Volume 17, Issue 1, January 2016, pages 20-26<br/>10.1080/15384047.2015.1108484<br/>Kailin Zou
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Σάββατο 6 Φεβρουαρίου 2016
Krüppel-like factor 2 promotes cell proliferation in hepatocellular carcinoma through up-regulation of c-myc
Absence of germline CDKN2A mutation in Sicilian patients with familial malignant melanoma: Could it be a population-specific genetic signature?
Volume 17, Issue 1, January 2016, pages 83-90<br/>10.1080/15384047.2015.1108494<br/>Sara Di Lorenzo
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A case report of primary cardiac capillary hemangioma
Volume 17, Issue 1, January 2016, pages 11-13<br/>10.1080/15384047.2015.1109391<br/>Jidan Fan
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The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells
Volume 17, Issue 1, January 2016, pages 1-10<br/>10.1080/15384047.2015.1121348<br/>Natalia Gawlik-Rzemieniewska
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First-line treatment with hepatic arterial infusion plus capecitabine vs capecitabine alone for elderly patients with unresectable colorectal liver metastases
Volume 17, Issue 1, January 2016, pages 14-19<br/>10.1080/15384047.2015.1108487<br/>Xiaodong Li
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C. elegans and mutants with chronic nicotine exposure as a novel model of cancer phenotype
Volume 17, Issue 1, January 2016, pages 91-103<br/>10.1080/15384047.2015.1108495<br/>Rajani Kanteti
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Long noncoding RNA MEG3 is downregulated in cervical cancer and affects cell proliferation and apoptosis by regulating miR-21
Volume 17, Issue 1, January 2016, pages 104-113<br/>10.1080/15384047.2015.1108496<br/>Jun Zhang
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Antitumor effects and molecular mechanisms of ponatinib on endometrial cancer cells harboring activating FGFR2 mutations
Volume 17, Issue 1, January 2016, pages 65-78<br/>10.1080/15384047.2015.1108492<br/>Do-Hee Kim
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Circulating miR-21-5p and miR-148a-3p as emerging non-invasive biomarkers in thymic epithelial tumors
Volume 17, Issue 1, January 2016, pages 79-82<br/>10.1080/15384047.2015.1108493<br/>Teresa Bellissimo
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Combination with vorinostat overcomes ABT-263 (navitoclax) resistance of small cell lung cancer
Volume 17, Issue 1, January 2016, pages 27-35<br/>10.1080/15384047.2015.1108485<br/>Wataru Nakajima
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Fat4 suppression induces Yap translocation accounting for the promoted proliferation and migration of gastric cancer cells
Volume 17, Issue 1, January 2016, pages 36-47<br/>10.1080/15384047.2015.1108488<br/>Liangang Ma
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Tangeretin derivative, 5-acetyloxy-6,7,8,4′-tetramethoxyflavone induces G2/M arrest, apoptosis and autophagy in human non-small cell lung cancer cells in vitro and in vivo
Volume 17, Issue 1, January 2016, pages 48-64<br/>10.1080/15384047.2015.1108491<br/>Yi Rong Li
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Menin localization in cell membrane compartment
Volume 17, Issue 1, January 2016, pages 114-122<br/>10.1080/15384047.2015.1108497<br/>Xin He
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The influence of dose distribution on treatment outcome in the SCOPE 1 oesophageal cancer trial
The first aim of this study was to assess plan quality using a conformity index (CI) and analyse its influence on patient outcome. The second aim was to identify whether clinical and technological factors incl...
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Gasless transumbilical laparoscopic-assisted appendectomy as a safe and cost-effective alternative surgical procedure for mild acute appendicitis
Abstract
Purpose
Several reports have demonstrated the effectiveness and feasibility of single incisional transumbilical laparoscopic-assisted appendectomy (TULAA). We developed a modified TULAA technique, gasless-TULAA, which involves lifting the abdominal wall with a retractor, without pneumoperitoneum or another incision.
Methods
We assessed the surgical outcomes of 257 patients treated for appendicitis in our hospital between 2005 and 2013. In a preoperative comprehensive evaluation, appendicitis without abscess was defined as mild appendicitis (mild appendicitis group: MAG), and appendicitis with abscess was defined as severe appendicitis (severe appendicitis group: SAG). The clinical outcomes were compared with those in other published reports. The cost-effectiveness of gasless-TULAA was compared with that of conventional multiport laparoscopic appendectomy (CMLA) in our hospital.
Results
In MAG (n = 228), the operation time and postoperative hospital stay were 46.9 ± 22.7 min and 2.6 ± 1.2 days, respectively. The gasless-TULAA was completed without trocars in 91.2 % of patients. The surgical outcomes of SAG were significantly worse than those of MAG (p < 0.001). The surgical cost of gasless-TULAA was significantly lower than that of CMLA (p < 0.001).
Conclusion
Gasless-TULAA is a cost-effective, safe, and readily available surgical technique for mild appendicitis, which can obviate the need for specialized equipment.
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Laparoscopic Roux-en-Y gastric bypass in obese Korean patients: efficacy and potential adverse events
Abstract
Purpose
This study aimed to evaluate the medium-term efficacy and adverse events of laparoscopic Roux-en-Y gastric bypass (LRYGB) performed at a single center in Korea.
Methods
The records of 412 consecutive patients who underwent LRYGB between January 2011 and February 2014 were retrospectively reviewed. The preoperative demographics, surgical outcomes, and follow-up data including anthropometrics indices and late complications were analyzed.
Results
The mean preoperative body mass index was 38.0 ± 5.8 kg/m2 and 338 patients (82.0 %) had at least one obesity-related comorbidity. Seven patients (1.7 %) developed severe complications requiring invasive intervention or reoperation. The %EWL of the eligible patients was 63.1, 74.3, 79.2, 65.4, and 89.8 % at 6, 12, 18, 24, and 36 months, respectively. Diabetes was resolved in 63.5 % of the followed up patients. Twenty-two out of 256 patients (8.6 %) with available follow-up data failed to achieve %EWL ≥50 % by 12 months after the surgery. The most frequent late complications were marginal ulcers (24.5 %) and anemia (18.0 %).
