The Novel Use of IL-28 as an Effective Radiosensitizer in Pancreatic Cancer.

BACKGROUND/AIM: Pancreatic cancer is the second most common gastrointestinal cancer in the world, yet the five-year survival outcome rate of less than 5% urges for improvement in medical interventions of pancreatic cancer. Currently, high dose radiation therapy (RT) is used as an adjuvant treatment; however, the high level of RT required to treat advanced neoplasms leads to high incidence rates of side effects. In recent years, the utilization of cytokines as radiosensitizing agents has been studied, in order to reduce the amount of radiation required. However, few studies have examined IL-28 regarding its potential as a radiosensitizer. This study is the first to utilize IL-28 as a radiosensitizing agent in pancreatic cancer. MATERIALS AND METHODS: MiaPaCa-2, a widely used pancreatic cancer cell line was used in this study. Clonogenic survival and cell proliferation assays were used to evaluate growth and proliferation of MiaPaCa-2 cells. Caspase-3 activity assay was used to evaluate apoptosis of MiaPaCa-2 cells and RT-PCR was used to study the possible molecular mechanisms. RESULTS: Our results showed that IL-28/RT enhanced RT-induced inhibition of cell proliferation and promoted apoptosis of MiaPaCa-2 cells. Furthermore, compared to RT alone, we found that IL-28/RT up-regulated the mRNA expression of TRAILR1 and P21, while down-regulating mRNA expression of P18 and survivin in MiaPaCa-2 cells. CONCLUSION: IL-28 has the potential to be used as a radiosensitizer for pancreatic cancer and warrants further investigation.

Green nanotechnology of MGF-AuNPs for immunomodulatory intervention in prostate cancer therapy.

Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent.

Association between interleukin­33 and ovarian cancer.

Ovarian cancer is the leading cause of cancer­ associated mortality in the female reproductive system. Interleukin (IL)­33 and its receptor IL 1 receptor like 1 (also termed ST2) are expressed by many cell types including epithelial cells. The role of IL­33 in the pathogenesis of neoplasia remains controversial. The authors previously demonstrated that IL­33 inhibits the growth of pancreatic cancer cells. The present study was performed to explore if IL­33 has any direct effects on ovarian cancer cells. A clonogenic survival assay, immunohistochemistry (IHC), proliferation kit and caspase­3 activity kit were all used to evaluate the direct effects of IL­33 on cell proliferation and apoptosis of a widely studied ovarian cancer cell line, A2780. The possible molecular mechanisms were further evaluated with reverse transcription­polymerase chain reaction and IHC. It was demonstrated that the percentage of colonies and the optical density value of cancer cells were all increased in the presence of IL­33; however, the relative caspase­3 activity in cancer cells was decreased in the presence of IL­33. Molecular mechanism studies revealed that the pro­proliferative effect of IL­33 on cancer cells was associated with decreased levels of p27, and the anti­apoptotic effect of IL­33 was associated with levels of Fas cell surface death receptor (Fas) and tumor necrosis factor­related apoptosis­inducing ligand receptor 1 (TRAILR1). Therefore, IL­33 promoted proliferation and inhibited apoptosis of ovarian cancer cells by downregulation of p27, Fas and TRAILR1. Contrary to previous studies demonstrating an anti­tumor effort in pancreatic cancer, the results of the present study indicated that IL­33 exhibited a significant onco­promoting effect on ovarian cancer. Accordingly, the inhibition of IL­33 may be a promising therapeutic strategy for ovarian cancer.

IL-33 notably inhibits the growth of colon cancer cells.

Interleukin-33 (IL-33), a damage-associated molecular pattern molecule, is a cytokine within the IL-1 interleukin family that binds to the plasma membrane receptor suppression of tumorigenicity 2 on numerous cell types. IL-33 has been extensively studied in its role in autoimmune diseases, host responses to pathogens and allergens, and has been associated with tumorigenic effects in cancer research. The present study was performed to investigate the effects of IL-33 on colon cancer cells, based off the previous data that have demonstrated an anti-tumor effect of IL-33 on pancreatic cancer cells. The effects of IL-33 on proliferation, cell survival and apoptosis on human HCT-116 colon cancer cells were examined using clonogenic survival assays, proliferation and caspase-3 activity kits, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and immunocytochemistry. It was determined that the HCT-116 cells demonstrated an notable decrease in optical density value upon incubation with IL-33, along with a decrease in the number of colonies, compared with the controls. It was further determined that the anti-proliferative effect of IL-33 on HCT-116 cells was associated with downregulation of the pro-proliferative molecules cyclin B, cyclin D and cyclin dependent kinase 2. An apoptosis-inducing effect of IL-33 on HCT-116 cells was associated with downregulation of the anti-apoptotic molecules Flice-like inhibitory protein and B-cell lymphoma 2. Taken together, the results indicated that IL-33 inhibits the growth of colon cancer by suppressing cellular proliferation, whilst simultaneously promoting apoptosis.

