Impacts of hyperthermic chemotherapeutic agent on cytotoxicity, chemoresistance-related proteins and PD-L1 expression in human gastric cancer cells.

Objective: Gastric cancer with peritoneal metastasis is considered to be final stage gastric cancer. One current treatment approach for this condition is combined cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the therapeutic mechanisms of HIPEC remain largely undescribed. Method: In order to assess the cellular effects of HIPEC in vitro, we treated AGS human gastric adenocarcinoma cells with or without 5-fluorouracil (5-Fu) at 37 °C or at 43 °C (hyperthermic temperature) for 1 h followed by incubation at 37 °C for 23 h. The impacts of hyperthermia/5-Fu on apoptosis, cell survival signals, oxidative stress, chemoresistance-related proteins and programmed death-ligand 1 (PD-L1) expression were measured. Results: Our results showed that hyperthermia potentiates 5-Fu-mediated cytotoxicity in AGS cells. Furthermore, the combination of 5-Fu and hyperthermia reduces levels of both phosphorylated STAT3 and STAT3, while increasing the levels of phosphorylated Akt and ERK. In addition, 5-Fu/hyperthermia enhances reactive oxygen species and suppresses superoxide dismutase 1. Chemoresistance-related proteins, such as multidrug resistance 1 and thymidylate synthase, are also suppressed by 5-Fu/hyperthermia. Interestingly, hyperthermia enhances 5-Fu-mediated induction of glycosylated PD-L1, but 5-Fu-mediated upregulation of PD-L1 surface expression is prevented by hyperthermia. Conclusion: Taken together, our findings provide insights that may aid in the development of novel therapeutic strategies and enhanced therapeutic efficacy of HIPEC.

Fucoidan Inhibits Radiation-Induced Pneumonitis and Lung Fibrosis by Reducing Inflammatory Cytokine Expression in Lung Tissues.

Purpose: Radiotherapy is a crucial treatment approach for many types of cancer. Radiation pneumonitis (RP) is one of the major complications in chest irradiation. Fucoidan is a sulfated polysaccharide found mainly in various species of brown seaweed. Recent studies have demonstrated the anti-inflammatory effects of fucoidan. However, no study has reported a well-established prophylactic agent for RP. Therefore, we investigated the effects of fucoidan on RP and radiotherapy (RT)-induced lung fibrosis. Materials and Methods: We compared RP and RT-induced fibrosis in lung tissue specimens obtained from irradiated (10 Gy/shot) C57BL/6 mice with or without fucoidan administration (200 mg/kg/day, oral gavage for 14 days). The expression patterns of cytokines in the pleural fluid were determined using a cytokine array and confirmed through enzyme immunoassays. Results: Fucoidan administration attenuated RP and RT-induced fibrosis in lung tissues. Decreased neutrophil and macrophage accumulation was observed in irradiated lung tissues, and radiation-induced lung fibrosis, as demonstrated by Masson trichrome staining, was attenuated. We investigated the expression patterns of inflammatory cytokines in the irradiated lung pleural fluid through the protein array; results revealed that fucoidan administration changed the expression patterns of inflammatory cytokines in irradiated lung tissues. Furthermore, the expression levels of TIMP-1, CXCL1, MCP-1, MIP-2, and interleukin-1Ra were substantially enhanced in the pleural fluid, but fucoidan administration significantly reduced their expression. Conclusions: Fucoidan changes the expression patterns of inflammatory cytokines, which may consequently attenuate RP and RT-induced lung fibrosis.

Combination of Vismodegib and Paclitaxel Enhances Cytotoxicity via Bak-mediated Mitochondrial Damage in EGFR-Mutant Non-Small Cell Lung Cancer Cells.