Conclusion
LRYGB achieves excellent weight loss and significant short- to medium-term comorbidity resolution in Korean obese patients with acceptable perioperative risks. However, late complications including marginal ulcers and nutritional deficiencies are not negligible. Therefore, regular and lifelong surveillance is mandatory in patients undergoing LRYGB.
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Early-phase peritoneal drainage and lavage in a rat model of severe acute pancreatitis
Abstract
Purpose
To evaluate the effects of early-phase drainage on the survival rates and pancreatic pathological changes associated with severe acute pancreatitis (SAP) in a rat model.
Methods
Sprague–Dawley rats were divided into the following groups: SAP model (control), early drainage and delayed drainage. The 24-h survival rates were compared among the groups. In addition, the serum and ascites concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α were measured, and pancreatic pathological changes were observed.
Results
The survival rate significantly improved in the early drainage group. Compared with that observed in the control group, the serum TNF-α and IL-8 concentrations in the early drainage group decreased, while the serum IL-10 levels increased, and the ascites concentrations of IL-1β, IL-6, IL-8 and TNF-α decreased, while that of IL-10 increased significantly. In the delayed drainage group, only the ascites concentrations of TNF-α decreased. Meanwhile, the pancreatic pathological changes at 3, 6 and 24 h worsened in the early drainage group; however, the pancreatic lesions in the early drainage group were less mild than those seen in the control group.
Conclusions
Rebalancing the cytokine levels in ascites after early drainage may be a key factor for enhancing the survival rate in rats.
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Current status of and perspectives regarding neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma
Abstract
The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.
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Significance of the mucinous component in the histopathological classification of colon cancer
Abstract
Purpose
Mucinous carcinoma is often independently classified as a histological type of colon cancer, but there are currently no established diagnostic criteria. The relationship between the proportions of mucinous components to the oncological outcomes was examined to determine whether mucinous carcinoma should be classified as an independent histological type.
Methods
The study group comprised 1,038 patients with colon cancer. The relationships between the survival rates and recurrence patterns with the mucinous component area ratio (MC area ratio) and clinical variables were evaluated.
Results
Tumors were classified into three groups: Group 1 (MC area ratio, 0 %), Group 2 (1–49 %), and Group 3 (≥50 %). Of the 1038 tumors studied, 877 (84 %) were classified as Group 1, 123 (12 %) as Group 2, and 38 (4 %) as Group 3. The tumor size was significantly larger in Group 3, and an increased MC area ratio was significantly related to a higher proportion of right-sided tumors. Among patients with stage II or III disease, stage III disease, poorly differentiated adenocarcinoma, and no adjuvant chemotherapy were poor prognostic factors. There was no relationship between the MC area ratio and the survival or recurrence pattern.
Conclusion
Mucinous carcinoma does not need to be classified as a separate histological type from ordinary differentiated adenocarcinoma.
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A case-matched comparison of single-incision versus multiport laparoscopic right colectomy for colon cancer
Abstract
Purpose
To minimize the parietal trauma associated with multiple surgical access sites, single-incision laparoscopic surgery for colectomy has been emerging with the improvements in instrumentation and surgical techniques. The purpose of this study was to compare the clinicopathological outcomes between single-incision laparoscopic right colectomy (SILC) and multiport laparoscopic right colectomy (MLC) for right colon cancer.
Methods
Thirty-five consecutive patients undergoing SILC from a prospective single-institution database were case matched according to demographic data to an equivalent number of patients who underwent MLC.
Results
The SILC patients had decreased scores for maximal pain assessed by a visual analog scale on postoperative days 1 and 3, and used fewer postoperative systemic narcotics. The median length of the hospital stay for the SILC patients was significantly shorter compared with the MLC patients. The postoperative morbidity rates were similar between the groups. The oncological findings were not significantly different between the groups.
Conclusion
SILC is a feasible and safe alternative to conventional MLC for patients with right colon cancer.
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Impact of synthetic ghrelin administration for patients with severe body weight reduction more than 1 year after gastrectomy: a phase II clinical trial
Abstract
Purpose
Ghrelin is mainly secreted from the stomach and plays a role in appetite, weight gain, and the promotion of a positive energy balance. The levels of ghrelin decrease immediately after gastrectomy. We herein investigated the effect of the administration of synthetic ghrelin to treat postoperative severe weight loss in a prospective, one-arm clinical trial to develop new strategies for weight gain.
Methods
Ten patients (four distal gastrectomy and six total gastrectomy) received ghrelin treatment. Eligibility criteria included patients who underwent gastrectomy more than 1 year previously and 15 % body weight loss from the preoperative weight or a body mass index under 19. Synthetic human ghrelin (3 μg/kg) was administered to the patients twice a day for 1 week. Oral intake of calories, appetite [evaluated using the visual analog scale (VAS)], and body weight before and during administration of ghrelin were compared.
Results
There was a significant difference in the oral food intake before and during treatment (before treatment: 1236 ± 409 kcal vs. during treatment: 1398 ± 365 kcal, p = 0.039), and the VAS for appetite significantly improved with each day of ghrelin administration (p < 0.05). Significant amounts of body weight were gained (39.5 ± 6.8 vs. 40.1 ± 6.9, p = 0.037).
Conclusions
The administration of synthetic ghrelin improved the food intake and was effective for treating appetite loss and body weight loss. Synthetic ghrelin may be a promising new therapy for severe body weight loss following gastrectomy.
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Minimally invasive esophagectomy performed with the patient in a prone position: a systematic review
Abstract
Purpose
We reviewed the surgical results of minimally invasive esophagectomy for esophageal cancer, performed with the patient in a prone position (MIE-PP), to assess its benefits.
Methods
A systematic literature search was performed, and articles that fully described the surgical results of MIE-PP were selected. Parameters such as operative time, blood loss, and postoperative outcomes were compared with those obtained for open transthoracic esophagectomy (OE) and minimally invasive esophagectomy in a lateral decubitus position (MIE-LP).
