Optimal use of antiplatelet agents, especially aspirin, in the perioperative management of colorectal cancer patients undergoing laparoscopic colorectal resection.

BACKGROUND: Laparoscopic abdominal surgery is considered superior to open surgery. However, efficacy and safety outcomes of laparoscopic surgery in colorectal cancer (CRC) are unclear, particularly in patients undergoing antiplatelet therapy (APT). The aim of this study was to evaluate safety of antiplatelet agents, especially aspirin, in peri-operative management of patients undergoing laparoscopic colorectal resection for CRC. METHODS: A total of 578 radical laparoscopic colorectal surgeries in CRC patients performed between January 2005 and December 2015 at the Kokura Memorial Hospital were retrospectively reviewed. Patients were divided into three groups based on the risk for thromboembolism: a high-risk group receiving APT (APT-HR), a low-risk group receiving APT (APT-LR), and a low-risk group not receiving APT (non-APT). Bleeding complications (BC) and thromboembolic complications (TC) were assessed. Perioperative and outcome variables in groups receiving APT were compared with those in the non-APT group. RESULTS: APT-HR, APT-LR, and non-APT groups included 54 (9.3%), 114 (19.7%), and 410 (70.9%) patients, respectively. Blood loss during operation (p = 0.304), operative time (p = 0.956), hospitalisation after surgery (p = 0.307), and Clavien-Dindo classification of surgery-related complications (p = 0.467) were not significantly different in the three groups. Occurrence of intra-operative BC (blood loss ≥ 200 ml) (p = 0.864), post-operative BC (p = 0.630), and TC (p = 0.287) were also not significantly different in the three groups. Results of our analysis indicated that APT and non-interrupted APT were not associated with BC or TC. CONCLUSIONS: Analysis of laparoscopic colorectal resection in CRC showed that APT was not a major factor for fatal BC or TC. In patients with high thromboembolic risk, continuing aspirin may inhibit the increase in TC without increasing BC in the peri-operative period.

[A Case of Subphrenic Lymph Node Metastasis from Gastric Cancer in Which FDG-PET/CT Was Useful for Diagnosis].

A 70-year-old man was admitted for lymph node metastasis detected by FDG-PET/CT showing a mass 10mm in diameter. He had a history of a distal gastrectomy for advanced gastric cancer and was administered postoperative adjuvant chemotherapy consisting of 2 courses of TS-1 with CDDP and TS-1 only for 1 year. Lymph node recurrence was diagnosed and resected 4 years after the initial surgery. Histological examination revealed lymph node metastasis of the gastric cancer. He was administered adjuvant chemotherapy using TS-1 and has been followed-up without recurrences for 17 months after the second operation. We reported a case in which FDG-PET/CT was potentially beneficial for the diagnosis of the postoperative small lymph node metastasis.

[A Case Report of Appendiceal Cancer Complicated Appendicitis Treated with Single-Incision Laparoscopic Ileocecal Resection].

We report a case of appendicitis with an abscess that was treated with single-incision laparoscopic ileocecal resection with D2 lymphadenectomy because of intraoperative suspicion of appendiceal cancer. A 73-year-old woman was admitted to the hospital because of right lower abdominal pain. She was diagnosed with appendicitis with an abscess. Although single-incision laparoscopic appendectomy was planned, appendiceal cancer was suspected from intraoperative findings. Therefore, we performed single-incision laparoscopic ileocecal resection with D2 lymphadenectomy. The pathological result was moderately differentiated adenocarcinoma in the appendix. Because of the high risk of fStage II appendiceal cancer, adjuvant chemotherapy was administered. Neither recurrence nor metastasis have been detected 7 months after surgery.

[A Case of Extragastric-Developing Gastric Cancer with Hepatic and Pancreatic Invasion Suggesting Squamous Differentiation].

A 69-year-old man presented with left upper abdominal pain and weight loss. Contrast-enhanced CT showed a 9 cmsized extragastric tumor located between the left lateral liver section and the gastric lesser curvature. Gastroendoscopy showed a type 3 tumor located at the lesser curvature of the antrum. Biopsy confirmed that the tumor was an adenocarcinoma. With a diagnosis of extragastric-developing gastric cancer with hepatic and pancreatic invasion, the patient underwent a totalgastrectomy, D2 lymph node dissection, partiall iver resection, and pancreatic body tailexcision. The pathologicaldiagnosis was poorly differentiated adenocarcinoma suggesting squamous differentiation. Despite receiving postoperative adjuvant chemotherapy, the patient died of recurrence 7 months later.