First 100 consecutive robotic inguinal hernia repairs at a Veterans Affairs hospital.

The utilization of robotics in general surgery has increased significantly including usage in the Veterans Affairs (VA) system. We implemented a robotic inguinal hernia repair (RIHR) program in our VA hospital and report on initial experience with safety and outcomes. The first 100 consecutive RIHR at a VA hospital were reviewed and compared against the results of contemporaneous open inguinal hernia repair (OIHR). Data were collected for operative characteristics, surgical complications and pain related outcomes. Overall, operative times for OIHR were less than RIHR (83.7 vs. 109.7 min, p < 0.0001); however, there was no difference in operative time for bilateral repairs (121.5 vs. 121.9 min, p = ns). Complication rates were similar between the groups. RIHR patients had less pain at POD 1 than OIHR patients (p = 0.05). RIHR were less likely to have multiple post-op visits for pain than OIHR patients (p = 0.003). RIHR can be implemented in the VA system with acceptable surgical outcomes. RIHR may be associated with less post-operative pain in the early post-operative period.

Unveil the mysterious mask of cytokine-based immunotherapy for melanoma.

Melanoma is the leading cause of death among all skin cancers and its incidence continues to rise rapidly worldwide in the past decades. The available treatment options for melanoma remain limited despite extensive clinical research. Melanoma is an immunogenic tumor and great advances in immunology in recent decades allow for the development of immunotherapeutic agents against melanoma. In recent years, immunotherapy utilizing cytokines has been particularly successful in certain cancers and holds promise for patients with advanced melanoma. In this review, an overview of the current status and emerging perspectives on cytokine immunotherapy for melanoma are discussed in details. Such a study will be helpful to unveil the mysterious mask of cytokine-based immunotherapy for melanoma.

IL-33 acts as a foe to MIA PaCa-2 pancreatic cancer.

IL-33 is a member of the IL-1 family of cytokines, and no study has been performed to address its direct anti-tumor effect. This study is designed to investigate whether IL-33 has any direct effect on pancreatic cancer. Clonogenic survival assay, immunohistochemistry, TUNEL staining, proliferation, caspase-3 activity kits and RT-PCR were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MIA PaCa-2. We found that the percentage of colonies of MIA PaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased in the presence of IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. We further found that its anti-proliferative effect on cancer cells correlated with downregulation of pro-proliferative molecules cdk2 and cdk4 and upregulation of anti-proliferative molecules p15, p21 and p53. Its pro-apoptotic effect correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL. These results suggest that IL-33 presents significant anti-tumor effects by inhibition of proliferation and induction of apoptosis of MIA PaCa-2 pancreatic cancer cells. Thus, strength of IL-33/ST2 signal pathway might be a promising way to treat pancreatic cancer.

Laparoscopic Versus Open Resection for Gastrointestinal Stromal Tumors (GISTs).

PURPOSE: Primary gastrointestinal stromal tumors (GISTs) are typically treated with open resection. There is growing interest in laparoscopic GIST resection; however, data is limited. We report our experience with GIST resections using both open and laparoscopic techniques. MATERIALS AND METHODS: Twenty-nine GIST patients underwent definitive intent resection at the University of Missouri from 1990 to 2010. Patients who underwent laparoscopic resection (n = 7) were matched on the basis of tumor size, age, tumor location, and National Comprehensive Cancer Network (NCCN) risk stratification with seven patients who underwent open resection. The two groups were compared with respect to age, gender, BMI, tumor size, tumor site, mitotic rate, surgical margins, NCCN risk stratification, estimated blood loss, hospital stay, surgical complications, disease recurrence, and overall survival. RESULTS: The cohorts did not differ with respect to age, gender, BMI, tumor location, tumor size, or positive margins (p > 0.05). Patients who underwent open resection had more NCCN high-risk patients, but the difference was not statistically significant (p = 0.08). There was significantly less estimated blood loss (median 15 vs. 150 mL, p < 0.05) and significantly shorter hospital stay (median 4 vs. 7 days, p < 0.05) for the laparoscopy group. There were no recurrences in the laparoscopy group, but there was one in the open group with a median follow-up of 55 and 63 months, respectively (p > 0.05). Five-year disease-free survival was 100 % for the laparoscopic group and 83 % for the open resection group. CONCLUSIONS: Laparoscopic resection for appropriately selected GISTs is feasible and associated with significantly less blood loss and shorter hospitalizations compared to open resection. Further studies are needed to better define its role for GIST.