Results
The conversion rate from MIE-PP to open surgery was very low. MIE-PP was associated with longer operative time and lower blood loss than OE. Although studies from a single institution did not show an apparent difference in morbidity or mortality among the three operative groups, results of a multicenter randomized controlled trial showed a reduction in pulmonary infection and recurrent laryngeal nerve palsy in MIE-PP, compared with OE. The benefits of MIE-PP vs. those of MIE-LP remain controversial.
Conclusion
Theoretically, the operative results of MIE-PP might be better than those of MIE-LP for patients with esophageal cancer; however, studies have not yet verified this. Further clinical studies are required to establish whether the advantages of MIE-PP can be translated into clinical outcome.
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Potential mechanisms mediating improved glycemic control after bariatric/metabolic surgery
Abstract
Conservative medical treatment for morbid obesity generally fails to sustain weight loss. On the other hand, surgical operations, so-called bariatric surgery, have evolved due to their long-term effects. The global increase in the overweight population and the introduction of laparoscopic surgery have resulted in the use of bariatric surgery spreading quickly worldwide in recent years. Recent clinical evidence suggests that bariatric surgery not only reduces body weight, but also improves secondary serious diseases, including type 2 diabetes mellitus, in so-called metabolic surgery. Moreover, several potential mechanisms mediating the improvement in glycemic control after bariatric/metabolic surgery have been proposed based on the animal and human studies. These mechanisms include changes in the levels of gastrointestinal hormones, bacterial flora, bile acids, intestinal gluconeogenesis and gastrointestinal motility as well as adipose tissue and inflammatory mediators after surgery. The mechanisms underlying improved glycemic control are expected to accelerate the promotion of both metabolic and bariatric surgery. This article describes the current status of bariatric surgery worldwide and in Japan, reviews the accumulated data for weight loss and diabetic improvements after surgery and discusses the potential mechanisms mediating improved glycemic control.
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Importance of the intraoperative appearance of preserved parathyroid glands after total thyroidectomy
Abstract
Purpose
Hypocalcemia after total thyroidectomy is a concern for every endocrine surgeon. We conducted this study to establish the value of the macroscopic appearance of preserved parathyroid glands after thyroidectomy in predicting post-thyroidectomy hypocalcemia.
Methods
In 2009, 237 patients underwent total thyroidectomy at our hospital. The macroscopic appearance of the preserved parathyroid glands was recorded and the serum calcium and intact parathyroid hormone levels were measured postoperatively.
Results
Thirteen patients (5.5 %) had transient hypocalcemia and 1 patient (0.4 %) had permanent hypocalcemia. All of the hypocalcemia patients with more than one normal preserved parathyroid had asymptomatic transient hypocalcemia that did not require medication. The sensitivity, specificity, positive predictive value, and negative predictive value for hypocalcemia with at least 1 normal preserved parathyroid were 78.6, 79.4, 19.3, and 98.3 %, respectively.
Conclusion
The macroscopic appearance of preserved parathyroid glands and the number of well-preserved parathyroid glands after thyroidectomy proved effective in predicting post-thyroidectomy hypocalcemia.
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Single-incision laparoscopic cholecystectomy versus traditional laparoscopic cholecystectomy performed by a single surgeon: findings of a randomized trial
Abstract
Purposes
Traditional laparoscopic cholecystectomy (TLC) is performed widely; however, single-incision cholecystectomy (SILC) has been proposed as a better and less traumatic procedure.
Methods
In this prospective, double-blinded, randomized study, patients were randomized to undergo either elective SILC or TLC. The primary endpoint was the level of pain after surgery and the secondary endpoints were complications, cosmetic outcomes, and patient satisfaction.
Results
A total of 59 patients were enrolled (SILC, n = 30; TLC, n = 29). The median operative time was longer for the SILC group (55 vs. 40 min; P < 0.0001). Patients in the SILC group had a lower median VAS pain score 4 h after surgery (20 mm for the TLC group vs. 15 mm for the SILC group). Complications were distributed equally. Twenty-eight of the 30 patients in the SILC group vs. 23 of the 29 patients in the TLC group were very satisfied with their operation (P = 0.032). The cosmetic results of SILC were better than those of TLC, with visible scars in 21 patients from the TLC group vs. 3 patients from the SILC group (P = 0.0001).
Conclusions
We found SILC to be a safe, feasible, and adaptable surgical technique. The pain scores at 4 h were significantly better for SILC than for TLC.
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Outcomes of lung cancer resection for patients with combined pulmonary fibrosis and emphysema
Abstract
Purpose
Combined pulmonary fibrosis and emphysema (CPFE) has recently been reported as a prognostic factor that may increase the risk of lung cancer for patients with respiratory disorders; however, there have been no reports published on mortality and morbidity following major lung resection for patients with CPFE.
Methods
The subjects of this retrospective study were 1507 patients who underwent surgical resection of lung cancer at our institute between 2008 and 2013. We reviewed the computed tomography findings and divided the patients into four groups: CPFE group, fibrosis group, emphysema group, and normal group. The surgical outcomes of the patients with CPFE were compared with those of the patients in the other groups.
Results
The CPFE group comprised 137 (10.0 %) patients. This group had worse surgical morbidity and mortality rates than either the fibrosis group or the emphysema group. The 90-day mortality rates for the CPFE, fibrosis, and emphysema groups were 7.3, 0, and 3.0 %, respectively. A multivariate analysis of the CPFE group revealed that the distribution of IIP (HR 13.29, p = 0.038) and blood loss (ml) (HR 1.001, p = 0.013) predicted the hazard ratio for 90-day mortality.
Conclusions
The postoperative outcome of patients with CPFE in this study was poor with respect to morbidity and mortality. The high rate of complications and poor survival warrants further investigation of the indications for surgery in patients with CPFE.
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Which prosthesis is more resistant to vascular graft infection: polytetrafluoroethylene or Omniflow II biosynthetic grafts?
Abstract
Purpose
The aim of this study was to determine whether polytetrafluoroethylene grafts or Omniflow II biosynthetic grafts are more resistant to infection caused by Staphylococcus aureus.