Half of NSCLC patients harbor epidermal growth factor receptor (EGFR) mutations, and their therapeutic responses are remarkably different from patients with wild-type EGFR (EGFR-WT) NSCLC. We previously demonstrated that the hedgehog inhibitor vismodegib (Vis) potentiates paclitaxel (PTX)-induced cytotoxicity via suppression of Bax phosphorylation, which promotes accumulation of mitochondrial damage and apoptosis in EGFR-WT NSCLC cells. In this study, we further delineated the anticancer activity and underlying mechanisms of this combination treatment in EGFR-mutant NSCLC cells. MTS/PMS activity and trypan blue exclusion assays were used to assess cell viability. Apoptosis was monitored by chromosome condensation, annexin V staining, and cleavage of PARP and caspase-3. Western blots were conducted to track proteins of interest after treatment. Reactive oxygen species (ROS) level was monitored by 2',7'-dichlorodihydrofluorescein diacetate. Mitochondrial status was analyzed by tetramethylrhodamine, ethyl ester. Hedgehog signaling was induced by PTX, which rendered H1975 and PC9 cells insensitive to PTX-induced mitochondrial apoptosis via suppression of Bak. However, Vis enhanced PTX-induced Bak activation, leading to mitochondrial damage, ROS accumulation, and subsequent apoptosis. Our findings suggest that the combination of Vis and PTX could be a potential therapeutic strategy to increase PTX sensitivity of EGFR-mutant NSCLC.

Repurposing the diuretic benzamil as an anti-osteosarcoma agent that acts by suppressing integrin/FAK/STAT3 signalling and compromising mitochondrial function.

Aims: Osteosarcoma is the most common primary bone malignancy among children and adolescents. We investigated whether benzamil, an amiloride analogue and sodium-calcium exchange blocker, may exhibit therapeutic potential for osteosarcoma in vitro. Methods: MG63 and U2OS cells were treated with benzamil for 24 hours. Cell viability was evaluated with the MTS/PMS assay, colony formation assay, and flow cytometry (forward/side scatter). Chromosome condensation, the terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay, cleavage of poly-ADP ribose polymerase (PARP) and caspase-7, and FITC annexin V/PI double staining were monitored as indicators of apoptosis. Intracellular calcium was detected by flow cytometry with Fluo-4 AM. The phosphorylation and activation of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) were measured by western blot. The expression levels of X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), SOD1, and SOD2 were also assessed by western blot. Mitochondrial status was assessed with tetramethylrhodamine, ethyl ester (TMRE), and intracellular adenosine triphosphate (ATP) was measured with BioTracker ATP-Red Live Cell Dye. Total cellular integrin levels were evaluated by western blot, and the expression of cell surface integrins was assessed using fluorescent-labelled antibodies and flow cytometry. Results: Benzamil suppressed growth of osteosarcoma cells by inducing apoptosis. Benzamil reduced the expression of cell surface integrins α5, αV, and ß1 in MG63 cells, while it only reduced the expression of αV in U2OS cells. Benzamil suppressed the phosphorylation and activation of FAK and STAT3. In addition, mitochondrial function and ATP production were compromised by benzamil. The levels of anti-apoptotic proteins XIAP, Bcl-2, and Bcl-xL were reduced by benzamil. Correspondingly, benzamil potentiated cisplatin- and methotrexate-induced apoptosis in osteosarcoma cells. Conclusion: Benzamil exerts anti-osteosarcoma activity by inducing apoptosis. In terms of mechanism, benzamil appears to inhibit integrin/FAK/STAT3 signalling, which triggers mitochondrial dysfunction and ATP depletion.

