies involving 909 patients met inclusion criteria. Clinical anastomotic leakage occurred in 3.49 % (14 of 401) of patients with transanal tubes and 12.01 % (61 of 508) of patients without transanal tubes. Meta-analysis of the studies showed a lower risk of anastomotic leakage (RR, 0.32; 95 % CI 0.18–0.58) and reoperation related to leakage (RR, 0.19; 95 % CI 0.08–0.46) when the transanal tube was placed.
Conclusions
While studies are few and mostly observational, the data to date indicate that placement of a transanal tube decreases the rate of clinical anastomotic leakage and reoperation related to leakage. More studies are needed to confirm these findings.
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Accuracy of intraoperative frozen section for the evaluation of ovarian neoplasms: an institutional experience
Abstract
Background
Ovarian neoplasms are a heterogeneous group of tumors including surface epithelial, germ cell and sex cord stromal tumors with a subset having low malignant potential (borderline tumors). While the surgical management plan differs in different categories of tumors, preoperative diagnosis is seldom available. In these circumstances, the role of frozen section becomes invaluable. In the current study, we aimed to evaluate the accuracy of the frozen section of ovarian tumors in our setup.
Methods
It was a retrospective study involving 141 cases of ovarian tumors undergoing surgical resection with frozen section evaluation from January 2009 to December 2014. After gross examination, one to five blocks were prepared on the frozen section depending upon the size of the specimen. After frozen section reporting, specimens were processed routinely for final paraffin section evaluation. Results of frozen and paraffin sections were categorized in benign, borderline, and malignant, and accuracy of frozen section was determined.
Results
Out of 141 cases, 107 were diagnosed as benign on final (paraffin) examination, while 6 were borderline and 28 were malignant. Out of 107 benign cases, 45 were non-neoplastic cystic lesions of the ovary including endometriotic, follicular, and corpus luteal cysts. The most common benign neoplastic tumor was mature cystic teratoma (20 cases) followed by mucinous cystadenoma (19 cases), serous cystadenoma (14 cases), sex cord stromal tumors (8 cases), and Brenner tumor (1 case). Among borderline cases, four cases were serous and two of mucinous neoplasms. The most common malignant neoplasm was serous carcinoma (11 cases) followed by mucinous carcinoma (6 cases). The overall accuracy of frozen section diagnosis is above 99 %. The sensitivity and specificity for benign tumors were found to be 100 and 97 %, respectively. The sensitivity and specificity for borderline tumors was 83 and 99 %, respectively, while for malignant tumors, it was 96 and 100 %, respectively.
Conclusions
We found a high sensitivity and specificity of frozen section for the diagnosis of ovarian tumors and to determine its malignant potential. Therefore, it should always be used when the preoperative diagnosis is not definite to govern extent of surgical resection. However, under-diagnosis can occur in tumors of borderline category which can be minimized by increased sampling on the frozen section.
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Pin1 is related with clinical stage of papillary thyroid carcinoma
Abstract
Background
The context and aim of this article was to investigate whether the expression level of Pin1 was in association with the clinical stage of papillary thyroid carcinomas.
Methods
Seventy-two patients who had been treated at the Affiliated Hospital of Qingdao University – Yantai YuHuangDing Hospital during January 2013 to December 2014 were rolled in. The expression levels of Pin1 using immunohistochemistry were tested and were divided into four groups according to the different clinical stages and final scores based on multiplying intensity and percentage value of IHC results. Data was analyzed with SPSS 20.0, and P value <0.05 had been chosen as significant.
Results
Considered from analysis result, the Pin1 expression status statistically significantly correlated with the PTC clinical stages (χ 2 = 8.128, P = 0.043); as the clinical stage proceeded, the intensity of Pin1 in PTC cells had been increased. But we did not find any relationships between immunohistochemical staining results and other clinicopathological characteristics.
Conclusions
The PTC cells' intensity of Pin1 was in association with the clinical stage. The role played by Pin1 in PTC has been studied, and we need to further investigate the application of Pin1 in the treatment of PTC.
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Laparoscopic gastrectomy versus open gastrectomy for elderly patients with gastric cancer: a systematic review and meta-analysis
Abstract
Background
The objective of this study was to evaluate the feasibility, safety, and potential benefits of laparoscopic gastrectomy (LG) comparing with open gastrectomy (OG) in elderly population.
Methods
Studies comparing LG with OG for elderly population with gastric cancer, published between January 1994 and July 2015, were identified in the PubMed, Embase, and ISI Web of Science databases. Operative outcomes (intraoperative blood loss, operative time, and the number of lymph nodes harvested) and postoperative outcomes (time to first ambulation, time to first flatus, time to first oral intake, postoperative hospital stay, postoperative morbidity) were included and analyzed. The Newcastle-Ottawa Scale was used to assess the quality of the pooled study. A funnel plot was used to evaluate the publication bias.
Results
Seven studies totaling 845 patients were included in the meta-analysis. LG in comparison to OG showed less intraoperative blood loss (weighted mean difference (WMD) −127.47; 95 % confidence interval (CI) −202.79 to −52.16; P < 0.01), earlier time to first ambulation (WMD −2.07; 95 % CI −2.84 to −1.30; P < 0.01), first flatus (WMD −1.04; 95 % CI −1.45 to −0.63; P < 0.01), and oral intake (WMD −0.94; 95 % CI −1.11 to −0.77; P < 0.01), postoperative hospital stay (WMD −5.26; 95 % CI −7.58 to −2.93; P < 0.01), lower overall postoperative complication rate (odd ratio (OR) 0.39; 95 % CI 0.28 to 0.55; P < 0.01), less surgical complications (OR 0.47; 95 % CI 0.32 to 0.69; P < 0.01), medical complication (OR 0.35; 95 % CI 0.22 to 0.56; P < 0.01), incisional complication (OR 0.40; 95 % CI 0.19 to 0.85; P = 0.02), and pulmonary infection (OR 0.49; 95 % CI 0.26 to 0.93; P = 0.03). No significant differences were observed between LG and OG for the number of harvested lymph nodes. However, LG had longer operative times (WMD 15.73; 95 % CI 6.23 to 25.23; P < 0.01).
Conclusions
LG is a feasible and safe approach for elderly patients with gastric cancer. Compared with OG, LG has less blood loss, faster postoperative recovery, and reduced postoperative morbidity.
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Total femoral reconstruction with custom prosthesis for osteosarcoma
Abstract
Background
The aim of this study was to assess total femur replacement for the treatment of femoral osteosarcomas.
Methods
Between January 1995 and January 2012, 21 patients with a mean age of 21.8 years old were treated for femoral osteosarcomas with total femur replacement. All tumors were staged according to Enneking's criteria with one stage IIA case and 20 stage IIB cases.
Results
The survival of patients with osteosarcoma without metastases was 66.7 % at 5 years. Twelve patients were alive with an overall mean follow-up of 71.2 months, and the mean postoperative functional score was 72.5 % at their last follow-up. Superficial infection occurred in two patients, which were resolved by changing dressing and intravenous antibiotics. Deep infection occurred in one patient, which was an amputation by hip disarticulation. Patella fracture occurred in one patient, which was treated by open reduction and tension band fixation. Local recurrence was seen in one patient, which was an amputation by hip disarticulation. Pulmonary metastases were observed in nine patients and all the patients subsequently died of disease within 12 months. Aseptic loosening in tibial stem occurred in three patients, whose whole prosthesis was revised.
Conclusions
Total femur replacement is a reliable method to restore mechanical and functional results after extensive resection of the femur.