Methods
Sixty rats were divided into six groups. In Groups 1A, 1B and 1C, a polytetrafluoroethylene graft was implanted in each rat, and, in Groups 2A, 2B and 2C, a biosynthetic graft was implanted in each rat. Staphylococcus aureus was inoculated into Groups 1B, 1C, 2B and 2C, and the rats in Groups 1C and 2C were treated with teicoplanin. One week later, the rats were euthanized, the grafts were removed and a microbiological count was performed. A histopathological examination was subsequently carried out, and the C-reactive protein, prealbumin and leukocyte levels were investigated.
Results
There were no significant differences in the C-reactive protein, prealbumin and leukocyte levels. The differences in the results of the microbiological evaluations between the groups were significant. The quantitative culture results showed no bacterial growth in Groups 1A, 1C and 2A. The number of bacteria in Group 1B was statistically lower than that in Group 2B. When the groups receiving treatment were compared, Group 2C had bacterial growth, whereas Group 1C did not. The histopathological examinations showed similar results.
Conclusions
Omniflow II grafts are more susceptible to infection than polytetrafluoroethylene grafts.
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Reconstruction using a divided latissimus dorsi muscle flap after conventional posterolateral thoracotomy and the effectiveness of indocyanine green-fluorescence angiography to assess intraoperative blood flow
Abstract
Purpose
In most general thoracic operations performed via standard posterolateral thoracotomy, such as for descending aortic aneurysms and lung cancer, the latissimus dorsi (LD) muscle is divided. However, division of the LD can hamper reconstructive surgery because the initial operation creates unstable blood flow to the divided LD. We conducted this study to assess blood flow in a divided distal LD muscle flap using intraoperative indocyanine green-fluorescence angiography (ICG-FA) with the Hyper Eye Medical System® (Mizuho Medical Co., Ltd., Tokyo, Japan).
Methods
The subjects were 11 patients who underwent posterolateral thoracotomy with reconstructive surgery using a divided distal LD and other peripheral muscle flaps. Intraoperative ICG-FA was conducted to assess blood flow to the LD.
Results
Intraoperative ICG-FA revealed that at least two intercostal perforators from the sixth to the tenth intercostal spaces were preserved as feeding vessels to the divided distal LD. There were no major complications associated with inadequate blood flow to the muscle flaps.
Conclusion
Intraoperative ICG-FA proved extremely useful for assessing altered blood flow of the divided LD and for selecting preserved intercostal perforators.
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Emergent laparoscopic cholecystectomy for acute acalculous cholecystitis revisited
Abstract
Purpose
To compare the safety of emergent laparoscopic cholecystectomy for acute acalculous cholecystitis (AAC) with surgery for acute calculous cholecystitis (ACC).
Methods
We retrospectively reviewed the perioperative records of 111 patients who underwent emergent laparoscopic cholecystectomy for acute cholecystitis under the care of the Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, between January 2010 and April 2014. Patients were divided into the AAC group (27 patients) and the ACC group (84 patients), and their perioperative outcomes were compared.
Results
Patients in the AAC group had significantly higher disease severity and American Society of Anesthesiologists physical status scores (p = 0.001 and 0.037, respectively), lower blood hemoglobin and albumin concentrations (p = 0.0005 and 0.017, respectively), and lower hematocrit and platelet count (p < 0.0001 and 0.040, respectively) than those in the ACC group. When we compared perioperative outcomes, we also found that patients in the AAC group were more likely to have received a blood transfusion (p = 0.002) and to have required conversion to open surgery (p = 0.008). There were no significant differences in morbidity, mortality or length of hospital stay.
Conclusions
Early laparoscopic cholecystectomy is safe in acute acalculous as well as acute calculous cholecystitis.
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Proteomic analysis in cardiovascular research
Abstract
Advances in mass spectrometry technology and bioinformatics using clinical human samples have expanded quantitative proteomics in cardiovascular research. There are two major proteomic strategies: namely, "gel-based" or "gel-free" proteomics coupled with either "top-down" or "bottom-up" mass spectrometry. Both are introduced into the proteomic analysis using plasma or serum sample targeting 'biomarker" searches of aortic aneurysm and tissue samples, such as from the aneurysmal wall, calcific aortic valve, or myocardial tissue, investigating pathophysiological protein interactions and post-translational modifications. We summarize the proteomic studies that analyzed human samples taken during cardiovascular surgery to investigate disease processes, in order to better understand the system-wide changes behind known molecular factors and specific signaling pathways.
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Solitary fibrous tumor of the pleura: morphogenesis and progression. A report of 36 cases
Abstract
Purpose
We attempted to identify the exact point of tumor eruption of a solitary fibrous tumor of the pleura (SFTP).
Methods
We morphologically classified 36 SFTPs into 5 categories. Type A showed a connection that included a bloodstream with the pleura on both sides. Type B only showed a connection that included a bloodstream with the visceral pleura, and had a non-bloodstream connection with the parietal pleura. Type C only showed a connection that included a bloodstream with the visceral pleura, and had no connection with the parietal pleura. Type D showed a non-bloodstream connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. Finally, type E had no connection with the visceral pleura, and only showed a connection that included a bloodstream with the parietal pleura. The clinicopathological profiles of the tumors were investigated according to their type.
Results
The distribution of the 36 SFTPs was as follows: A (19 %), B (6 %), C (67 %), D (0 %) and E (8 %). The tumors categorized as type A tended to be large in size.
Conclusions
SFTPs commonly arise from the visceral pleura and in accordance with tumor progression they will form a non-bloodstream connection with the parietal pleura. Finally, a vascular pedicle will arise with the parietal pleura.