Effect of antiplatelet therapy on patients undergoing gastroenterological surgery: thromboembolic risks versus bleeding risks during its perioperative withdrawal.

BACKGROUND: Antiplatelet agents given to prevent thromboembolic disease are frequently withdrawn prior to surgical procedures to reduce bleeding complications. This action may expose patients to increased thromboembolic morbidity and mortality. METHODS: A series of 2012 patients who had undergone gastroenterologic surgery between January 2005 and June 2010 at our institution were reviewed. Among this cohort, antiplatelet therapy (APT) was used in 519 patients (25.8 %). The perioperative management included interruption of APT 1 week before surgery and early postoperative reinstitution in patients at low thromboembolic risk, although APT was maintained until surgery in those at high thromboembolic risk. Bleeding and thromboembolic complications, as well as other outcome variables, were assessed in patients with and without APT. RESULTS: Among 519 patients with APT, 99 (19.1 %) underwent multidrug APT. Among them, 124 (23.9 %) required preoperative continuation of APT. None suffered from excessive bleeding intraoperatively. There were 19 thromboembolic events (0.9 %) in the whole cohort. Postoperative bleeding complications occurred in 37 patients (1.8 %). Multivariate analysis showed that increased postoperative bleeding complications were independently associated with multidrug APT [hazard ratio (HR) 4.3, p = 0.014], high-risk surgical procedures (HR 3.5, p = 0.003), and perioperative heparin bridging (HR 2.8, p = 0.029). High-risk surgery (HR 8.3, p < 0.001) and poor performance status (HR 4.9, p = 0.005)--but neither APT nor anticoagulation use--were significant prognostic factors for thromboembolic complications. CONCLUSIONS: Satisfactory outcomes were obtained during gastroenterologic surgery under rigorous perioperative management, including single-agent APT continuation in patients at high thromboembolic risk. Patients treated with multidrug APT still represent a challenging group, however, and need to be carefully managed to prevent perioperative complications.

[A case of adenocarcinoma occurring in the bladder mucosa after a surgical operation for colovesical fistula].

We report a case of adenocarcinoma occurring in the bladder mucosa 6 years after a surgical operation for colovesical fistula due to colonic diverticulitis of the sigmoid colon. The patient was a 76-year-old woman who had undergone a sigmoidectomy and ligation of the colovesical fistula at the age of 70 years. She presented with a complaint of gross hematuria. Cystoscopy and computed tomography revealed bladder cancer at the site of the original colovesical fistula surgery. She underwent transurethral resection of the bladder tumor. Histopathological findings revealed intestinal adenocarcinoma in the urinary bladder. A radical partial cystectomy was subsequently performed because of a positive and involved margin. This tumor may have originated from the bladder mucosa and then replaced by intestinal metaplastic cells that originated from the same initiating event.

[A case of unresectable hilar cholangiocarcinoma successfully treated by gemcitabine and S-1 combination chemotherapy].

A 52-year-old male was presented with obstructive jaundice and liver dysfunction. He was diagnosed as hilar cholangiocarcinoma involving the confluence of the right and left hepatic duct and bifurcation of the main portal vein trunk. Swollen lymph nodes in the hepatoduodenal ligament were also detected. ERBD tubes were placed in each B2, 3, and 5 branch. GEM and S-1 combination chemotherapy was carried out for four months. As a reduction in the primary tumor and lymph nodes was observed on CT scan surgical exploration was conducted, and an extended left hepatectomy with partial resection of the portal vein and regional lymph node dissection was achieved. The postoperative course was uneventful, and the patient remained free of recurrence, 34 months after the original diagnosis was made, and 29 months after surgical resection. Thus, GEM and S-1 combination chemotherapy is one of the options for the management of advanced hilar cholangiocarcinoma.

[A long survival of a patient with poor performance status who suffered from advanced right breast cancer with multiple lung metastases controlled by trastuzumab as a key drug].

We report a case of a 60-year-old woman with poor performance status (PS). She suffered from advanced right breast cancer with multiple lung metastases, which was controlled by chemotherapy with trastuzumab as the key drug. The patient presented with a 4 cm-sized large right breast mass. Her PS was poor due to progressive spinocerebellar degeneration. The biopsy specimen of the breast mass showed scirrhous type of the invasive ductal carcinoma (ER+, HER2 2+). Multiple lung metastases were also detected by computed tomography. Considering her poor PS, the patient was treated with mild systemic therapy using trastuzumab as the key drug. A different drug response was achieved between the breast mass and lung metastatic lesions, and the tumors were maintained as stable disease (SD) during first 18 months. However, she finally passed away due to respiratory failure resulting from lung metastasis, 33 months after starting treatment. The autopsy findings showed a difference of HER2 expression between the breast tumor and lung metastatic lesions. It must be recognized that differences of HER2 expression between the primary tumor and metastatic lesions are sometimes demonstrated in patients with breast cancer, and that trastuzumab can be used as a key drug in some patients as in the current case.