Vismodegib Potentiates Marine Antimicrobial Peptide Tilapia Piscidin 4-Induced Cytotoxicity in Human Non-Small Cell Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is a common cancer with several accepted treatments, such as chemotherapy, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and immune checkpoint inhibitors. Nevertheless, NSCLC cells often become insensitive to these treatments, and therapeutic resistance is a major reason NSCLC still has a high mortality rate. The induction of therapeutic resistance in NSCLC often involves hedgehog, and suppression of hedgehog can increase NSCLC cell sensitivity to several conventional therapies. In our previous work, we demonstrated that the marine antimicrobial peptide tilapia piscidin 4 (TP4) exhibits potent anti-NSCLC activity in both EGFR-WT and EGFR-mutant NSCLC cells. Here, we sought to further explore whether hedgehog might influence the sensitivity of NSCLC cells to TP4. Our results showed that hedgehog was activated by TP4 in both WT and EGFR-mutant NSCLC cells and that pharmacological inhibition of hedgehog by vismodegib, a Food and Drug Administration-approved hedgehog inhibitor, potentiated TP4-induced cytotoxicity. Mechanistically, vismodegib acted by enhancing TP4-mediated increases in mitochondrial membrane potential and intracellular reactive oxygen species (ROS). MitoTempo, a specific mitochondrial ROS scavenger, abolished vismodegib/TP4 cytotoxicity. The combination of vismodegib with TP4 also reduced the levels of the antioxidant proteins catalase and superoxide dismutase, and it diminished the levels of chemoresistance-related proteins, Bcl-2 and p21. Thus, we conclude that hedgehog regulates the cytotoxic sensitivity of NSCLC cells to TP4 by protecting against mitochondrial dysfunction and suppressing oxidative stress. These findings suggest that combined treatment of vismodegib and TP4 may be a promising therapeutic strategy for NSCLC.

Marine Antimicrobial Peptide Epinecidin-1 Inhibits Proliferation Induced by Lipoteichoic acid and Causes cell Death in non-small cell lung cancer Cells via Mitochondria Damage.

Non-small cell lung cancer (NSCLC) is among the deadliest cancers worldwide. Despite the recent introduction of several new therapeutic approaches for the disease, improvements in overall survival and progression-free survival have been minimal. Conventional treatments for NSCLC include surgery, chemotherapy and radiotherapy. Except for surgery, these treatments can impair a patient's immune system, leaving them susceptible to bacterial infections. As such, Staphylococcus aureus infections are commonly seen in NSCLC patients receiving chemotherapy, and a major constituent of the S. aureus cell surface, lipoteichoic acid (LTA), is thought to stimulate NSCLC cancer cell proliferation. Thus, inhibition of LTA-mediated cell proliferation might be a useful strategy for treating NSCLC. Epinecidin-1 (EPI), a marine antimicrobial peptide, exhibits broad-spectrum antibacterial activity, and it also displays anti-cancer activity in glioblastoma and synovial sarcoma cells. Furthermore, EPI has been shown to inhibit LTA-induced inflammatory responses in murine macrophages. Nevertheless, the anti-cancer and anti-LTA activities of EPI and the underlying mechanisms of these effects have not been fully tested in the context of NSCLC. In the present study, we demonstrate that EPI suppresses LTA-enhanced proliferation of NSCLC cells by neutralizing LTA and blocking its effects on toll-like receptor 2 and interleukin-8. Moreover, we show that EPI induces necrotic cell death via mitochondrial damage, elevated reactive oxygen species levels, and disrupted redox balance. Collectively, our results reveal dual anti-cancer activities of EPI in NSCLC, as the peptide not only directly kills cancer cells but it also blocks LTA-mediated enhancement of cell proliferation.

Benefit of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy and Bidirectional Chemotherapy for Patients with Gastric Cancer with Peritoneal Carcinomatosis Considering Cytoreductive Surgery.

Comprehensive treatment comprising neoadjuvant laparoscopic HIPEC (L-HIPEC) and bidirectional intraperitoneal and systemic induction chemotherapy (BISIC) followed by cytoreductive surgery (CRS) for gastric cancer with peritoneal carcinomatosis (PC) has been developed. However, its benefits and patient selection criteria have not been thoroughly investigated. We retrospectively reviewed 113 patients, with 25 having received comprehensive treatment (L-HIPEC, BISIC, and then CRS-HIPEC; the BISIC group) and 88 having received direct CRS-HIPEC (the CRS group). The BISIC group showed greater tumor clearance in terms of post-CRS peritoneal cancer index ((PCI) 6 vs. 14, p = 0.002) compared to CRS group. The median survival was 20.0 months in the BISIC group and 8.6 months in the CRS group (p = 0.031). Multivariable analysis revealed that the factors associated with increased survival were the BISIC protocol, age, and post-CRS tumor clearance. BISIC significantly improved survival in cases of moderate severity (PCI 11-20) and severe cases (PCI 21-39) without increasing the morbidity rate. We recommend the use of this neoadjuvant strategy for patients with gastric cancer-associated PC and an initial PCI of >10 to provide superior survival outcomes.