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Evaluating HPV negative CIN2+ in the ATHENA trial
Abstract
A post-hoc analysis of the ATHENA study was performed to determine whether true HPV negative cervical lesions occur and whether they have clinical relevance. The ATHENA database was searched for all CIN2 or worse (CIN2+) cases with cobas HPV negative results and comparison was made with Linear Array (LA) and Amplicor to detect true false-negative HPV results. Immunostaining with p16 was performed on these cases to identify false-positive histology results. H&E slides were re-reviewed by the study pathologists with knowledge of patient age, HPV test results and p16 immunostaining. Those with positive p16 immunostaining and/or a positive histopathology review underwent whole tissue section HPV PCR by the SPF10/LiPA/RHA system. Among 46,887 eligible women, 497 cases of CIN2+ were detected, 55 of which tested negative by the cobas® HPV Test (32 CIN2, 23 CIN3/ACIS). By LA and/or Amplicor, 32 CIN2+ (20 CIN2, 12 CIN3/ACIS) were HPV positive and categorized as false-negatives by cobas HPV; 9 of 12 false negative CIN3/ACIS cases were p16+. There were 23 cases (12 CIN2, 11 CIN3/ACIS) negative by all HPV tests; 7 of 11 CIN3/ACIS cases were p16+. H&E slides were available for 6 cases for re-review and all were confirmed as CIN3/ACIS. Tissue PCR was performed on the 6 confirmed CIN3/ACIS cases (and 1 without confirmation): 4 were positive for HPV types not considered oncogenic, 2 were positive for oncogenic genotypes and 1 was indeterminate. In summary, subanalysis of a large cervical cancer screening study did not identify any true CIN3/ACIS not attributable to HPV. This article is protected by copyright. All rights reserved.
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Home-based HPV self-sampling improves participation by never- and under-screened women: Results from a large randomised trial (iPap) in Australia
Abstract
We conducted a randomised controlled trial to determine whether HPV self-sampling increases participation in cervical screening by never- and under-screened (not screened in past five years) women when compared with a reminder letter for a Pap test. Never- or under-screened Victorian women aged 30-69 years, not pregnant and with no prior hysterectomy were eligible. Within each stratum (never-screened and under-screened), we randomly allocated 7,140 women to self-sampling and 1,020 to Pap test reminders. The self-sampling kit comprised a nylon tipped flocked swab enclosed in a dry plastic tube. The primary outcome was participation, as indicated by returning a swab or undergoing a Pap test; the secondary outcome, for women in the self-sampling arm with a positive HPV test, was undergoing appropriate clinical investigation. The Roche Cobas® 4800 test was used to measure presence of HPV DNA. Participation was higher for the self-sampling arm: 20.3% versus 6.0% for never-screened women (absolute difference 14.4%, 95% CI: 12.6%-16.1%, p<0.001) and 11.5% versus 6.4% for under-screened women (difference 5.1%, 95% CI: 3.4%-6.8%, p<0.001). Of the 1,649 women who returned a swab, 45 (2.7%) were positive for HPV16/18 and 95 (5.8%) were positive for other high-risk HPV types. Within six months, 28 (62.2%) women positive for HPV16/18 had colposcopy as recommended and nine (20%) had cytology only. Of women positive for other high-risk HPV types, 78 (82.1%) had a Pap test as recommended. HPV self-sampling improves participation in cervical screening for never- and under-screened women and most women with HPV detected have appropriate clinical investigation. This article is protected by copyright. All rights reserved.
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Alleviating effect of active hexose correlated compound (AHCC) on chemotherapy-related adverse events in patients with unresectable pancreatic ductal adenocarcinoma.
Alleviating effect of active hexose correlated compound (AHCC) on chemotherapy-related adverse events in patients with unresectable pancreatic ductal adenocarcinoma.
Nutr Cancer. 2016 Feb 4;:1-7
Authors: Yanagimoto H, Satoi S, Yamamoto T, Hirooka S, Yamaki S, Kotsuka M, Ryota H, Michiura T, Inoue K, Matsui Y, Tsuta K, Kon M
Abstract
The present study was conducted to determine whether active hexose correlated compound (AHCC), a functional food extracted from cultured basidiomycetes, possesses the potential to attenuate adverse events in unresectable pancreas ductal adenocarcinoma (PDAC) patients receiving chemotherapy. Unresectable PDAC patients receiving gemcitabine treatment (GEM) as the first-line chemotherapy were prospectively divided into 2 groups according to AHCC intake (AHCC group, n = 35) or not (control group, n = 40). The patients in the AHCC group ingested 6.0 g of AHCC for 2 mo. Hematological and nonhematological toxicity was compared between the AHCC and control groups. The C-reactive protein (CRP) elevation and albumin decline of the AHCC group were significantly suppressed as compared to the control group during the GEM administration (P = 0.0012, P = 0.0007). Patients in the AHCC group had less frequency of taste disorder caused by GEM (17% vs. 56%, P = 0.0007). Frequency of grade 3 in the modified Glasgow Prognostic Score (mGPS) during chemotherapy was found significantly less in the AHCC group (14%) than the control group (53%, P = 0.0005). AHCC intake can be effective in reducing the adverse events associated with chemotherapy and may contribute to maintaining the QOL of patients with PDAC during GEM administration.
PMID: 26847832 [PubMed - as supplied by publisher]
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Visceral obesity is associated with poor prognosis in pancreatic adenocarcinoma.
Visceral obesity is associated with poor prognosis in pancreatic adenocarcinoma.
Nutr Cancer. 2016 Feb 4;:1-7
Authors: Kim B, Chung MJ, Park SW, Park JY, Bang S, Park SW, Song SY, Chung JB
Abstract
An association between obesity and unfavorable outcomes for various types of malignancy has been established. Nevertheless, the impact of visceral obesity (VO) on outcomes in pancreatic cancer is still unknown and controversial. The aim of this study was to uncover an association between VO and pancreatic cancer outcomes. We retrospectively reviewed 499 patients with pancreatic cancer who were diagnosed and treated in Severance Hospital from January 2006 to December 2011. Compared to the low-VO group (n = 260), the high-VO group (n = 239) was mostly male (68.2% vs. 31.8%, P < 0.001) and was more likely to have current smoking status (29.7% vs. 17.7%, P < 0.001), current alcohol intake status (52.3% vs. 26.4%, P < 0.001) and diabetes mellitus (54.4% vs. 31.9%, P = 0.028). The progression free survival (PFS) and overall survival (OS) were found to be significantly shorter by the Kaplan-Meier method in the high-VO group than in the low-VO group (PFS; P = 0.044, OS: P = 0.013). In addition, the higher percentage of visceral fat was correlated with more lymph node metastasis and shorter OS (P = 0.011 and P = 0.017, respectively). In patients with pancreatic cancer, VO at the time of diagnosis is associated with negative outcomes, such as shorter PFS and OS.