Salvage PTBD With Chemotherapy Improves Survival in Patients With Unresectable Malignant Biliary Obstruction - A Single Center Retrospective Study.

BACKGROUND/AIM: Malignant biliary obstruction (MBO) is a life-threatening condition. We aimed to investigate the outcome of salvage percutaneous transhepatic biliary drainage (PTBD) in patients with unresectable MBO due to failure of management by endoscopic retrograde cholangiopancreatography (ERCP) and/or prior surgical bypass. PATIENTS AND METHODS: Fifty-two consecutive patients (mean age, 69 years; 44.2% women) underwent salvage PTBD between 2013 and 2020. RESULTS: The median overall survival rate was 4.2 months, with a 95% confidence interval (CI) of 1.9-5.7. The median overall survival (OS) were 11.1 months and 1.9 months for patients who underwent chemotherapy (n=17) and best supportive care (n=35), respectively (p=0.0005). Independent factors predicting poor outcome were best supportive care, with a hazard ratio (HR) of 3.3 (95%CI=1.3-8.5), American Society of Anesthesiologists physical status classification (ASA) with a HR of 13.5 (95%CI=1.3-136.0) and Eastern Cooperative Oncology Group (ECOG) performance status of 4, with a HR of 3.3 (95%CI=1.0-6.2). CONCLUSION: Salvage PTBD with chemotherapy has the potential to achieve prolonged survival in patients with unresectable MBO, including those with failure of ERCP and/or surgical bypass.

Inhibition of poly(ADP-ribose) polymerase enhances the effect of chemotherapy in an animal model of regional therapy for the treatment of advanced extremity malignant melanoma.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is an important regulator of programmed cell death in response to alkylating agents such as temozolomide (TMZ). The goal of this study was to determine if a systemically administered PARP-inhibitor (INO-1001) could augment the efficacy of TMZ in a rat model of extremity malignant melanoma. MATERIALS AND METHODS: PARP activity was measured in vitro across a panel of 5 human malignant melanoma-derived cell lines. To evaluate tumor response to PARP inhibition in combination with regional isolated limb infusion (ILI) therapy with TMZ, two TMZ-resistant malignant melanoma cell lines were grown as xenografts in the hind limb of rats. INO-1001 (400 mg/kg) was injected intraperitoneally 7 times every 8 hours prior to ILI. Tumor volume was measured for up to 40 days. RESULTS: In vitro inhibition of PARP activity by INO-1001 ranged from 25.5% to 65.6%. In a mismatch repair (MMR)-deficient xenograft, treatment with INO-1001 prior to ILI significantly (P < .04) increased the efficacy of TMZ. The increase in tumor volume at day 40 following TMZ-ILI with INO-1001 was only 22.6% compared with 322.8% with TMZ-ILI alone. In a xenograft that was MMR-proficient and had high levels of O(6)-methylguanine-DNA methyltransferase (MGMT) activity, there was little improvement in TMZ efficacy with INO-1001 treatment. CONCLUSION: The PARP-inhibitor, INO-1001, can enhance the response of TMZ-resistant, MMR-deficient, malignant melanoma xenografts to intra-arterially administered TMZ in a regional treatment model of advanced extremity malignant melanoma.

Genomic and molecular profiling predicts response to temozolomide in melanoma.

PURPOSE: Despite objective response rates of only approximately 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor. EXPERIMENTAL DESIGN: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O(6)-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform. RESULTS: The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC(50) values ranging from 100 micromol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature-derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P

Novel surgical approach without bowel resection for multiple gastrointestinal lipomatosis: A case report.