Hedgehog Suppresses Paclitaxel Sensitivity by Regulating Akt-Mediated Phosphorylation of Bax in EGFR Wild-Type Non-Small Cell Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is one of the most common and deadly cancers worldwide. Among NSCLC patients, almost half have wild-type epidermal growth factor receptor (EGFR WT). The primary therapeutic option for these EGFR WT NSCLC patients is chemotherapy, while NSCLC patients with EGFR mutations have more diverse therapeutic options, including EGFR tyrosine kinase inhibitors. Moreover, NSCLC patients with EGFR WT have worse chemotherapy response than EGFR mutant NSCLC patients. Thus, an urgent need exists for novel therapeutic strategies to improve chemotherapy response in EGFR WT NSCLC patients. Hedgehog signaling is known to be highly active in NSCLC; however, its potential role in chemoresistance is not fully understood. In the present study, we found that paclitaxel (PTX) treatment induces hedgehog signaling in EGFR WT NSCLC cells, and inhibition of hedgehog signaling with GDC-0449 (Vismodegib) increases sensitivity to PTX-stimulated apoptosis. Furthermore, GDC-0449 potentiates PTX-induced reactive oxygen species and mitochondrial dysfunction. In contrast, a hedgehog agonist, Hh-Ag1.5, attenuates PTX-induced apoptosis. Mechanistic experiments revealed that hedgehog induces phosphorylation of Akt at Ser473. Akt then phosphorylates Bax at Ser184, which can switch its activity from pro-apoptosis to anti-apoptosis. Taken together, our findings suggest that inhibition of hedgehog signaling might be a promising therapeutic strategy to improve PTX response in EGFR WT NSCLC.

Exendin-4 Attenuates Hepatic Steatosis by Promoting the Autophagy-Lysosomal Pathway.

Dysregulated hepatic steatosis may lead to chronic liver inflammation and nonalcoholic steatohepatitis (NASH). Recent studies have suggested that exendin-4, a glucagon-like peptide-1 agonist, may be a promising therapeutic for hepatic steatosis and NASH. However, the molecular mechanisms underlying the antihepatic steatosis actions of exendin-4 are not fully clear. Here, we demonstrate that autophagy is activated by either palmitic acid (PA) or oleic acid (OA) in HepG2 cells, and exendin-4 further enhances the autophagy-lysosomal pathway. We show that inhibition of autophagy by shLC3 attenuates exendin-4-mediated antisteatotic activity. Furthermore, expression of a key lysosomal marker, lysosome associated membrane protein 1 (LAMP1), is upregulated in OA + exendin-4-treated cells. The colocalization of LAMP1 and LC3 puncta further suggests that autophagic flux was enhanced by the cotreatment. Based on these findings, we conclude that autophagic flux might play an important role in the antisteatotic action of exendin-4.

Zinc deficiency in patients undergoing pancreatoduodenectomy for periampullary tumors is associated with pancreatic exocrine insufficiency.