PMID: 26847707 [PubMed - as supplied by publisher]
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Bladder cancer is associated with low plasma 25-hydroxyvitamin D concentrations in Tunisian population.
Bladder cancer is associated with low plasma 25-hydroxyvitamin D concentrations in Tunisian population.
Nutr Cancer. 2016 Feb 4;:1-6
Authors: Ben Fradj MK, Gargouri MM, Hammami MB, Ben Rhouma S, Kallel A, Jemaa R, Feki M, Nouira Y, Kaabachi N
Abstract
Little evidence suggests an impact of vitamin D on bladder cancer risk in Caucasians. This study aimed to investigate association of plasma 25-hydroxyvitamin D (25-OHD) with urothelial bladder cancer (UBC) risk in Tunisians. A case-control study included 250 patients with UBC and 250 healthy controls. Plasma 25-OHD was assessed by a competitive chemiluminescence immunoassay. Vitamin D deficiency and insufficiency were defined as 25-OHD <30 nmol/L and 30 to 49.99 nmol/L, respectively. Logistic regression models adjusting for gender, age, smoking status, duration of smoking, occupational exposure, and season were applied. Vitamin D deficiency (50.4% vs. 34.8%; P < 0.001) and insufficiency (40.4% vs. 26.8%; P < 0.001) were more frequent in patients than controls. Multivariate analysis showed that UBC is associated with vitamin D deficiency [odd-ratio (95% confidence interval), 3.71 (1.76-7.80); P = 0.001] and vitamin D insufficiency [2.65 (1.40-5.01); P = 0.003]. Other predictors of UBC were female gender, tobacco use, smoking duration, and occupational exposure. Plasma 25-OHD concentrations are low in Tunisian patients with UBC. These findings support experimental and epidemiological evidence of protective role of vitamin D against UBC but could not ascertain causal relationship. Further prospective studies and clinical trials are warranted to check causality.
PMID: 26847528 [PubMed - as supplied by publisher]
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Dietary total antioxidant capacity is inversely associated with prostate cancer aggressiveness in a population-based study.
Dietary total antioxidant capacity is inversely associated with prostate cancer aggressiveness in a population-based study.
Nutr Cancer. 2016 Feb 4;:1-11
Authors: Vance TM, Wang Y, Su LJ, Fontham ET, Steck SE, Arab L, Bensen JT, Mohler JL, Chen MH, Chun OK
Abstract
The purpose of this study was to determine the relationship between total antioxidant capacity (TAC) from diet and supplements and prostate cancer aggressiveness among 855 African Americans (AA) and 945 European Americans (EA) in the North Carolina-Louisiana Prostate Cancer Project (PCaP). Cases were classified as either high aggressive, low aggressive, or intermediate aggressive. TAC was calculated from the vitamin C equivalent antioxidant capacity of 42 antioxidants measured via food frequency questionnaire. EA reported greater dietary TAC from diet and supplements combined (P < 0.0001). In both minimally and fully adjusted logistic regression models, TAC from diet and supplements combined was associated with a reduced odds of high aggressive prostate cancer in all men, AA and EA: odds ratios for highest vs. lowest level (>1500 vs. <500 mg vitamin C equivalent/day): 0.31 [95% confidence interval (CI): 0.15, 0.67; P-trend < 0.01], 0.28 (95% CI: 0.08, 0.96; P-trend < 0.001), and 0.36 (95% CI: 0.15, 0.86; P-trend = 0.58), respectively. These associations did not appear to differ between AA and EA. These data suggest that greater intake of antioxidants is associated with less aggressive prostate cancer. Additional research is needed to confirm these results and determine the underlying mechanisms.
PMID: 26847416 [PubMed - as supplied by publisher]
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Zapotin (5,6,2',6'-tetramethoxyflavone) modulates the crosstalk between autophagy and apoptosis pathways in cancer cells with overexpressed constitutively active PKCϵ.
Zapotin (5,6,2',6'-tetramethoxyflavone) modulates the crosstalk between autophagy and apoptosis pathways in cancer cells with overexpressed constitutively active PKCϵ.
Nutr Cancer. 2016 Feb 4;:1-15
Authors: Toton E, Romaniuk A, Budzianowski J, Hofmann J, Rybczynska M
Abstract
Autophagy is important in the regulation of survival and death signaling pathways in cancer. PKCϵ revealed high transforming potential and the ability to increase cell migration, invasion, and metastasis. Zapotin (5,6,2',6'-tetramethoxyflavone), a natural flavonoid, showed chemopreventive and anticancer properties. Previously, we reported that downmodulation of induced PKCϵ level by zapotin was associated with decreased migration and increased apoptosis in HeLa cell line containing doxycycline-inducible constitutively active PKCϵ (PKCϵA/E, Ala(159) → Glu). Depending on the genetic and environmental content of cells, autophagy may either precede apoptosis or occur simultaneously. The purpose of this study was to assess the effect of zapotin on autophagy. Increasing concentration of zapotin (from 7.5 µM to 30 µM) caused an inhibition of the formation of autophagosomes and a decline in microtubule-associated protein 1 light chain 3 (LC3) protein levels. The gene expression level of major negative regulator of autophagy was noticeably increased. Moreover, the expression of the pivotal autophagy genes was decreased. These changes were accompanied by alternation in autophagy-related protein levels. In conclusion, our results implied that both the antiautophagic and the proapoptosis effect of zapotin in HeLaPKCϵA/E cells are associated with the protein kinase C epsilon signaling pathway and lead to programmed cell death.
PMID: 26847268 [PubMed - as supplied by publisher]
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Pre-clinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R/IR selectivity
Summary
Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize pre-clinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Pre-clinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg exhibited modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously: dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pre-treated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with HER2-postive metastatic breast cancer.
This article is protected by copyright. All rights reserved.