INTRODUCTION: Asymptomatic lipoma only requires observation, whereas symptomatic lipoma requires treatment such as endoscopic or surgical resection. However, in case of multiple lipomas, with evident diffusion and malignancy, resection procedure and range cannot be determined. We experienced GI lipomatosis (multiple lipomas) diffusely existing from the duodenum to the small intestine and involved recurrent intussusception. PRESENTATION OF CASE: 47 year-old female was a history of open bowel resection for intestinal obstruction caused by intussusceptions of multiple small intestinal lipoma 11 years ago. EGD showed duodenal lipoma, and CT showed diffuse multiple lipomas from the proximal jejunum to the distal ileum. Another CT also showed intussusception of small intestine, but no signs of intestinal obstruction. Surgical procedures performed included diagnostic laparoscopy. All intestinal lipomas were resected with local excision, and duodenal lipoma was resected with ESD without any bowel resection. DISCUSSION: Multiple local excision ESD for multiple GI lipomatosis have not been reported. The most problematic thing is that if extensive resection is performed to cut off all multiple lipoma, short bowel syndrome may occur. Determining the range to be cut remains unclear. CONCLUSIONS: Multiple local excision ± ESD seemed to be one of the methods in resecting multiple GI lipomatosis. In the future, cases and indications of surgery and resection method for GI lipoma should be accumulated and considered, respectively.

Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents.

Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O(6)-alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity. In three other xenografts, there was no significant difference in response between the two chemotherapy agents. This study shows that AGT activity may be useful in predicting the utility of temozolomide-based regional therapy for advanced extremity melanoma tumors. Our observations also point out the limited ability of analysis of the GST/glutathione pathway to predict response to chemotherapies like melphalan whose resistance is primarily mediated through a complex mechanism of detoxification.

Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity.

PURPOSE: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion. EXPERIMENTAL DESIGN: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5 degrees C), or hyperthermic (43 degrees C) conditions. RESULTS: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion. CONCLUSION: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide.

Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine.

This study investigated whether the therapeutic index of regional melanoma therapy using parenteral temozolomide could be improved by chemomodulation with O6-benzylguanine (O6BG), an inhibitor of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT). Using a nude rat s.c. human melanoma xenograft model of the extremity, tumors were analyzed for AGT level 2 to 3 hours after the i.p. injection of 3.5 to 70.0 mg/kg O6BG to inhibit AGT activity. Survival studies were conducted using animals that were treated with a 15-minute isolated limb infusion with 10% DMSO in PBS (control), temozolomide alone, or temozolomide in conjunction with single or multiple doses of i.p. O6BG. Tumor volume and toxicity level were monitored every other day. Administration of 3.5 mg/kg O6BG depleted tumor AGT activity by 93.5% (P < 0.01). Groups treated with regional temozolomide alone (350 mg/kg), systemic temozolomide with O6BG, or vehicle combined with O6BG showed no significant tumor responses compared with controls. Whereas use of regional temozolomide alone at a higher dose (750 mg/kg) showed some degree of tumor response, regional temozolomide given in conjunction with multiple dosages of O6BG showed a marked (P < 0.01) reduction in tumor growth with minimal toxicity. Our findings suggest that AGT modulation by the administration of O6BG in combination with temozolomide regional chemotherapy leads to a significant improvement in melanoma antitumor responses. Clinical trials using chemotherapy modulation may improve response rates in future regional infusion and perfusion drug trials.

Is breast cancer surgery safely performed in patients receiving antithrombotic therapy?

AIM: The aim of the study was to assess the safety of surgery for breast cancer in patients with antithrombotic therapy (ATT), including antiplatelet therapy (APT) and anticoagulation therapy (ACT) for thromboembolic risks. METHODS: One hundred ninety-three consecutive patients receiving breast surgery for breast cancer at our institution between 2010 and 2015 were retrospectively reviewed. Among them, ATT was regularly used in 50 patients (25.9%). Our perioperative management included maintenance of preoperative aspirin monotherapy for APT and bridging heparin for ACT in patients at high thromboembolic risks and early postoperative reinstitution in all ATT cases. The outcome variables of patients with ATT (ATT group) were compared to those of patients without ATT (non-ATT group), and the significant risk factors for postoperative complications were determined by multivariate analysis. RESULTS: This series included 127 mastectomy and 66 breast-conserving surgery. ATT group showed significantly high frequency of history of cerebral infarction and percutaneous coronary intervention (PCI). In the ATT group, 32 patients (16.6%) were categorized as high risk for thromboembolism, but there was neither thromboembolic event nor perioperative death in the whole cohort. Surgical blood loss and rates of intraoperative transfusion were identical between the groups. Whereas overall postoperative bleeding complication was more frequently observed in the ATT group compared to the non-ATT group (12.0% vs. 3.5%, p=0.360) in univariate analyses, multivariate analysis showed that neither ATT nor preoperative aspirin continuation affected postoperative bleeding complications. CONCLUSION: Even in patients undergoing ATT, surgery for breast cancer is safely performed without any increase in blood loss or postoperative bleeding, and no thromboembolism was experienced in the series. Our perioperative management of ATT patients is valid during breast surgery, although this patient population is still challenging and should be rigorously managed.