BACKGROUND AND PURPOSE: The present study was done to investigate the prevalence of zinc deficiency after pancreatoduodenectomy (PD) and its correlation with pancreatic exocrine insufficiency. MATERIALS AND METHODS: Patients were included in this study if they had undergone PD for periampullary tumors without recurrence and had received follow-up for more than 6 months between February 2006 and June 2007. Serum levels of zinc, fasting glucose, albumin, and iron were obtained. The pancreatic exocrine function was evaluated by a fecal elastase-1 assay, stool fat assessment, and a pancreatic duct-parenchymal ratio (DPR) at the L1 level using abdominal computed tomography (CT). The quality of life was estimated with a questionnaire of EORTC QLQ-C30 and PAN26. All of these patients were then supplemented with oral pancreatic enzymes for 4 weeks to evaluate the effect of these enzymes on zinc deficiency. RESULTS: Forty-eight eligible patients, 27 men and 21 women, were included. The mean age was 61.3 ± 1.7 years. Thirty-three (68%) patients had a zinc deficiency with a mean zinc level of 72.3 ± 2.9 mcg/dl (normal range: 80-120 mcg/dl). Patients with lower serum zinc levels tended to have typical presentations of zinc deficiency (P = 0.039, χ(2)). The serum zinc level was significantly negatively correlated with pancreatic duct diameter, DPR, and positive stool fat during the late follow-up period. The most common presentations of patients with lower serum zinc levels were skin rash, photophobia, and glossitis. These gastrointestinal disorders, as well as symptoms of zinc deficiency, improved after pancreatic enzyme supplementation. CONCLUSIONS: Zinc deficiency after PD was a common phenomenon and correlated with pancreatic exocrine insufficiency.

Effect of pancreaticoduodenectomy on the course of hepatic steatosis.

BACKGROUND: The progression of hepatic steatosis after pancreaticoduodenectomy (PD) is controversial. This study was designed to determine whether PD would influence the course of hepatic steatosis. METHODS: Patients admitted for PD and distal pancreatectomy (DP) from January 2004 to January 2008 were enrolled. Exclusion criteria included liver metastasis, severe obesity (body mass index >30), diabetic mellitus, excessive alcohol consumption, and unavailable preoperative and 6-month postoperative unenhanced CT images. The pre-PD and post-PD liver attenuation, ratio, and difference of liver-to-spleen attenuation between liver and spleen attenuation were compared. RESULTS: Fifty patients who underwent PD and 20 patients who underwent DP were eligible. The mean follow-up period was 18.2 +/- 1.6 months for the PD group and 19.7 +/- 1.7 months for the DP group. Liver attenuation after PD was significantly decreased from 52.3 +/- 1.1 H. to 47.6 +/- 2 H. (p = 0.044), but no difference was observed in spleen attenuation. The liver-to-spleen attenuation ratio after PD also was significantly decreased: 1.12 +/- 0.02 versus 1.01 +/- 0.04 (p = 0.033). No difference in liver attenuation was found in the DP group. The female gender was a significant risk factor. CONCLUSIONS: The liver attenuation of CT images decreases in patients who receive PD, which implicates that hepatic steatosis can develop after PD; however, the mechanism needs to be elucidated.

Effects of duodenal-jejunal bypass surgery in ameliorating nonalcoholic steatohepatitis in diet-induced obese rats.

BACKGROUND: Duodenal-jejunal bypass (DJB) is an important component of many types of current bariatric surgery including Roux-en-Y gastric bypass, mini-gastric bypass, biliopancreatic diversion, duodenal switch, and DJB plus sleeve gastrectomy. Surgery is often observed to ameliorate nonalcoholic steatohepatitis (NASH), but without a clearly delineated mechanism. In this study, we investigated the effects of DJB in diet-induced obese rats with NASH. MATERIALS AND METHODS: Male Wistar rats were divided into four groups and fed the following diets over 6 months: A) normal chow (NC group, n=6); B) methionine-choline-deficient (MCD)-high-fat (HF) diet (HF group, n=6); C) MCD-HF diet for 3 months followed by DJB and MCD-HF diet for subsequent 3 months (DJB group, n=6); and D) MCD-HF diet for 3 months followed by treatment with pioglitazone (PGZ) with MCD-HF diet for subsequent 3 months (PGZ group, n=6). Body weight, glucose tolerance, the homeostatic model assessment-insulin resistance index, and lipid profiles were compared. Liver and visceral adipose tissue histology, inflammatory marker and hepatic stellate cell (HSC) activity, and hepatocyte autophagy were assessed. RESULTS: Compared with the HF group, the DJB group showed improved body weight, insulin sensitivity, lipid metabolism, and steatosis severity. The DJB group exhibited a significantly lower nonalcoholic fatty liver disease activity score than the HF and PGZ group (P<0.001 and P=0.003, respectively). Furthermore, DJB significantly reduced fat mass and adipocyte size. These effects were also observed in the PGZ group. Therefore, we speculated that the improvements induced by DJB are closely related to an alteration in insulin sensitivity. Moreover, DJB reduced HSC activity and TNF-α expression and enhanced hepatocyte autophagy. CONCLUSION: DJB improves NASH through several mechanisms, particularly by altering insulin sensitivity, inflammatory responses, HSC activity, and hepatocyte autophagy.