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Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype
Abstract
The phenotypic diversity of tumor-associated macrophages (TAMs) increases with tumor development. One of the hallmarks of malignancy is the polarization of TAMs from a pro-immune (M1) phenotype to an immunosuppressive (M2) phenotype. However, the molecular basis of this process is still unclear. Endostatin is a powerful inhibitor of angiogenesis capable of suppressing tumor growth and metastasis. Here, we demonstrate that endostatin induces RAW264.7 cell polarization toward the M1 phenotype in vitro. Endostatin has no effect on TAM numbers in vivo, but results in an increased proportion of F4/80+Nos2+ cells and a decreased proportion of F4/80+CD206+ cells. Overexpression of endostatin in RAW264.7 cells resulted in a decrease in the phosphorylation of STAT3, an increase in expression of vascular endothelial growth factor A and placental growth factor, and an increase in the phosphorylation of STAT1, IκBα and p65 proteins compared with controls. These results indicate that endostatin regulates macrophage polarization, promoting the M1 phenotype by targeting NF-κB and STAT signaling.
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4-1BB agonism: adding the accelerator to cancer immunotherapy
Abstract
The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8+ T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously "removing the brakes" via blocking inhibitory signaling and "stepping on the accelerator" via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.
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2′–5′ Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons
Abstract
Type I interferon (IFN-I) plays a critical role in antiviral and antitumor defense. In our previous studies, we showed that IFN-I-inducible 2′–5′ oligoadenylate synthetase-like 1 (OASL1) negatively regulates IFN-I production upon viral infection by specifically inhibiting translation of the IFN-I-regulating master transcription factor, interferon regulatory factor 7 (IRF7). In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 −/−) mice and transplantable syngeneic tumor cell models. We found that Oasl1 −/− mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8+ T cells (including tumor antigen-specific CD8+ T cells) and NK cells as well as CD8α+ DCs (the major antigen cross-presenting cells) were much more frequent (>fivefold) in the Oasl1 −/− mouse tumors. Furthermore, the cytotoxic effector cells in Oasl1 −/− mouse tumors seemed to be more functionally active. However, the proportion of immunosuppressive myeloid-derived suppressor cells within hematopoietic cells and of regulatory T cells within CD4+ T cells in Oasl1 −/− mouse tumors did not differ significantly from that of WT mice. Tumor-challenged Oasl1 −/− mice expressed increased levels of IFN-I and IRF7 protein in the growing tumor, indicating that the enhanced antitumor immune response observed in Oasl1 −/− mice was caused by higher IFN-I production in Oasl1 −/− mice. Collectively, these results show that OASL1 deficiency promotes the antitumor immune response, and thus, OASL1 could be a good therapeutic target for treating tumors.
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Adoptive transfer of osteoclast-expanded natural killer cells for immunotherapy targeting cancer stem-like cells in humanized mice
Abstract
Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment. In our recent studies, we have observed that oral, pancreatic, and melanoma CSCs were capable of forming large tumors in humanized bone marrow, liver, thymus (hu-BLT) mice with fully reconstituted human immune system. In addition, major human immune subsets including NK cells, T cells, B cells, and monocytes were present in the spleen, bone marrow, peripheral blood, and tumor microenvironment. Similar to our previously published in vitro data, CSCs differentiated with split anergized NK cells prior to implantation in mice formed smaller tumors. Intravenous injection of functionally potent osteoclast-expanded NK cells inhibited tumor growth through differentiation of CSCs in humanized mice. In this review, we present current approaches, advances, and existing limitations in studying interactions of the immune system with the tumor, in particular NK cells with CSCs, using in vivo preclinical hu-BLT mouse model. In addition, we discuss the use of osteoclast-expanded NK cells in targeting cancer stem-like tumors in humanized mice—a strategy that provides a much-needed platform to develop effective cancer immunotherapies.
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Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands
Abstract
Synthetic toll-like receptor (TLR) ligands stimulate defined immune cell subsets and are currently tested as novel immunotherapeutic agents against cancer with, however, varying clinical efficacy. Recent data showed the expression of TLR receptors also on tumor cells. In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy.
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AGK-BRAF gene fusion is a recurrent event in sporadic pediatric thyroid carcinoma
Abstract
Thyroid cancer is the fastest increasing cancer worldwide in all age groups. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in both adults and children. PTC genomic landscape has been extensively studied in adults, but information regarding sporadic pediatric patients is lacking. Although BRAF V600E mutation is highly prevalent in adults, this mutation is uncommon in pediatric cases. As adult and pediatric PTC is a mitogen-activated protein kinase-driven cancer, this altered pathway might be activated by different genetic events. The aim of this study was to investigate the occurrence of AGK-BRAF fusion gene, recently described in radiation-exposed pediatric PTC, in a cohort of exclusively sporadic pediatric PTC. The series consisted of 30 pediatric PTC younger than 18 years of age at the time of diagnosis and 15 matched lymph node metastases (LNM). Primary tumors and matched LNM were screened for the presence of the AGK-BRAF fusion transcript by RT-PCR. To confirm the identity of the amplified products, randomly selected samples positive for the presence of the fusion transcripts were sequenced. Moreover, BRAF dual-color, break-apart probes confirmed BRAF rearrangement. Overall, the AGK-BRAF fusion gene was detected in 10% (3/30) of primary tumors. For one of these cases, paired LNM was also available, which also shows the presence of AGK-BRAF fusion gene. This study described, for the first time, the presence of AGK-BRAF in sporadic pediatric PTC. Understanding the molecular events underlying pediatric PTC may improve preoperative diagnosis, allow molecular prognostication and define a therapeutic approach toward sporadic PTC patients.
This study described, for the first time, the presence of AGK-BRAF in sporadic pediatric PTC. Understanding the molecular events underlying pediatric PTC may improve preoperative diagnosis, allow molecular prognostication and define a therapeutic approach toward sporadic PTC patients.
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The real role of pseudokinase: linking diabetes to cancers
Abstract
A recent paper in Nature Communications shows that pseudokinase TRIB3 has a critical role in the development of diabetes-related cancers via interacting with SQSTM1, a selective autophagy receptor. Interrupting the TRIB3-SQSTM1 interaction using an α-helix peptide shows a significant antitumor effect both in normal and diabetic mice. This work provides a potential strategy against cancers in patients with diabetes.
Pseudokinase TRIB3 has a critical role in the development of diabetes-related cancers via interacting with SQSTM1, a selective autophagy receptor. Interrupting the TRIB3-SQSTM1 interaction, using an α-helix peptide shows a significant antitumor effect both in normal and diabetic mice.
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Can metronomic maintenance with weekly vinblastine prevent early relapse/progression after bevacizumab–irinotecan in children with low-grade glioma?
Abstract
The association of bevacizumab and irinotecan has been shown to display a quick efficacy in low-grade glioma (LGG), but most patients relapse within months after cessation of therapy. From October 2012 to March 2014, four patients have been treated with irinotecan–bevacizumab followed by a metronomic maintenance with weekly vinblastine to try to prevent relapses. After a median follow-up of 23 months after the end of the bevacizumab–irinotecan induction, no patient relapsed. These observations suggest that maintenance chemotherapy with weekly vinblastine after an induction by irinotecan–bevacizumab can improve progression-free survival in children with LGG.
Metronomic maintenance with vinblastine after irinotecan–bevacizumab induction may prevent relapse in children with low-grade glioma.