Does antiplatelet therapy affect outcomes of patients receiving abdominal laparoscopic surgery? Lessons from more than 1,000 laparoscopic operations in a single tertiary referral hospital.

BACKGROUND: The effect of antiplatelet therapy (APT) on surgical blood loss and perioperative complications in patients receiving abdominal laparoscopic surgery still remains unclear. STUDY DESIGN: A total of 1,075 consecutive patients undergoing abdominal laparoscopic surgery between 2005 and 2011 were reviewed. Our perioperative management protocol consisted of interruption of APT 1 week before surgery and early postoperative reinstitution in low thromboembolic risk patients (n = 160, iAPT group). Preoperative APT was maintained in patients with high thromboembolic risk or emergent situation (n = 52, cAPT group). Perioperative and outcomes variables of cAPT and iAPT groups, including bleeding and thromboembolic complications, were compared with those of patients without APT (non-APT group, n = 863). RESULTS: In this cohort, 715 basic and 360 advanced laparoscopic operations were included. No patient suffering excessive intraoperative bleeding due to continuation of APT was observed. There were 10 postoperative bleeding complications (0.9%) and 3 thromboembolic events (0.3%), but the surgery was free of both complications in the cAPT group. No significant differences were found between the groups in operative blood loss, blood transfusion rate, and the occurrence of bleeding and thromboembolic complications. Multivariable analyses showed that multiple antiplatelet agents (p = 0.015) and intraoperative blood transfusion (p = 0.046) were significant prognostic factors for postoperative bleeding complications. Increased thromboembolic complications were independently associated with high New York Heart Association class (p = 0.019) and history of cerebral infarction (p = 0.048), but not associated with APT use. CONCLUSIONS: Abdominal laparoscopic operations were successfully performed without any increase in severe complications in patients with APT compared with the non-APT group under our rigorous perioperative assessment and management. Maintenance of single APT should be considered in patients with high thromboembolic risk, even when an abdominal laparoscopic approach is considered.

Enlarged extrahepatic portal vein aneurysm in a non-cirrhotic patient: a therapeutic dilemma.

The authors report a case of a 75-year-old woman who was seen about 5 years ago and found to have asymptomatic gallstone and extrahepatic portal vein aneurysm (PVA) adjacent to the gallbladder. Further investigations revealed no evidence of cirrhosis. A follow-up ultrasound revealed that the PVA increased in diameter from 20 to 25 mm over 5 years and surgical intervention was recommended. Cholecystectomy and omental wrapping around PVA were performed. Postoperative follow-up investigations for 3 years revealed no increases in PVA diameter. Although PVA is clinically rare, the authors believe that their case report presents an overview of related literature, discusses indications for surgery in PVA and describes their surgical method for managing PVA.

Gene expression signatures as a guide to treatment strategies for in-transit metastatic melanoma.

In-transit metastatic melanoma, which typically presents as multifocal lesions, provides a unique setting to evaluate the utility of gene signatures for defining optimal regional therapeutic strategies and assessing the efficacy of treatment. The goal of this study was to determine whether a single multifocal lesion is representative of residual tumor burden in terms of gene expression signatures predictive of response to therapy. Using microarray-based gene expression profiling, we examined 55 in-transit melanoma lesions across 29 patients with multifocal disease. Principal component analysis, unsupervised hierarchical clustering, one-way ANOVA, binary regression analysis, and gene signatures predictive of oncogenic pathway activation were used to compare patterns of gene expression across all multifocal lesions from a patient. Patterns of gene expression were highly similar (P < 0.006; average r = 0.979) across pretreatment lesions from a single patient compared with the significantly different patterns observed across patients (P < 0.05). The findings presented in this study show that individual melanoma tumor nodules in patients with multifocal disease harbor similar patterns of gene expression and a single lesion can be used to predict response to chemotherapy, evaluate the activation status of oncogenic signaling pathways, and characterize other aspects of the biology of an individual patient's disease. These results will facilitate the use of gene expression profiling in melanoma regional therapy clinical trials to not only select optimal regional chemotherapeutic agents but to also allow for a more rational identification of candidates for specific targeted therapies and evaluation of their therapeutic efficacy. Mol Cancer Ther; 9(4); 779-90. (c)2010 AACR.

Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy.

Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.