Experience of applying cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for ovarian teratoma with malignant transformation and peritoneal dissemination.

OBJECTIVES: The prognosis of ovarian teratoma with malignant transformation and peritoneal dissemination (PD) is poor. This condition is rare but associated with a high recurrence rate even after aggressive debulking surgery and adjuvant chemotherapy. In the present paper, we describe our experience of using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for this condition. METHODS: The data of ten female patients having ovarian teratoma with malignant transformation and PD between June 2007 and June 2017 were collected and reviewed retrospectively. CRS-HIPEC was performed according to the standard protocol. Patient characteristics, pathological reports, tumor markers, perioperative operative parameters, postoperative events, and disease status during the follow-up period were recorded. RESULTS: The primary ovarian neoplasms were pure mature cystic teratoma with malignant transformation (n=6, including 5 of mucinous adenocarcinoma), mixed germ cell tumor with mature cystic teratoma and yolk sac tumor (YST) (n=1), pure immature teratoma (n=1), immature teratoma with growing teratoma syndrome (GTS) (n=1), and immature teratoma mixed YST with GTS (n=1). The mean levels of tumor markers, including carcinoembryonic antigen, cancer antigen 19-9 (CA19-9), and CA125, were markedly elevated. The recurrence rate was 10%. The median and mean disease-free survival (DFS) after CRS-HIPEC were 22.3 and 36.2 months, respectively, and the 5-year DFS rate is 88%. CONCLUSION: CRS-HIPEC is a safe therapeutic option for reducing the recurrence rate in selected patients with PD originating from ovarian teratoma with malignant transformation.

Adjuvant radiotherapy and chemotherapy improve survival in patients with pancreatic adenocarcinoma receiving surgery: adjuvant chemotherapy alone is insufficient in the era of intensity modulation radiation therapy.

In the era of intensity modulation radiation therapy (IMRT), no prospective randomized trial has evaluated the efficacy of adjuvant therapies such as adjuvant concurrent chemoradiotherapy (CCRT), adjuvant sequential chemotherapy and radiotherapy (CT-RT), and adjuvant CT alone in resectable pancreatic adenocarcinoma (PA). Through propensity score matching, we designed a nationwide, population-based, head-to-head cohort study to determine the effects of dissimilar adjuvant treatments on resectable PA. We minimized the confounding of various adjuvant treatment outcomes among the following resectable PA groups of patients from the Taiwan Cancer Registry database: group 1, adjuvant CCRT; group 2, adjuvant sequential CT-RT; and group 3, adjuvant CT alone. All the studied techniques are IMRTs. The matching process yielded a final cohort of 588 patients (196, 196, and 196 patients in groups 1, 2, and 3, respectively). In both univariate and multivariate Cox regression analyses, adjusted hazard ratios (aHRs; 95% confidence interval [CI]) of death derived for the adjuvant CCRT and adjuvant sequential CT-RT cohorts compared with the adjuvant CT alone cohort were 0.398 (0.314-0.504) and 0.307 (0.235-0.402), respectively. A combination of adjuvant IMRT and CT for resectable PA treatment improves survival to a greater extent than does adjuvant CT alone.

Zinc deficiency with acrodermatitis enteropathica-like eruption after pancreaticoduodenectomy.