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ADH1B and ALDH2 are associated with metachronous SCC after endoscopic submucosal dissection of esophageal squamous cell carcinoma
Abstract
A previous genome-wide association study identified two novel esophageal squamous cell carcinoma (ESCC) susceptibility genes, ADH1B and ALDH2. We investigated the characteristics of ESCC, and the relationship between metachronous esophageal and/or pharyngeal squamous cell carcinoma (SCC) and the ADH1B & ALDH2 risk alleles. One hundred and seventeen superficial ESCC patients who underwent treatment with endoscopic submucosal dissection (ESD) were followed up using endoscopy for ≥12 months. First, we performed a replication analysis to confirm the relationship between ESCC and the ADH1B & ALDH2 risk alleles using 117 superficial ESCC cases and 1125 healthy controls. Next, we investigated the incidence and genetic/environmental factors associated with metachronous SCC development after ESD. We also analyzed the potential risk factors for metachronous SCC development using Cox's proportional hazards model. rs1229984 GG located on ADH1B and rs671 GA located on ALDH2 were significantly associated with ESCC progression (P = 7.93 × 10−4 and P = 1.04 × 10−5). Patients with rs1229984 GG, those with rs671 GA, smokers, heavy alcohol drinkers (44 g/day ethanol), and presence of multiple Lugol-voiding lesions (LVLs) developed metachronous SCC more frequently (P = 3.20 × 10−3, 7.00 × 10−4, 4.00 × 10−4, 2.15 × 10−2, and 4.41 × 10−3, respectively), with hazard ratios were 2.84 (95% confidence interval [CI] = 1.43–5.63), 4.57 (95% CI = 1.80–15.42), 4.84 (95% CI = 1.89–16.41), and 2.34 (95% CI = 1.12–5.31), respectively. Multiple logistic regression analysis revealed that rs1229984 GG, rs671 GA, and smoking status were independently associated with the risk of developing metachronous SCCs after ESD. Moreover, we found cumulative effects of these two genetic factors (rs1229984 GG and rs671 GA) and one environmental factor (tobacco smoking) which appear to increase metachrous SCCs after ESD of ESCC risk approximately nearly 12-fold. Our findings elucidated the crucial role of multiple genetic variations in ADH1B and ALDH2 as biomarkers of metachronous ESCC.
The main contribution of our paper is the characteristics of esophageal squamous cell carcinoma (ESCC), and the relationship between metachronous esophageal and/or pharyngeal squamous cell carcinoma (SCC) and the ADH1B & ALDH2 risk alleles. We show that rs1229984, rs671, and smoking status are independently associated with the risk of developing metachronous SCCs. In addition, individuals with three risk factors have a 11.95-fold higher risk for metachrous SCCs than those with no or one risk factors, indicating the cumulative effects of these variations.
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Robust Intensity Modulated Proton Therapy (IMPT) Increases Estimated Clinical Benefit in Head and Neck Cancer Patients
by Lisanne V. van Dijk, Roel J. H. M. Steenbakkers, Bennie ten Haken, Hans Paul van der Laan, Aart A. van 't Veld, Johannes A. Langendijk, Erik W. Korevaar
PurposeTo compare the clinical benefit of robust optimized Intensity Modulated Proton Therapy (minimax IMPT) with current photon Intensity Modulated Radiation Therapy (IMRT) and PTV-based IMPT for head and neck cancer (HNC) patients. The clinical benefit is quantified in terms of both Normal Tissue Complication Probability (NTCP) and target coverage in the case of setup and range errors.
Methods and MaterialsFor 10 HNC patients, PTV-based IMRT (7 fields), minimax and PTV-based IMPT (2, 3, 4, 5 and 7 fields) plans were tested on robustness. Robust optimized plans differed from PTV-based plans in that they target the CTV and penalize possible error scenarios, instead of using the static isotropic CTV-PTV margin. Perturbed dose distributions of all plans were acquired by simulating in total 8060 setup (±3.5 mm) and range error (±3%) combinations. NTCP models for xerostomia and dysphagia were used to predict the clinical benefit of IMPT versus IMRT.
ResultsThe robustness criterion was met in the IMRT and minimax IMPT plans in all error scenarios, but this was only the case in 1 of 40 PTV-based IMPT plans. Seven (out of 10) patients had relatively large NTCP reductions in minimax IMPT plans compared to IMRT. For these patients, xerostomia and dysphagia NTCP values were reduced by 17.0% (95% CI; 13.0–21.1) and 8.1% (95% CI; 4.9–11.2) on average with minimax IMPT. Increasing the number of fields did not contribute to plan robustness, but improved organ sparing.
ConclusionsThe estimated clinical benefit in terms of NTCP of robust optimized (minimax) IMPT is greater than that of IMRT and PTV-based IMPT in HNC patients. Furthermore, the target coverage of minimax IMPT plans in the presence of errors was comparable to IMRT plans.
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The Impact of the Overall Radiotherapy Time on Clinical Outcome of Patients with Nasopharyngeal Carcinoma; A Retrospective Study
by S. D. Stoker, R. Fles, C. Herdini, F. J. F. Rijntjes, M. Tjokronagoro, S. R. Dwidanarti, K. Sikorska, C. R. Leemans, M. K. Schmidt, A. Al-Mamgani, M. A. Wildeman, S. M. Haryana, S. R. Indrasari, I. B. Tan
PurposeIn Yogyakarta, nasopharyngeal carcinoma (NPC) shows a poor response to radiotherapy treatment. Previous study showed a prolonged overall treatment time (OTT), due to interruptions during treatment. This study explores the association between clinical outcome and OTT. Secondary, the relation between clinical outcome and disease stage, waiting time to radiation (WT) and chemotherapy schedule was explored.
MethodsIn this retrospective cohort, 142 patients who started curative intent radiotherapy for NPC between March 2009 and May 2014, with or without chemotherapy, were included. The median follow up time was 1.9 years. Data was collected on WT, OTT, disease stage, and chemotherapy schedule. Time factors were log-transformed. Clinical outcome was defined as therapy response, loco-regional control (LRC), disease free survival (DFS) and overall survival (OS).
ResultsThe median WT was 117 days (range 12–581) and OTT was 58 days (43–142). OTT and disease stage were not associated to any of the clinical outcome parameters. The log- WT was associated to poor therapy outcome (HR 1.68; 95% ci: 1.09–2.61), LRC (HR 1.66; 95% ci: 1.15–2.39), and DFS (HR 1.4; 95% ci: 1.09–1.81). In the multivariable analysis, significant hazard risk for poor therapy response, LRC, DFS and OS were seen for patients who didn't received concurrent chemotherapy.
ConclusionNot receiving concurrent chemotherapy showed the strongest risk for poor outcome. Since the choice of chemotherapy is related to a variety of factors, like the WT and patient's physical condition when radiation can start, careful interpretation is needed. Reason for not finding a relation between OTT and clinical outcome might be the low number of patients who finished radiotherapy within 7 weeks, or by a stronger detrimental effect of other factors.
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2′–5′ Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons
Abstract
Type I interferon (IFN-I) plays a critical role in antiviral and antitumor defense. In our previous studies, we showed that IFN-I-inducible 2′–5′ oligoadenylate synthetase-like 1 (OASL1) negatively regulates IFN-I production upon viral infection by specifically inhibiting translation of the IFN-I-regulating master transcription factor, interferon regulatory factor 7 (IRF7). In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 −/−) mice and transplantable syngeneic tumor cell models. We found that Oasl1 −/− mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8+ T cells (including tumor antigen-specific CD8+ T cells) and NK cells as well as CD8α+ DCs (the major antigen cross-presenting cells) were much more frequent (>fivefold) in the Oasl1 −/− mouse tumors. Furthermore, the cytotoxic effector cells in Oasl1 −/− mouse tumors seemed to be more functionally active. However, the proportion of immunosuppressive myeloid-derived suppressor cells within hematopoietic cells and of regulatory T cells within CD4+ T cells in Oasl1 −/− mouse tumors did not differ significantly from that of WT mice. Tumor-challenged Oasl1 −/− mice expressed increased levels of IFN-I and IRF7 protein in the growing tumor, indicating that the enhanced antitumor immune response observed in Oasl1 −/− mice was caused by higher IFN-I production in Oasl1 −/− mice. Collectively, these results show that OASL1 deficiency promotes the antitumor immune response, and thus, OASL1 could be a good therapeutic target for treating tumors.
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Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype
Abstract
The phenotypic diversity of tumor-associated macrophages (TAMs) increases with tumor development. One of the hallmarks of malignancy is the polarization of TAMs from a pro-immune (M1) phenotype to an immunosuppressive (M2) phenotype. However, the molecular basis of this process is still unclear. Endostatin is a powerful inhibitor of angiogenesis capable of suppressing tumor growth and metastasis. Here, we demonstrate that endostatin induces RAW264.7 cell polarization toward the M1 phenotype in vitro. Endostatin has no effect on TAM numbers in vivo, but results in an increased proportion of F4/80+Nos2+ cells and a decreased proportion of F4/80+CD206+ cells. Overexpression of endostatin in RAW264.7 cells resulted in a decrease in the phosphorylation of STAT3, an increase in expression of vascular endothelial growth factor A and placental growth factor, and an increase in the phosphorylation of STAT1, IκBα and p65 proteins compared with controls. These results indicate that endostatin regulates macrophage polarization, promoting the M1 phenotype by targeting NF-κB and STAT signaling.