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Surgery in the era of neoadjuvant therapy for cancer of the esophagus
Abstract
Multimodality treatment strategies have become commonplace and stand-of-care in the management of esophageal cancer. In Japan, preoperative chemotherapy is routine, while in many centers around the globe chemoradiotherapy is widely practiced. How surgery should be integrated and the manner in which esophagectomy should be carried out remain controversial. From the literature, it seems that esophagectomy for salvage after definitive chemoradiotherapy is associated with increased morbidity rates. In the neoadjuvant setting, however, where less chemotherapy and lower dose of radiotherapy is usually given, results are comparable with upfront surgery. Video-assisted thoracoscopic esophagectomy is also safe after neoadjuvant therapy; special adjunct like recurrent laryngeal nerve monitoring may be helpful for extended mediastinal lymphadenectomy. There is not enough evidence to suggest that lesser degree of lymphadenectomy is required after neoadjuvant therapy. As such the same degree of nodal dissection is recommended. Further work is required to delineate the role of surgery in multimodality treatment programs.
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Genomic alterations of the JAK2 and PDL loci occur in a broad spectrum of lymphoid malignancies
The recurrent 9p24.1 aberrations in lymphoid malignancies potentially involving four cancer-related and druggable genes (JAK2, CD274/PDL1, PDCD1LG2/PDL2, and KDM4C/JMJD2Cl) are incompletely characterized. To gain more insight into the anatomy of these abnormalities, at first we studied 9p24.1 alterations in 18 leukemia/lymphoma cases using cytogenetic and molecular techniques. The aberrations comprised structural (nine cases) and numerical (nine cases) alterations. The former lesions were heterogeneous but shared a common breakpoint region of 200 kb downstream of JAK2. The rearrangements predominantly targeted the PDL locus. We have identified five potential partner genes of PDL1/2: PHACTR4 (1p34), N4BP2 (4p14), EEF1A1 (6q13), AK2 (9p24.1), and IGL (22q11). Interestingly, the cryptic JAK2-PDL1 rearrangement was generated by a microdeletion spanning the 3′JAK2−5′PDL1 region. JAK2 was additionally involved in a cytogenetically cryptic IGH-mediated t(9;14)(p24.1;q32) found in two patients. This rare but likely underestimated rearrangement highlights the essential role of JAK2 in B-cell neoplasms. Cases with amplification of 9p24.1 were diagnosed as primary mediastinal B-cell lymphoma (five cases) and T-cell lymphoma (four cases). The smallest amplified 9p24.1 region was restricted to the JAK2-PDL1/2-RANBP6 interval. In the next step, we screened 200 cases of classical Hodgkin lymphoma by interphase FISH and identified PDL1/2 rearrangement (CIITA- and IGH-negative) in four cases (2%), what is a novel finding. Forty (25%) cases revealed high level amplification of 9p24.1, including four cases with a selective amplification of PDL1/2. Altogether, the majority of 9p24.1 rearrangements occurring in lymphoid malignancies seem to target the programmed death-1 ligands, what potentiates the therapeutic activity of PD-1 blockade in these tumors. © 2016 Wiley Periodicals, Inc.
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Evaluation of the antineoplastic activity of gallic acid in oral squamous cell carcinoma under hypoxic conditions.
The purpose of the current study was to develop and test a theoretical model that could explain the mechanism of action of gallic acid (GA) in the oral squamous cell carcinoma context for the first time. The theoretical model was developed using bioinformatics and interaction network analysis to evaluate the effect of GA on oral squamous cell carcinoma. In a second step to confirm theoretical results, migration, invasion, proliferation, and gene expression (Col1A1, E-cadherin, HIF-1[alpha], and caspase-3) were performed under normoxic and hypoxic conditions. Our study indicated that treatment with GA resulted in the inhibition of cell proliferation, migration, and invasion in neoplastic cells. Observation of the molecular mechanism showed that GA upregulates E-cadherin expression and downregulates Col1A1 and HIF-1[alpha] expression, suggesting that GA might be a potential anticancer compound. In conclusion, the present study demonstrated that GA significantly reduces cell proliferation, invasion, and migration by increasing E-cadherin and repressing Col1A1. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.
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Involved-field radiotherapy for esophageal squamous cell carcinoma: theory and practice
Abstract
Esophageal carcinoma (EC) is characterized by a high rate of lymph node metastasis and its spread pattern is not always predictable. Chemoradiotherapy has an important role in the treatment of EC in both the inoperable and the pre-operative settings. However, regarding the target volume for radiation, different clinical practices exist. Theoretically, in addition to the clinical target volume administered to the gross lesion, it might seem logical to deliver a certain dose to the uninvolved regional lymph node area at risk for microscopic disease. However, in practice, it is difficult because of the intolerance of normal tissue to radiotherapy (RT), particularly if all regions containing the cervical, mediastinal, and upper abdominal nodes are covered. To date, the use of elective nodal irradiation (ENI) is still controversial in the field of radiotherapy. Some investigators use involved-field radiotherapy (IFRT) in order to reduce treatment-related toxicities. It is thought that micrometastases can be controlled, to some extent, by chemotherapy and the abscopal effects of radiation. It is the presence of overtly involved lymph nodes rather than the micrometastatic nodes negatively affects survival in patients with EC. In another hand, lymph nodes stationed near primary tumors also receive considerable incidental irradiation doses that may contribute to the elimination of subclinical lesions. These data indicate that an irradiation volume covering only the gross tumor is appropriate. When using ENI or IFRT, very few patients experience solitary regional node failure and out-of-field lymph node failure is not common. Primary tumor recurrence and distant metastases, rather than regional lymph node failure, affect the overall survival in patients with EC. The available evidence indicates that the use of ENI seems to prevent or delay regional nodal relapse rather than improve survival. In a word, these data suggest that IFRT is feasible in EC patients.