Pancreaticoduodenectomy (PD) is the standard operation for periampullary lesions. Most reports have focused on the clinical outcome, complications and tumor recurrence after PD. Few studies have focused on the nutritional sequelae that result from the extended resection of the upper gastrointestinal tract and disruption of the normal physiologic process of digestion. Zinc is absorbed mainly in the duodenum and proximal jejunum, which are removed during PD. Herein, we report two patients who experienced zinc deficiency with acrodermatitis enteropathica-like eruption, alopecia, glossitis and nail dystrophy after PD. The lesions improved dramatically after supplementation with zinc sulfate, pancreatic enzyme and diet instructions. No symptoms related to zinc deficiency were noted on follow-up after nutritional instructions had been given to the patients.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal goblet cell carcinomas with peritoneal carcinomatosis: results from a single specialized center.

BACKGROUND: Goblet cell carcinomas (GCCs) of the appendix are rare and aggressive malignancies with early peritoneal dissemination. The aim of the present article is to describe our experience in the management of GCCs with peritoneal carcinomatosis (PC) through cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) and to determine the impact of multiple clinical characteristics on the prognosis. METHODS: From a prospectively maintained database of patients receiving CRS and HIPEC for peritoneal surface malignancy, the data of 15 patients with GCC and PC were collected. Neo-adjuvant laparoscopic HIPEC was performed if indicated. CRS and HIPEC with mitomycin-C or 5-fluorouracil plus oxaliplatin were performed. Adjuvant chemotherapy was also arranged if suitable for the patient's condition. RESULTS: Nine males and six females with a mean age of 52.4 years were enrolled. The estimated median survival after the diagnosis of GCC with PC and after definitive CRS-HIPEC was 28 and 17 months, respectively. The 1-, 2-, 3-, 4-year survival rates were 86%, 69%, 57%, and 24%, respectively. Log-rank test revealed that the significant independent risk factors for more favorable outcomes were age >50 years, peritoneal cancer index (PCI) <27, postoperative PCI <20, administration of HIPEC, and adjuvant chemotherapy. Multivariate analyses confirmed that administration of HIPEC played a crucial role in providing prognostic benefit. CONCLUSION: The management of GCC with PC remains challenging. We recommend CRS and HIPEC, followed by adjuvant systemic chemotherapy, as a promising strategy to improve survival, especially in selected patients with low PCI and possibility to achieve complete cytoreduction.

Hyperparathyroid crisis: the timing of surgery.

BACKGROUND: Hyperparathyroid crisis is a rare, critical, and potentially fatal disease. The aim of this study was to classify different clinical courses of this disease, according to their preoperative medical responses and suggest the proper timing for surgery. METHODS: Patients who had undergone parathyroidectomies for hyperparathyroid crisis, were enrolled between January 1, 1994 and January 31, 2009. Preoperative medical treatment and responses in terms of predisposing factors, preoperative localization, operative and pathological findings, postoperative outcome, and intervals from medicine to surgery, were retrospectively reviewed. RESULTS: A total of 11 patients, receiving more than 72 hours of medical treatment, were divided into three types by preoperative medical responses. These included: Type I (three patients were resistant to medicine with persistent serum Ca > 14 mg/mL and were eventually treated with emergency surgery; two died of postoperative respiratory and hepatic failure), Type II (six patients with abnormal serum Ca < 14 mg/mL) and Type III (two patients in whom serum calcium returned to normal preoperatively. One patient was successfully treated with emergency surgery 18 hours post-hospitalization). We found no method for predicting the medical response, but all Type I patients exhibited high serum Ca >14 mg/mL after 48 hours of medical treatment. All abnormal parathyroid glands were >1.8 cm in length and easily detectable using preoperative ultrasonography. CONCLUSION: Because the response to pharmaceutical treatment of hyperparathyroid crisis is unpredictable, relieving the patient's dehydration is necessary first. Making a definite diagnosis and performing an early parathyroidectomy within 48 hours are then required, especially in patients exhibiting poor medical response.