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Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands
Abstract
Synthetic toll-like receptor (TLR) ligands stimulate defined immune cell subsets and are currently tested as novel immunotherapeutic agents against cancer with, however, varying clinical efficacy. Recent data showed the expression of TLR receptors also on tumor cells. In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy.
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4-1BB agonism: adding the accelerator to cancer immunotherapy
Abstract
The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8+ T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously "removing the brakes" via blocking inhibitory signaling and "stepping on the accelerator" via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.
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Radiation Therapy for Glioblastoma: Executive Summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline
Publication date: Available online 31 March 2016
Source:Practical Radiation Oncology
Author(s): Alvin R. Cabrera, John Kirkpatrick, John Fiveash, Helen A. Shih, Eugene Koay, Stephen Lutz, Joshua Petit, Samuel Chao, Paul D. Brown, Michael Vogelbaum, David Reardon, Arnab Chakravarti, Patrick Y. Wen, Eric Chang, Caroline Patton
PurposeTo present evidence-based guidelines for radiotherapy in treating glioblastoma not arising from the brainstem.Methods and MaterialsThe American Society for Radiation Oncology convened the Glioblastoma Guideline Panel to perform a systematic literature review investigating the following: (1) Is radiation therapy indicated after biopsy/resection of glioblastoma and how does systemic therapy modify its effects?; (2) What is the optimal dose-fractionation schedule for external beam radiation therapy after biopsy/resection of glioblastoma and how might treatment vary based on pretreatment characteristics such as age or performance status?; (3) What are ideal target volumes for curative-intent external beam radiotherapy of glioblastoma?; (4) What is the role of re-irradiation among glioblastoma patients whose disease recurs following completion of standard first-line therapy? Guideline recommendations were created using predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength.ResultsFollowing biopsy or resection, glioblastoma patients with reasonable performance status up to 70 years of age should receive conventionally fractionated radiotherapy (e.g., 60 Gy in 2-Gy fractions) with concurrent and adjuvant temozolomide. Routine addition of bevacizumab to this regimen is not recommended. Elderly patients (≥70 years old) with reasonable performance status should receive hypofractionated radiotherapy (e.g., 40 Gy in 2.66-Gy fractions); preliminary evidence may support adding concurrent and adjuvant temozolomide to this regimen. Partial brain irradiation is the standard paradigm for radiation delivery. A variety of acceptable strategies exist for target volume definition, generally involving two phases (primary and boost volumes) or one phase (single volume). For recurrent glioblastoma, focal re-irradiation can be considered in younger patients with good performance status.ConclusionsRadiotherapy occupies an integral role in treating glioblastoma. Whether and how radiotherapy should be applied depends on characteristics specific to tumor and patient, including age and performance status.
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Highlights of Children with Cancer UK’s Workshop on Drug Delivery in Paediatric Brain Tumours
Audrey Nailor, David A Walker, Thomas S Jacques, Kathy E Warren, Henry Brem, Pamela R Kearns, John Greenwood, Jeffrey I Penny, Geoffrey J Pilkington, Angel M Carcaboso, Gudrun Fleischhack, Donald Macarthur, Irene Slavc, Lisethe Meijer, Steven Gill, Stephen Lowis, Dannis G van Vuurden, Monica S Pearl, Steven C Clifford, A Sorana Morrissy, Delyan P Ivanov, Kévin Beccaria, Richard J Gilbertson, Karin Straathof, Jordan J Green, Stuart Smith, Ruman Rahman and John-Paul Kilday
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Body mass index and risk of colorectal cancer according to tumor lymphocytic infiltrate
ABSTRACT
Higher body mass index (BMI), higher body adiposity, and obesity have been associated with increased risk of colorectal cancer. Evidence suggests that excess energy balance may influence systemic immune and inflammatory status. Thus, we hypothesized that the positive association between BMI and colorectal cancer risk might differ according to colorectal carcinoma subtypes according to levels of histopathological lymphocytic reaction to tumor. We collected biennial questionnaire data on weight and baseline height information in two prospective cohort studies, the Nurses' Health Study (1980-2010) and the Health Professionals Follow-up Study (1986-2010). Utilizing duplication-method Cox proportional hazards regression models, we prospectively assessed the association between BMI and risk of colorectal cancer subtypes according to the degree of Crohn's-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, the overall lymphocytic reaction score, or T-cell [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+] density in tumor tissue. Statistical significance level was adjusted for multiple hypotheses testing by Bonferroni correction. During follow up of 1,708,029 men and women (over 3,346,752 person-years), we documented 1,436 incident rectal and colon cancer cases with available formalin-fixed paraffin-embedded tumor tissue materials and pathological immunity data. BMI was significantly associated with higher risk of overall colorectal cancer (Ptrend<0.001); however, the association of BMI with colorectal carcinoma risk did not significantly differ by the level of lymphocytic reaction or T-cell infiltration in tumor tissue status (Pheterogeneity>0.10). BMI may be associated with risk of colorectal cancer regardless of levels of lymphocytic response to tumor.
A vigorous immune response does not particularly hinder obesity-related cancer, according to new results. Being fat increases risk of colorectal cancer, and a vigorous T-cell response can improve colorectal cancer prognosis. These authors suspected that immune cells around the tumor may suppress the oncogenic pathway induced by excess fat. Using data from the Nurses' Health Study and the Health Professionals Follow-up Study, they investigated whether the impact of BMI varied depending on the degree of lymphocytic infiltration. BMI association with colorectal cancer, they determined, did not vary with lymphocytic reaction or the density of T-cells infiltrating the tumor tissue. This article is protected by copyright. All rights reserved.
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Host genetic influence on papillomavirus-induced tumors in the horse
Abstract
The common equine skin tumors known as sarcoids have been causally associated with infection by bovine papillomavirus (BPV). Additionally, there is evidence for host genetic susceptibility to sarcoids. We investigated the genetic basis of susceptibility to sarcoid tumors on a cohort of 82 affected horses and 270 controls genotyped on a genome-wide platform and two custom panels. A Genome Wide Association Study (GWAS) identified candidate regions on six chromosomes. Bayesian probability analysis of the same dataset verified only the regions on equine chromosomes (ECA) 20 and 22. Fine mapping using custom-produced SNP arrays for ECA20 and ECA22 regions identified two marker loci with high levels of significance: SNP BIEC2-530826 (map position 32,787,619) on ECA20 in an intron of the DQA1 gene in the Major Histocompatibility Complex (MHC) class II region (P=4.6e-06), and SNP BIEC2-589604 (map position 25,951,536) on ECA22 in a 200 kb region containing four candidate genes: PROCR, EDEM2, EIF6, and MMP24 (P=2.14e-06). The marker loci yielded odds ratios of 5.05 and 4.02 for ECA20 and ECA22, respectively. Associations between genetic MHC class II variants and papillomavirus-induced tumors have been reported for human papillomavirus (HPV) and cottontail rabbit papillomavirus (CRPV) infections. This suggests a common mechanism for susceptibility to tumor progression that may involve subversion of the host immune response. This study also identified a genomic region other than MHC that influenced papillomavirus-induced tumor development in the studied population. This article is protected by copyright. All rights reserved. © 2014 Wiley Periodicals, Inc.