IL-32α has differential effects on proliferation and apoptosis of human melanoma cell lines.

BACKGROUND: Interleukin-32 (IL-32) is a recently recognized intracellular, proinflammatory cytokine which may play a role in cancer metastasis and patient survival. The role of IL-32 in cancer, especially its direct effect on cancer cells, is not well understood. MATERIAL AND METHODS: Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining, and caspase-3 activity assay were used to investigate the in vitro role for IL-32α in human melanoma growth. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. RESULTS: Exogenous administration of IL-32α inhibited proliferation of the HTB-72 human melanoma cell line, but had little effect on other melanoma cell lines. Inhibition of proliferation in HTB-72 correlated with increased expression of p21 and p53. IL-32α administration also increased apoptosis in HTB-72. This finding correlated with increased expression of TRAILR1. CONCLUSIONS: The data presented suggest a direct effect of IL-32α on the growth of human melanoma and give some insight into the mechanisms which may in part govern this effect. J. Surg. Oncol. 2016;113:364-369. © 2016 Wiley Periodicals, Inc.

IL-9 inhibits HTB-72 melanoma cell growth through upregulation of p21 and TRAIL.

BACKGROUND: IL-9 is a pleiotropic cytokine produced mainly by Th9 cells. IL-9 may have an anti-proliferative role in murine melanoma, however, its effect on human melanoma is unknown. METHODS: We examined the effects of IL-9 on proliferation and apoptosis in four human melanoma cell lines, HTB-65, HTB-72, CRL-11147, and SK-Mel-5. Clonogenic assay, PCNA staining, Quick Cell Proliferation assay, TUNEL staining and caspase-3 activity assay were used to assess proliferation and apoptosis, as appropriate. RESULTS: We found that IL-9 decreased the percentage of colonies of HTB-72 and SK-Mel-5 cells but not that of HTB-65 or CRL-11147 cells. PCNA mRNA, PCNA+ cells, PCNA staining intensity, and the OD value of HTB-72 melanoma cells were consistently decreased in the present of IL-9. IL-9 also increased TUNEL+ cells and the relative caspase-3 activity in HTB-72 melanoma cells. We further investigated the possible molecular mechanisms using RT-PCR and immunohistochemical staining. The anti-proliferative effect of IL-9 on HTB-72 cells correlated with higher expression of anti-proliferative molecule p21. Its pro-apoptotic effect on HTB-72 cells correlated with higher expression of the pro-apoptotic molecule TRAIL. CONCLUSIONS: IL-9 inhibits melanoma HTB-72 cell growth by upregulation of p21 and TRAIL. Understanding the interactions between IL-9 and melanoma may help direct strategies for cytokine-based immunotherapy development.

IL-35 promotes pancreas cancer growth through enhancement of proliferation and inhibition of apoptosis: evidence for a role as an autocrine growth factor.

Interleukin-35 (IL-35), an IL-12 cytokine family member, mediates the immune inhibitory function of regulatory T cells (Treg). We assayed the presence of IL-35 in paraffin-embedded human pancreas cancer (PCAN) and unexpectedly found IL-35 was expressed mainly by epithelial derived PCAN cells, but not by Treg. We further examined the expression and effect of exogenous IL-35 in human PCAN cell lines and found IL-35 promoted growth and inhibited apoptosis in PCAN cell lines. IL-35 induced proliferation correlated with an increase in cyclin B, cyclin D, cdk2, and cdk4 and a decrease in p27 expression, while inhibition of apoptosis was associated with an increase in Bcl-2 and a decrease in TRAILR1. We conclude IL-35 is produced by PCAN in vivo and promotes PCAN cell line growth in vitro. These results might indicate an important new role for IL-35 as an autocrine growth factor in PCAN growth.

Repeat PEG placement is safe for head and neck cancer patients.