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CD57 in human natural killer cells and T-lymphocytes
Abstract
The CD57 antigen (alternatively HNK-1, LEU-7, or L2) is routinely used to identify terminally differentiated 'senescent' cells with reduced proliferative capacity and altered functional properties. In this article, we review current understanding of the attributes of CD57-expressing T-cells and NK cells in both health and disease and discuss how this marker can inform researchers about their likely functions in human blood and tissues in vivo. While CD57 expression on human lymphocytes indicates an inability to proliferate, these cells also display high cytotoxic potential, and CD57pos NK cells exhibit both memory-like features and potent effector functions. Accordingly, frequencies of CD57-expressing cells in blood and tissues have been correlated with clinical prognosis in chronic infections or various cancers and with human aging. Functional modulation of senescent CD57pos T-cells and mature CD57pos NK cells may therefore represent innovative strategies for protection against human immunological aging and/or various chronic diseases.
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A Randomized Phase 2/3 Study of Naptumomab Estafenatox + IFN-{alpha} vs IFN-{alpha} in Renal Cell Carcinoma: Final Analysis with Baseline Biomarker Subgroup and Trend Analysis
Purpose: To prospectively determine the efficacy of naptumomab estafenatox (Nap) + interferon α (IFN) versus IFN in metastatic renal cell carcinoma (RCC). Experimental Design: In a randomized, open-label, multicenter, phase 2/3 study, 513 RCC patients received Nap (15 µg/kg intravenously in three cycles of four once daily injections) + IFN (9 MU subcutaneously three times weekly) or the same regimen of IFN monotherapy. The primary endpoint was overall survival (OS). Results: This phase 2/3 study did not meet its primary endpoint. Median OS/PFS for Nap+IFN patients was 17.1/5.8 months versus 17.5/5.8 months for the patients receiving IFN alone (p=0.56, hazard ratio 1.08/p=0.41, hazard ratio 0.92). Post-hoc exploratory subgroup and trend analysis revealed that the baseline plasma concentrations of anti-SEA/E-120 (anti-Nap antibodies) for drug exposure and IL-6 for immune status could be used as predictive biomarkers. A subgroup of patients (SG; n=130) having concentrations below median of anti-SEA/E-120 and IL-6 benefitted greatly from addition of Nap. In SG median OS/PFS for the patients treated with Nap+IFN was 63.3/13.7 months versus 31.1/5.8 months for the patients receiving IFN alone (p=0.02, hazard ratio 0.59/p=0.02, hazard ratio 0.62). Addition of Nap to IFN showed predicted and transient immune related AEs and the treatment had an acceptable safety profile. Conclusions: The study did not meet its primary endpoint. Nap+IFN has an acceptable safety profile and results from post-hoc subgroup analyses showed that the treatment might improve OS/PFS in a baseline biomarker defined RCC patients subgroup. The results warrant further studies with Nap in this subgroup.
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STAT3/5 dependent IL-9 overexpression contributes to neoplastic cell survival in mycosis fungoides
Purpose: Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL-9-producing T- cells have been found in skin infections and certain inflammatory skin diseases but their role in MF is currently unknown. Experimental Design: We analyzed lesional skin from MF patients for expression of IL-9 and its regulators. To determine which cells were producing IL-9, high-throughput sequencing was used to identify malignant clones and Vb specific antibodies were employed to visualize malignant cells in histological preparations. To explore the mechanism of IL-9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) +/-anti-IL-9 antibody. To further examine the role of IL-9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice. Results: Malignant and reactive T-cells produce IL-9 in lesional skin. Expression of the Th9 transcription factor IRF4 in malignant cells was heterogeneous whereas reactive T- cells expressed it uniformly. PUVA or UVB phototherapy diminished the frequencies of IL-9- and IL-9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL-9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL-9 with neutralizing antibodies potentiated cell death after PUVA in vitro. IL-9 depleted mice exhibited a reduction of tumor growth, higher frequencies of regulatory T-cells, and activated CD4 and CD8 T lymphocytes. Conclusions: Our results suggest that IL-9 and its regulators are promising new targets for therapy development in MF.
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Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma
Purpose: Promising results in the treatment of NSCLC have been seen with agents targeting immune checkpoints, such as PD-1 or PD-L1. However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents. Methods: We conducted an integrated analysis of three independent large datasets, including The Cancer Genome Atlas (TCGA) of lung adenocarcinoma and two datasets from MD Anderson Cancer Center, Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse phase protein array (RPPA), immunohistochemistry and correlation with clinical data were performed. Results: Epithelial-mesenchymal transition (EMT) is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation co-existent with elevation of multiple targetable immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, B7-H3, BTLA and CTLA-4, along with increases in tumor infiltration by CD4+Foxp3+ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Furthermore, we identify B7-H3 as a prognostic marker for NSCLC. Conclusions: The strong association between EMT status and an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoint molecules warrants further investigation of using EMT as a predictive biomarker for immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers.
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Antitumor Activity of BRAF Inhibitor and IFN{alpha} Combination in BRAF-Mutant Melanoma
Background:
BRAFV600E-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFNα, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFNα therapy of BRAFV600E melanoma can be increased by its combination with BRAF-I.
Methods:BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAFV600E metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFNα combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). All statistical tests were two-sided. Differences were considered statistically significant when the P value was less than .05.
Results:The IFNAR1 level was statistically significantly (P < .001) lower in BRAFV600E primary melanoma tumors than in BRAF wild-type tumors. IFNAR1 downregulation was reversed by BRAF-I treatment in the three melanoma cell lines (P ≤ .02) and in three out of four metastases. The IFNAR1 level in the melanoma tumors analyzed was increased as early as 10 to 14 days following the beginning of the treatment. These changes were associated with: 1) an increased susceptibility in vitro of melanoma cells to the antiproliferative (P ≤ .04), pro-apoptotic (P ≤ .009) and immunomodulatory activity, including upregulation of HLA class I antigen APM component (P ≤ .04) and MA expression as well as recognition by cognate T-cells (P < .001), of BRAF-I and IFNα combination and 2) an increased survival (P < .001) and inhibition of tumor growth of melanoma cells (P < .001) in vivo by BRAF-I and IFNα combination.
Conclusions:The described results provide a strong rationale for the clinical trials implemented in BRAFV600E melanoma patients with BRAF-I and IFNα combination.
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