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h-Prune is associated with poor prognosis and epithelial-mesenchymal transition in patients with colorectal liver metastases
Abstract
The prognosis of patients with colorectal liver metastases (CRLM) remains low despite advances in chemotherapy and surgery. The expression of h-prune (human homolog of Drosophila prune protein; HGNC13420), an exopolyphosphatase, is correlated with progression and aggressiveness in several cancers and promotes migration and invasion. We investigated the role of h-prune in CRLM. To investigate the role of h-prune, immunohistochemical analysis for h-prune was performed in 87 surgically resected specimens of colorectal liver metastases obtained between 2001 and 2009 at the Hiroshima University Hospital. Immunohistochemical analysis revealed positive staining for h-prune in 24 (28%) cases. The overall survival rate was significantly lower in h-prune-positive cases than in h-prune-negative cases (p = 0.003). Multivariate analysis showed that h-prune positivity was the only independent factor related to poor overall survival of patients after curative hepatectomy of CRLM. In vitro and in vivo, h-prune-knocked-down and h-prune-overexpressing cells were analyzed. In vitro, h-prune was associated with increased cell motility and upregulation of epithelial-mesenchymal transition (EMT) markers. In a mouse model, h-prune was associated with invasion of the tumor and distant metastases. In summary, h-Prune expression is a useful marker to identify high-risk patients for resectable colorectal liver metastasis. h-Prune expression is necessary for cancer cell motility and EMT and is associated with liver and lung metastasis in colorectal cancer cells. h-Prune could be a new prognostic marker and molecular target for CRLM.
Once colorectal cancer spreads to the liver, it becomes much more deadly, despite advances in treatment. Could there be a way to predict survival for these cancers? These authors investigated the protein h-prune, which is associated with tumor aggressiveness. When they analyzed specimens of colorectal liver tumor metastases, they found h-prune in 28% of cases, and these had poorer survival than patients whose tumors lacked h-prune. In cell culture, h-prune promoted cell motility and boosted production of proteins involved in metastasis, while in mice it increased tumor invasiveness. Thus, h-prune could be a valuable prognostic tool or therapeutic target. This article is protected by copyright. All rights reserved.
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Induction of Antigen-Specific TH9 Immunity Accompanied by Mast Cell Activation Blocks Tumor Cell Engraftment
ABSTRACT
The engraftment of circulating cancer cells at distal sites represents a key step in the metastatic cascade, yet remains an unexplored target for therapeutic intervention. In the present study, we establish that a vaccination strategy yielding antigen-specific TH9 responses induces long term host surveillance and prevents the engraftment of circulating cancer cells. Specifically, we show that vaccination with a recombinant CEA IgV-like N domain, formulated with the TLR3 ligand poly I:C, elicits CEA-specific TH9 responses, wherein IL-9 secreting TH cells act in concert with CEA N domain-specific antibodies as well as activated mast cells in preventing tumor cell engraftment. The development of this immune response was dependent on TLR3, since interference with the TLR3-dsRNA complex formation led to a reduction in vaccine-imparted protection and a shift in the resulting immune response towards a TH2 response. These findings point to the existence of an alternate tumor targeting immune mechanism that can be exploited for the purpose of developing vaccine therapies targeting tumor dissemination and engraftment. This article is protected by copyright. All rights reserved.
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Obesity, weight gain, and ovarian cancer risk in African American women
ABSTRACT
While there is growing evidence that higher adiposity increases ovarian cancer risk, little is known about its impact in African American (AA) women, the racial/ethnic group with the highest prevalence of obesity. We evaluated the impact of body mass index (BMI) one year before diagnosis and weight gain since age 18 years on ovarian cancer risk in a population-based case-control study in AA women in 11 geographical areas in the US. Cases (n=492) and age and site matched controls (n=696) were identified through rapid case ascertainment and random-digit-dialing, respectively. Information was collected on demographic and lifestyle factors, including self-reported height, weight at age 18, and weight one year before diagnosis/interview. Multivariable logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential covariates.
Obese women had elevated ovarian cancer risk, particularly for BMI≥40 kg/m2 compared to BMI <25 (OR=1.72, 95% CI: 1.12, 2.66; p for trend: 0.03). There was also a strong association with weight gain since age 18 (OR: 1.52; 95% CI: 1.07-2.16; p for trend: 0.02) comparing the highest to lowest quartile. In stratified analyses by menopausal status, the association with BMI and weight gain was limited to postmenopausal women, with a 15% (95% CI: 1.05-1.23) increase in risk per 5 kg/m2 of BMI and 6% (95% CI: 1.01-1.10) increase in risk per 5 kg of weight gain. Excluding hormone therapy users essentially did not change results. Obesity and excessive adult weight gain may increase ovarian cancer risk in post-menopausal AA women. This article is protected by copyright. All rights reserved.
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The association of soy food consumption with the risk of subtype of breast cancers defined by hormone receptor and HER2 status
ABSTRACT
Soy-food intake has previously been associated with reduced breast cancer risk. Epidemiological evidence for subgroups of breast cancer, particularly by menopausal and hormone receptor status, is less consistent. To evaluate the role of hormone receptor and menopausal status on the association between soy-food intake and breast cancer risk, we measured usual soy-food intake in adolescence and adulthood via food frequency questionnaire in 70,578 Chinese women, aged 40-70 years, recruited to the Shanghai Women's Health Study (1996-2000). After a median follow-up of 13.2 years (range:0.01-15.0), 1,034 incident breast cancer cases were identified. Using Cox models, we found that adult soy intake was inversely associated with breast cancer risk (hazard ratio-HR) for fifth versus first quintile soy protein intake=0.78; 95% confidence interval (CI):0.63-0.97). The association was predominantly seen in premenopausal women (HR=0.46; 95% CI:0.29-0.74). Analyses further stratified by hormone receptor status showed that adult soy intake was associated with significantly decreased risk of ER+/PR+ breast cancer in postmenopausal women (HR=0.72; 95% CI:0.53-0.96) and decreased risk of ER-/PR- breast cancer in premenopausal women (HR=0.46; 95% CI:0.22-0.97). The soy association did not vary by HER2 status. Furthermore, we found that high soy intake during adulthood and adolescence was associated with reduced premenopausal breast cancer risk (HR=0.53; 95% CI:0.32-0.88; comparing third versus first tertile) while high adulthood soy intake was associated with postmenopausal breast cancer only when adolescent intake was low (HR=0.63; 95% CI:0.43-0.91). Our study suggests that hormonal status, menopausal status, and time window of exposure are important factors influencing the soy-breast cancer association. This article is protected by copyright. All rights reserved.
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Do founder mutations characteristic of some cancer sites also predispose to pancreatic cancer?
ABSTRACT
Understanding of the etiology and risk of pancreatic cancer (PaCa) is still poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in 4 genes among PaCa patients and assesses their possible association with the risk of disease in Poland.
In the study 383 PaCa patients and 4000 control subjects were genotyped for founder mutations in: BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2 + 1G>A del5395, I157T), NBS1 (657del5) and PALB2 (509_510delGA, 172_175delTTGT). A statistically significant association between the 657del5 mutation and an increased risk of pancreatic cancer was observed for NBS1. The Slavic NBS1 mutation (657delACAAA) was detected in 8 of 383 (2,09%) unselected cases compared with 22 of 4000 (0.55%) controls (OR – 3,80, p = 0,002).
The PALB2 509_510delGA and 172_175delTTGT mutations combined were seen in 2 (0,52%) unselected cases of PaCa and in 8 (0,20%) of 4000 controls (OR – 2,61, p = 0,49). For BRCA1, the three mutations combined were detected in 4 of 383 (1,04%) PaCa patients and in 17 of 4000 (0,42%) controls (OR – 2,46, p = 0,20). CHEK2 mutations were not associated with the risk of pancreatic cancer (OR – 1,11 p= 0,72). The founder mutation in NBS1 (657del5) was associated with an increased risk of PaCa in heterozygous carriers, indicating that this mutation appears to predispose to cancer of the pancreas. By identifying pancreatic cancer risk groups, founder mutation testing in Poland should be considered for people at risk for PaCa. This article is protected by copyright. All rights reserved.