PURPOSE: Percutaneous endoscopic gastrostomy (PEG) provides durable nutritional access for head and neck (HNC) patients as they undergo treatment. Continuing treatment of HNC may necessitate repeat PEG placement. We report our outcomes with repeat PEG compared to first-time PEG in HNC patients. MATERIALS AND METHODS: A retrospective chart review identified morbidity, mortality, and possible risk factors for complications. RESULTS: Repeat PEG tubes constituted 17% of PEG procedures. Morbidity was rare and similar complication rates were found between the initial PEG and repeat PEG groups (2% vs. 11%, p=0.131). There were no mortalities. CONCLUSIONS: Repeat PEG plays an important role in the care of HNC patients and can be considered a safe means to establish durable enteric feeding access for patients with recurrent cancer or treatment complications.

A dual role for sirtuin 1 in tumorigenesis.

Sirtuin 1 (SIRT1) is an NAD+-dependent histone deacetylase which regulates many normal physiological and pathological processes. In addition to its place in cellular energy metabolism, increasing evidence shows a role for SIRT1 in tumorigenesis, wherein it can function as either a tumor promoter or suppressor. Its function in malignancy varies with concentration, cellular location, temporal and spatial distribution, and regulation by upstream and downstream factors. In this mini-review, we present the existing data which implicates SIRT1 in tumorigenesis.

Age Influences Likelihood of Pancreatic Cancer Treatment, but not Outcome.

BACKGROUND: Pancreatic cancer (PanCA) is predominantly diagnosed in elderly patients; nevertheless, a significant number of young patients are affected. We hypothesized more aggressive treatment of young PanCA patients would result in better overall survival (OS). METHODS: A retrospective review of our institutional cancer database identified subjects for inclusion. Age 50 years was selected to stratify patients into age groups. RESULTS: Of 309 PanCA patients, 54 (17%) were ≤ 50 years old. Exocrine cancer was the most common histology (90%). Patients ≤ 50 years old were more likely to have endocrine cancer (22% vs. 7%, P = 0.001). There was no difference in stage or curative intent surgery between age groups. Despite patients ≤ 50 years old receiving more chemotherapy (61% vs. 41%, P = 0.007) and radiotherapy (28% vs. 15%, P = 0.03), there was no difference in OS (24.1 months vs. 14.1 months, P = 0.08). When only exocrine cancers were considered, there was no difference between young and old patients regarding stage, grade, location or surgery. Exocrine cancer patients ≤ 50 years old received more chemotherapy (67% vs. 42%, P = 0.003) and radiation therapy (36% vs. 17%, P = 0.004), but there was no difference in OS. CONCLUSIONS: A substantial number of PanCA patients are ≤ 50 years old. Patients ≤ 50 years old received more treatment but did not have improved OS. Significant improvements in PanCA survival await development of new treatment strategies.

Case report of pancreatic dermoid cyst: can fine needle aspiration make the diagnosis?

CONTEXT: Pancreatic dermoid cysts are rare, benign, germ cell tumors and part of the differential diagnosis for cystic neoplasms of the pancreas. CASE REPORT: A 35-year-old man presented with an incidentally discovered, 2 cm cystic pancreatic neoplasm of the pancreatic tail identified on CT scan. Endoscopic ultrasound (EUS) revealed a complex, honeycomb lesion. Fine needle aspiration (FNA) yielded a sample of whitish, necrotic material containing histiocytes, benign epithelial cells, and lymphocytes. After distal pancreatectomy and splenectomy was performed, histology revealed a cyst lined by stratified squamous epithelium with benign sebaceous units consistent with a pancreatic dermoid cysts. DISCUSSION: Although axial imaging reliably detects cystic neoplasms of the pancreas, diagnostic criteria for rare lesions are lacking; therefore alternative modalities such as EUS/FNA can be utilized. This case report highlights the EUS and FNA findings associated with pancreatic dermoid cysts.

Hydrogen peroxide enhances radiation-induced apoptosis and inhibition of melanoma cell proliferation.

The efficacy of radiation therapy (RT) for melanoma is limited in part by its radioresistance. Here, we examined the radiosensitizing effect of hydrogen peroxide (H(2)O(2)) on a radioresistant melanoma cell line, HTB-65. We found that H(2)O(2) synergized with RT to inhibit melanoma cell proliferation and promote apoptosis. The antiproliferative effect of H(2)O(2)/RT correlated with increased expression of p15 and reduced expression of cyclin D, cyclin E, cyclin-dependent kinase (CDK)2 and CDK4. The pro-apoptotic effect of H(2)O(2) /RT correlated with reduced expression of the B-cell CLL/lymphoma (BCL)2. These data highlight the potential of H(2)O(2) as a radiation sensitizer for melanoma treatment and show that this warrants further study.