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2′–5′ Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons
Abstract
Type I interferon (IFN-I) plays a critical role in antiviral and antitumor defense. In our previous studies, we showed that IFN-I-inducible 2′–5′ oligoadenylate synthetase-like 1 (OASL1) negatively regulates IFN-I production upon viral infection by specifically inhibiting translation of the IFN-I-regulating master transcription factor, interferon regulatory factor 7 (IRF7). In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 −/−) mice and transplantable syngeneic tumor cell models. We found that Oasl1 −/− mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8+ T cells (including tumor antigen-specific CD8+ T cells) and NK cells as well as CD8α+ DCs (the major antigen cross-presenting cells) were much more frequent (>fivefold) in the Oasl1 −/− mouse tumors. Furthermore, the cytotoxic effector cells in Oasl1 −/− mouse tumors seemed to be more functionally active. However, the proportion of immunosuppressive myeloid-derived suppressor cells within hematopoietic cells and of regulatory T cells within CD4+ T cells in Oasl1 −/− mouse tumors did not differ significantly from that of WT mice. Tumor-challenged Oasl1 −/− mice expressed increased levels of IFN-I and IRF7 protein in the growing tumor, indicating that the enhanced antitumor immune response observed in Oasl1 −/− mice was caused by higher IFN-I production in Oasl1 −/− mice. Collectively, these results show that OASL1 deficiency promotes the antitumor immune response, and thus, OASL1 could be a good therapeutic target for treating tumors.
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Endostatin inhibits the growth and migration of 4T1 mouse breast cancer cells by skewing macrophage polarity toward the M1 phenotype
Abstract
The phenotypic diversity of tumor-associated macrophages (TAMs) increases with tumor development. One of the hallmarks of malignancy is the polarization of TAMs from a pro-immune (M1) phenotype to an immunosuppressive (M2) phenotype. However, the molecular basis of this process is still unclear. Endostatin is a powerful inhibitor of angiogenesis capable of suppressing tumor growth and metastasis. Here, we demonstrate that endostatin induces RAW264.7 cell polarization toward the M1 phenotype in vitro. Endostatin has no effect on TAM numbers in vivo, but results in an increased proportion of F4/80+Nos2+ cells and a decreased proportion of F4/80+CD206+ cells. Overexpression of endostatin in RAW264.7 cells resulted in a decrease in the phosphorylation of STAT3, an increase in expression of vascular endothelial growth factor A and placental growth factor, and an increase in the phosphorylation of STAT1, IκBα and p65 proteins compared with controls. These results indicate that endostatin regulates macrophage polarization, promoting the M1 phenotype by targeting NF-κB and STAT signaling.
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Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands
Abstract
Synthetic toll-like receptor (TLR) ligands stimulate defined immune cell subsets and are currently tested as novel immunotherapeutic agents against cancer with, however, varying clinical efficacy. Recent data showed the expression of TLR receptors also on tumor cells. In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy.
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4-1BB agonism: adding the accelerator to cancer immunotherapy
Abstract
The success of checkpoint inhibitors has validated immunomodulatory agents as a valuable class of anticancer therapeutics. A promising co-stimulatory immunologic target is 4-1BB, or CD137, a member of the tumor necrosis factor receptor superfamily. Ligation of 4-1BB induces an activating signal in CD8+ T cells and natural killer cells, resulting in increased pro-inflammatory cytokine secretion, cytolytic function, and antibody-dependent cell-mediated cytotoxicity. Targeting 4-1BB with agonistic monoclonal antibody (mAb) therapy demonstrated potent antitumor effects in murine tumor models. While anti-4-1BB mAbs have entered clinical trials, optimal efficacy of 4-1BB-targeted agents will inevitably come from combination therapeutic strategies. Checkpoint blockade is a compelling combination partner for 4-1BB agonism. This novel immunotherapeutic approach has the potential to active antitumor immune effectors by a complementary mechanism: simultaneously "removing the brakes" via blocking inhibitory signaling and "stepping on the accelerator" via co-stimulation. While important considerations should be given to 4-1BB-mediated toxicities, the current understanding of 4-1BB biology suggests it may play a key role in advancing the capabilities of cancer combination therapy.
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Oncologic and Functional Hazards of Obesity Among Patients With Locally Advanced Rectal Cancer Following Neoadjuvant Chemoradiation Therapy.
Objective: Obesity is a major health concern and risk factor for colorectal cancer that may also impact cancer treatment and outcomes. Rectal cancer response to chemoradiotherapy (CXRT) is associated with long-term survival and sphincter preservation. The purpose of this study was to evaluate the impact of obesity on treatment outcomes after neoadjuvant CXRT for rectal cancer. Methods: A retrospective cohort study of patients diagnosed (1993 to 2010) with cT3-4 or cN+ (by endorectal ultrasound, computed tomography, or magnetic resonance imaging) rectal carcinoma and treated with CXRT and total mesorectal excision was performed. Patients were classified as obese (body mass index >=30 kg/m2) or nonobese (body mass index
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Use of Metabolic Parameters as Prognostic Factors During Concomitant Chemoradiotherapy for Locally Advanced Cervical Cancer.
Objectives: To investigate the use of metabolic parameters as early prognostic factors during concomitant chemoradiotherapy for locally advanced cervix carcinoma (LACC). Materials and Methods: Between February 2008 and January 2012, 34 consecutive patients treated for LACC (International Federation of Gynecology and Obstetrics Staging System stage IB2-IVA) were included in a retrospective study. Treatment was standard of care: total dose of 45 Gy in 1.8 Gy per fraction with concurrent cisplatin followed by brachytherapy. 18F-FDG PET-CT modalities were performed before treatment and per-treatment (at 40 Gy). The analyzed parameters were: maximum standardized uptake value (SUVmax), SUVmax variations of the primary tumor between the 2 investigations (DSUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Survival was assessed according to early metabolic changes during chemoradiotherapy. Results: Median follow-up was 16 months (range, 5.3 to 32.4 mo). Median SUVmax before treatment was 13.15 (5.9 to 31) and was 5.05 (0 to 12) per-treatment. Median DSUVmax was 63.97% (0% to 100%). Median MTV before treatment was 44.16 mL (3.392 to 252.768 mL) and was 5.44 mL (0 to 69.88 mL) per-treatment. Median TLG before treatment was 249.82 mL (13.40 to 1931.10 mL) and was 20.14 mL (0 to 349.99 mL) per-treatment. At 40 Gy, SUVmax>=6, DSUVmax=5.6 mL, and TLG>=21.6 mL were significantly associated with overall survival and progression-free survival reduction. MTV predicted progression with a sensitivity of 80% and a specificity of 87.5% and TLG with a sensitivity of 80% and a specificity of 83.3%. Conclusions: PET-CT imaging could be useful as an early prognostic factor during treatment for LACC. MTV and TLG seem to provide better prognostic information than SUVmax and DSUVmax. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Use of a Magnetic Tracer for Sentinel Lymph Node Detection in Early-Stage Breast Cancer Patients: A Meta-analysis
Abstract
Background
Sentinel lymph node (SLN) dissection involves lymphatic mapping and selective removal of clinically negative lymph nodes at highest risk for harboring metastases. Lymphatic mapping is most often performed using radioisotope with or without blue dye (standard tracers). Sienna+®, a superparamagnetic iron oxide that can be detected using the Sentimag® magnetometer, is an alternative mapping agent to identify SLNs that has been investigated in five clinical trials. This meta-analysis was performed to determine if Sienna+® is non-inferior for SLN detection when compared to standard tracers.
Methods
Five clinical trials comparing Sienna+® to a standard technique were identified, and data from these studies were used to determine the agreement by Kappa statistic between Sienna+® and standard tracers in identifying SLNs and malignant SLNs. The trials included 1683 SLNs identified in 804 patients. Data from the studies were imbalanced, therefore additional agreement indices were utilized to compare techniques. The estimated difference between the techniques was analyzed and a margin of ≤5 % was used to determine non-inferiority.
Results
Agreement between the Sienna+® and standard tracers was strong for SLN detection by patient [prevalence-adjusted bias-adjusted kappa (PABAK) 0.94, 95 % confidence interval (CI) 0.89–0.98], moderate to substantial for SLN detection by node (PABAK 0.68, 95 % CI 0.54–0.82), and strong for the detection of malignant SLNs by patient (PABAK 0.89, 95 % CI 0.84–0.95). Sienna+® demonstrated non-inferiority compared with standard tracers.
Conclusions
The Sienna+® mapping agent is non-inferior to the standard method for SLN detection in patients with clinically node-negative breast cancer.
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Phosphodiesterase Type 5 Inhibitor Use Following Radical Prostatectomy is not Associated with an Increased Risk of Biochemical Recurrence
Abstract
Objective
Recently, conflicting findings have been reported on the effect of phosphodiesterase type 5 inhibitor (PDE5I) use on biochemical outcome following radical prostatectomy (RP). Thus, we investigated the impact of PDE5I treatment following RP, including therapeutic strategy, timing, duration, and drug type, on oncologic outcomes.
Methods
We analyzed records of 1082 patients who underwent bilateral nerve-sparing RP for clinically localized prostate cancer (PCa) between 2005 and 2014. Patients were categorized according to PDE5I use within 2 years following RP: non-user, on-demand, and rehabilitation (daily PDE5I use for ≥3 months) groups. Associations of various factors with biochemical recurrence (BCR) were analyzed using a Cox multivariate proportional hazards model. Propensity score-matched analysis was also performed.
Results
Among the subjects included in our study, PDE5I use was as follows: 253 (23.4 %) non-users, 475 (43.9 %) on-demand users, and 354 (32.7 %) in the rehabilitation. Multivariate analysis showed that PDE5I use was not a significant factor with regard to BCR risk [hazard ratio 1.47 (0.765–2.826); p = 0.248). Among the PDE5I users, a strategy for PDE5I use (on-demand vs. rehabilitation), timing of initiating PDE5I treatment following RP, duration of PDE5I use, and type of PDE5I used were not associated with an increased BCR risk in multivariate analyses (p = 0.304, p = 0.177, p = 0.332, and p = 0.105, respectively). In addition, PDE5I use was not associated with an increased risk of BCR among 478 matched cohorts (p = 0.672).
Conclusions
PDE5I treatment following RP was not found to have any significant impact on biochemical outcome regardless of therapeutic strategy, timing, duration, and drug type. Such findings suggest that PDE5I treatment following RP is oncologically safe.
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Long-Term Survival for Platinum-Sensitive Recurrent Ovarian Cancer Patients Treated with Secondary Cytoreductive Surgery Plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
Abstract
Background
To analyze the 5- and 7-year survival outcomes for women with platinum-sensitive recurrent epithelial ovarian cancer (REOC) who underwent secondary cytoreductive surgery (SCS) plus platinum-based hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods
From the electronic databases of the Department of Obstetrics and Gynecology at the Catholic University of the Sacred Heart of Rome and of the S. Orsola Hospital, University of Bologna, a consecutive series of REOC patients were selected using the following inclusion criteria: primary platinum-free interval (PFI-1) of 6 months or longer, completeness of secondary cytoreduction score (CC) of 1 or lower, minimum follow-up period of 48 months, Eastern Cooperative Group (ECOG) performance status at recurrence of 1 or less, and platinum-based HIPEC. Progression-free survival (PFS) and post-relapse survival (PRS) were calculated as the time between SCS + HIPEC and secondary recurrence or death, respectively.
Results
The final study population included 70 women with platinum-sensitive REOC. The median follow-up time was 73 months (range 48–128 months), and the median PFI-1 was 19 months (range 6–100 months). At the time of recurrence, the median peritoneal cancer index was 7 (range 1–21), and a CC score of 0 was achieved for 62 patients (88.6 %). As the HIPEC drug, we used oxaliplatin in 17 cases (38.6 %) and cisplatin in 43 cases (61.4 %). No postoperative deaths were observed, and the complication rate for grades 3 and 4 disease was 8.6 %. The median PFS duration was 27 months (range 5–104 months), and the 5- and 7-year PRS rates were respectively 52.8 and 44.7 %, (median PRS 63 months).
Conclusions
The current study demonstrated favorable 5- and 7-year PRS rates for platinum-sensitive REOC patients undergoing SCS + HIPEC, which encourages the inclusion of patients in randomized clinical trials for definitive conclusions to be drawn.
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Prognostic Significance of Lymph Node Ratio in Metastatic Cutaneous Squamous Cell Carcinoma of the Head and Neck
Abstract
Background
The prognostic variables in patients with metastatic cutaneous nodal squamous cell carcinoma (SCC) are well documented; however, the relationship between lymph node ratio (LNR) and outcome is not well researched. LNR represents the ratio of positive lymph nodes to total excised lymph nodes. We analyzed the correlation between LNR and outcome in patients who have undergone surgery for metastatic cutaneous nodal SCC of the head and neck.
Methods
Analysis was performed on retrospectively collected data, identifying patients who underwent surgery at Westmead Hospital, Sydney. Pathology reports were reviewed to ascertain LNR. A log-rank test identified a specific LNR value to compare time to disease progression (TTDP) and overall survival (OS). Multivariate proportional hazard regression models were used to review outcome.
Results
In total, 193 males and 45 females with a median of age 68 years were identified, with a mean recorded LNR of 0.15. On multivariate analysis, an LNR cutpoint of 0.21 was a significant predictor of decreased TTDP [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 4.40–0.49; p = 0.009] and OS (HR 2.75, 95 % CI 1.57–4.82; p < 0.001). Forty-nine of 238 patients (21 %) developed recurrence, with most recurrences being regional (29 of 49; 59 %). A total of 17 % of patients with an LNR ≤0.21 recurred compared with 40 % for patients with an LNR >0.21.
Conclusions
LNR is potentially an independent predictor of outcome in patients with metastatic cutaneous nodal SCC. The clinical relevance of this finding requires further validation.
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Prognostic Role of Multiple Lymphatic Basin Drainage in Sentinel Lymph Node-Negative Trunk Melanoma Patients: A Multicenter Study from the Italian Melanoma Intergroup
Abstract
Background
Multiple lymphatic basin drainage (MLBD) is frequently observed in patients with trunk melanoma undergoing sentinel lymph node (SLN) biopsy. Conflicting data regarding the prognostic association of MLBD in SLN-negative patients have been reported. This study aimed to investigate the prognostic role of MLBD in patients with negative SLN biopsy.
Methods
Retrospective data from 656 melanoma patients who underwent a SLN biopsy (1991–2012) at six Italian centers were gathered in a multicenter database. MLBD was defined as lymphoscintigraphic and intraoperative identification of an SLN in more than one nodal basin. Clinical and pathologic variables were recorded and analyzed for their impact on survival.
Results
SLN-negative patients with MLBD were at lower risk of melanoma recurrence [hazard ratio (HR) 0.73, P = 0.05) and melanoma-related death (HR 0.68, P = 0.001) independent of common staging features. Multivariable Cox analyses of disease-free interval (DFI) and disease-specific survival (DSS) showed that MLBD maintained a favorable role and ulceration an unfavorable role. Histologic regression was independently associated only with DFI. When survival was stratified according to presence of MLBD, histologic regression and Breslow thickness <2 mm were associated with improved DFI (5-year DFI: 96.9 vs. 66,1 %, respectively; HR 0.48, P < 0.001) and DSS (5-year DSS: 96.7 vs. 71.8 %, respectively; HR 0.52, P = 0.005) compared to patients without these three favorable parameters.
Conclusions
Patients with negative SLN biopsy results have better prognosis when two or more lymphatic basins are identified and analyzed. Further research is required to investigate the mechanisms behind this evidence.
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What Should We Expect After a Complete Cytoreduction at the Time of Interval or Primary Debulking Surgery in Advanced Ovarian Cancer?
Abstract
Purpose
To compare the impact, in terms of survival, of complete cytoreduction after primary debulking surgery (PDS) and interval debulking surgery (IDS) in patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stages III–IV) by reviewing the recent literature.