A potential role for resveratrol as a radiation sensitizer for melanoma treatment.

BACKGROUND: Radiotherapy (XRT) is used to improve local control of melanoma and for palliation of metastatic disease. Clinical use of XRT for melanoma is often limited by extent of disease and the relative radioresistance of melanoma may limit the effectiveness of XRT. Our group and others have previously shown that resveratrol (RSV) enhances radiation sensitivity in radioresistant prostate cancer cell lines. MATERIAL AND METHODS: In this study, the effects of XRT in combination with RSV on radioresistant melanoma lines, SK-Mel-5 and HTB-65, were evaluated by assessment of proliferation and apoptosis. Clonogenic assay, comparison of proliferating cell nuclear antigen staining, Quick Cell Proliferation assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay were used to assess proliferation and apoptosis, as appropriate. RESULTS: We found that the percentage of colonies, proliferating cell nuclear antigen + cells and the optical density value of melanoma cells were decreased after addition of RSV to XRT (XRT/RSV). TUNEL + cells and the relative caspase-3 activity in melanoma cells were increased after addition of RSV to XRT (XRT/RSV). We investigated the possible molecular mechanisms of decreased proliferation and increased apoptosis by using reverse transcriptase-polymerase chain reaction and immunohistochemical staining. The anti-proliferative effect of XRT/RSV correlated with decreased expression of pro-proliferative molecule cyclin B, cyclin D, cdk2 and cdk4. The pro-apoptotic effect of XRT/RSV correlated with decreased expression of the anti-apoptotic molecule FLIP, Bcl-2, and survivin. CONCLUSION: These data suggest that RSV enhances radiation sensitivity of melanoma cells by inhibiting proliferation and promoting apoptosis. Resveratrol may have a potential role as a radiation sensitizer for melanoma treatment.

Principles and Innovations in Peritoneal Surface Malignancy Treatment.

Cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC) remains a controversial treatment for malignant disease of the peritoneal cavity. We review the scientific principles underscoring the rationale for CRS/HIPEC, recent innovations and ongoing controversies. Lack of level 1 data limits the understanding of the true benefit of CRS/HIPEC.

Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis.

Radiation therapy (XRT) for treatment of localized prostate cancer (PCA) has outcomes similar to surgery and medical therapy. Toxicities of XRT and the relative radioresistance of PCA limit the effectiveness of this treatment method. Safe and effective radiosensitizing agents are lacking to enhance the effectiveness for XRT for PCA. In this study, the effect of XRT in combination with the radiosensitizing agent resveratrol (RSV) was investigated in a radioresistant PCA cell line, PC-3. Our results show the addition of RSV to XRT (XRT/RSV) synergistically enhanced XRT-induced apoptosis and inhibition of PC-3 proliferation. The antiproliferative effect of XRT/RSV treatment correlated with increased expression of p15, p21, and mutant p53 and decreased expression of cyclin B, cyclin D, and cdk2. Increased apoptosis correlated with increased expression of Fas and TRAILR1. Furthermore, XRT/RSV had little effect on the expression of p-AKT, whereas it increased the expression level of p-H2A.X, a marker for senescence. These data highlight the potential of RSV as a radiation sensitizer for PCA treatment and warrant further investigation.

A possible role for perforin and granzyme B in resveratrol-enhanced radiosensitivity of prostate cancer.

Perforin and granzyme B are expressed primarily by activated lymphocytes (cytotoxic T cells, natural killer cells, and natural killer T cells) and function together to induce apoptosis of target cells. Typically, these proteins are not expressed in tumor cells. In the present study, we established the constitutive expression of perforin and granzyme B by the PC-3 and DU145 prostate cancer (PCA) cell lines with reverse transcription polymerase chain reaction, immunohistochemistry, Western blot, or a combination of techniques. The combination of radiation and resveratrol (XRT/RSV) additively/synergistically decreased survival of PCA because, at least in part, of increased apoptosis. We further demonstrated that treatment with RSV up-regulated the expression of both perforin and granzyme B, whereas treatment with XRT up-regulated the expression of granzyme B, but not that of perforin. Combined XRT/RSV treatment of PCA cells further increased the expression of both perforin and granzyme B compared with RSV or XRT alone. Thus, increased radiosensitivity of prostate cancer cells induced by RSV correlated with up-regulation of perforin and granzyme B, demonstrating a possible mechanism for tumor apoptosis. These findings might be helpful in devising new strategies for treating PCA.