Methods
A search of the PubMed database during the last 7 years (2008–2014) was carried out looking for studies specifically showing data on median survival or disease-free survival after complete cytoreduction after either PDS or IDS.
Results
We found 24 publications including 14,182 patients with stages III to IV ovarian cancer. A total of 11871 patients (83.7 %) underwent PDS and 2311 (16.3 %) underwent interval debulking after neoadjuvant chemotherapy. A total of 4684 patients (33 %) were considered completely resected with microscopic residual disease. After PDS, the weighted average of median overall and progression-free survival was 43 and 17 months, respectively, for the whole group. After IDS, median and progression-free survival were 33 and 14 months. The rate of complete cytoreduction after PDS was inferior to the obtained in patients with IDS (27 vs. 59 %). However, the median survival in patients with complete cytoreduction with primary cytoreduction was 23 months longer than in the group with interval debulking (69 vs. 45 months).
Conclusions
Complete cytoreduction after IDS yields a inferior outcome in terms of median survival than PDS of almost 2 years. Despite the higher rate of complete resection, IDS apparently fails to improve the results obtained by primary debulking.
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Metformin Increases Overall Survival in Patients with Diabetes Undergoing Surgery for Colorectal Cancer
Abstract
Background
Emerging evidence suggests that metformin decreases the risk of developing colorectal cancer in patients with diabetes, but only few studies have examined potential survival benefits after surgery for colorectal cancer (CRC). The purpose of the study was to examine the association between diabetes and overall survival after resection for CRC. Furthermore, the association between antidiabetic medication and overall survival was examined.
Methods
Patients diagnosed with CRC between January 1, 2003 and December 31, 2012 were identified through the Danish Colorectal Cancer Group's National Clinical Database (DCCG). The Danish National Patient Register (NPR) records all hospital contacts in Denmark, and the diagnosis of diabetes was identified by combining NPR data with use of antidiabetic drugs identified through the Danish National Prescription Registry and DCCG. The Kaplan–Meier estimator and the Cox regression model adjusted for important clinical risk factors were used.
Results
A total of 30,493 patients were included in the study, of which 3391 were diagnosed with diabetes and 1962 were treated with metformin. The adjusted HR of all-cause mortality for the diabetes group was 1.12 (1.06–1.18, p < 0.0001) compared with the nondiabetes group. The adjusted HR was 0.85 (0.73–0.93, p = 0.03) for the metformin-treated group compared with the insulin-treated group.
Conclusions
A 12 % increase in all-cause mortality among patients with CRC and diabetes was found. Treatment with metformin was associated with a 15 % decreased all-cause mortality compared with patients with insulin-treated diabetes.
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Risk of Local Recurrence of Benign and Borderline Phyllodes Tumors: A Danish Population-Based Retrospective Study
Abstract
Purpose
To determine the recurrence rate of benign and borderline phyllodes tumors (PTs) of the breast, the association between the size of resection margin and risk of recurrence and the risk of progression of histological grading at recurrence.
Methods
Nationwide retrospective study on Danish women aged 18 years or older, operated from 1999 to 2014, with resected benign or borderline PTs. Information on age, size of primary tumor and recurrence, histological grade, surgical treatment, margin size, and local recurrence were collected from the national Danish Pathology Register.
Results
A total of 479 cases were identified; 354 benign (74 %), 89 borderline (19 %), 6 uncertain histological grading (1.2 %), and 30 possibly PT (6 %). The mean age at presentation was 45.6 years (range 18–85), the mean tumor size was 3.5 cm (range 0.5–21), and the mean follow-up time was 98 months (range 1.1–192). We identified 30 local recurrences, i.e., a recurrence rate of 6.3 %. Twenty-three recurrences had similar or lower histological grading than the primary tumor, one primary benign PT recurred as a tumor with unclear diagnosis, and one primary borderline PT recurred as malignant. The number of recurrences was too low, and the information on the size of the closest resection margin was too sparse to estimate an adequate margin size for excision of nonmalignant PTs.
Conclusions
The recurrence rate of PTs was considerably lower than previously stated in literature. No apparent pattern of progression in histological grading was found. The results do not justify wide excision margins of nonmalignant phyllodes tumors of the breast.
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Single-Institution Experience with Irreversible Electroporation for T4 Pancreatic Cancer: First 50 Patients
Abstract
Background
Irreversible electroporation (IRE) for treatment of locally advanced pancreatic tumors is garnering increasing attention. This study was conducted to determine perioperative morbidity and mortality for locally advanced pancreatic cancer.
Methods
Prospective data of 50 consecutive patients receiving IRE for T4 lesions at a single tertiary center were analyzed. The primary end point was Clavien–Dindo complications at 90 days, and the secondary outcomes were survival and recurrence.
Results
A total of 50 patients underwent 53 IRE procedures for primary treatment (n = 29) or margin extension (n = 24), and 47 patients had adenocarcinoma. Six patients died within 90 days after the procedure (5 in the primary control group). Mortality occurred a median of 26 days (range, 8–42 days) after the procedure. Five patients in both the margin-extension and primary control groups experienced grade 3 or 4 morbidity (p = 0.739). The incidences of grades 3 to 5 complications did not differ significantly based on the adjustable parameters of IRE, tumor size, or primary treatment versus margin extension. After a median follow-up period of 8.69 months [interquartile range (IQR), 0.26–16.26 months], the median overall survival period for the primary control group was 7.71 months [95 % confidence interval (CI), 6.03–12.0 months) and was not reached in the margin-extension group (p = 0.01, log-rank).
Conclusions
At the authors' center, the mortality rate after IRE was higher than reported in other series, with the majority occurring in the primary control group. Major morbidity trended around upper gastrointestinal bleeding, visceral ulcerations/perforations, and portal vein thromboses. This favors further investigation of the safety and efficacy of IRE.
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Prospective Randomized Study to Compare Lymphocele and Lymphorrhea Control Following Inguinal and Axillary Therapeutic Lymph Node Dissection With or Without the Use of an Ultrasonic Scalpel
Abstract
Background
Many attempts to prevent lymphatic complications following therapeutic lymph node dissection (TLND) have included modifications in surgical techniques through the use of ultrasonic scalpels (USS) or lymphostatic agents. Previous randomized studies that enrolled heterogeneous groups of patients attempted to confirm the efficacy of such techniques. The aim of the present study was to evaluate the efficacy of the USS following TLND.
Methods
Between 2009 and 2013, patients undergoing inguinal or axillary TLND or completion lymph node dissection after positive sentinel lymph node biopsy for melanoma, squamous cell carcinoma or sarcoma were randomized into two surgical dissection technique groups. In the USS dissection arm, surgery was conducted using a USS. These were compared with a control group whereby ligation and monopolar electrocautery was utilized. For axillary dissection, a standardized level III lymphadenectomy was performed. A complete inguinal lymphadenectomy including Cloquet's node was performed, and at the end of the procedure a Redon suction drain was routinely placed in the axilla and groin. The primary endpoint was to compare the time to drain removal in both groups, while the secondary endpoint was to evaluate the rate of complications (infection, fistula, lymphocele formation, wound dehiscence, lymphedema) between the two groups.
Results
A total of 80 patients were enrolled in this trial; 40 patients were randomly assigned to both the USS group and the control (C) group. No significant differences were observed in terms of duration of drainage (USS: 31 ± 20 vs. C: 32 ± 18; p = 0.83); however, a significantly increased rate of lymphedema (defined as an increased circumference of the operated limb of more than 10 %) was identified in the USS group (USS: 50 % vs. C: 27.5 %; p = 0.04). No other significant differences were recorded for postoperative complications, including surgical site infection (USS: 5 % vs. C: 7.5 %; p = 0.68), lymphatic fistula (USS: 5 % vs. C: 2.5 %; p = 0.62), lymphocele (USS: 32.5 % vs. C: 22.5 %; p = 0.33), and hematoma (USS: 5 % vs. C: 2.5 %; p = 0.62).
Conclusion
The use of USS failed to offer any significant reduction in length of drain usage and operative complication, but it seems to increase the rate of lymphedema formation.
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