Munehiro Yoshitomi

A phase II study of a personalized peptide vaccination for chemotherapy-resistant advanced pancreatic cancer patients

Pancreatic cancer is one of the most aggressive cancers with a median survival time (MST) of <6 months in chemotherapy-resistant patients. Therefore, the development of novel treatment modalities is needed. In the present study, a phase II study of personalized peptide vaccination (PPV) was conducted, in which vaccine antigens were selected and administered based on the pre-existing IgG responses to 31 different pooled peptides, for 41 chemotherapy-resistant advanced pancreatic cancer patients. No vaccine-related severe adverse events were observed. IgG responses specific to at least one of the vaccine peptides were augmented in 14 of 36 patients (39%) and in 18 of 19 patients (95%) tested after the 5th and 11th vaccination, respectively. MST from the first vaccination was 7.9 months with a 1-year survival rate of 26.8%. Higher serum amyloid A (SAA) and C-reactive protein (CRP) levels in pre-vaccination plasma were unfavorable factors for overall survival (OS). Due to the safety profile and the potential clinical efficacy, the conduction of additional clinical trials of PPV for chemotherapy-resistant advanced pancreatic cancer patients is warranted.

Intraductal neoplasm of the intrahepatic bile duct: Clinicopathological study of 24 cases

AIM To investigate the clinicopathological features of intraductal neoplasm of the intrahepatic bile duct (INihB). METHODS Clinicopathological features of 24 cases of INihB, which were previously diagnosed as biliary papillomatosis or intraductal growth of intrahepatic biliary neoplasm, were reviewed. Mucin immunohistochemistry was performed for mucin (MUC)1, MUC2, MUC5AC and MUC6. Ki-67, P53 and β-catenin immunoreactivity were also examined. We categorized each tumor as adenoma (low grade), borderline (intermediate grade), and malignant (carcinoma in situ, high grade including tumors with microinvasion). RESULTS Among 24 cases of INihB, we identified 24 tumors. Twenty of 24 tumors (83%) were composed of a papillary structure; the same feature observed in intraductal papillary neoplasm of the bile duct (IPNB). In contrast, the remaining four tumors (17%) showed both tubular and papillary structures. In three of the four tumors (75%), macroscopic mucin secretion was limited but microscopic intracellular mucin was evident. Histologically, 16 tumors (67%) were malignant, three (12%) were borderline, and five (21%) were adenoma. Microinvasion was found in four cases (17%). Immunohistochemical analysis revealed that MUC1 was not expressed in the borderline/adenoma group but was expressed only in malignant lesions (P = 0.0095). Ki-67 labeling index (LI) was significantly higher in the malignant group than in the borderline/adenoma group (22.2 ± 15.5 vs 7.5 ± 6.3, P < 0.01). In the 16 malignant cases, expression of MUC5AC showed borderline significant association with high Ki-67 LI (P = 0.0622). Nuclear expression of β-catenin was observed in two (8%) of the 24 tumors, and these two tumors also showed MUC1 expression. P53 was negative in all tumors. CONCLUSION Some cases of INihB have a tubular structure, and are subcategorized as IPNB with tubular structure. MUC1 expression in INihB correlates positively with degree of malignancy.

Metastatic Pulmonary Adenocarcinoma 13 Years After Curative Resection for Pancreatic Cancer: Report of a Case and Review of Japanese Literature

CONTEXT For the majority of patients, ductal adenocarcinoma of the pancreas remains a lethal disease. Currently, surgical extirpation for localized disease offers the only chance for long-term survival. CASE REPORT We report a patient who underwent successful resection of isolated lung metastasis occurring 13 years after pancreatic cancer resection. A 59-year-old woman underwent distal pancreatectomy for pancreatic cancer 13 years previously, followed by adjuvant chemotherapy, and was followed-up at the outpatient clinic of a local hospital. From around June 2010, she noticed bloody sputum, so she visited a local hospital. Since her chest X-ray and CT revealed a 1.5 cm mass shadow in the segment 10 of her right lung and she was referred to the Respiratory Disease Center of our hospital. As a result of through examinations, she was strongly suspected of having lung metastasis of pancreatic cancer, and underwent partial pneumonectomy. Postoperative histopathological examination of the resected specimen was consistent with lung metastasis of pancreatic cancer. She is still alive and currently receives third line of chemotherapy. CONCLUSION Patients who have achieved long-term survival after pancreatic cancer resection and can tolerate surgery may benefit from resection of a lung metastasis of pancreatic cancer in terms of survival, if it controls the metastasis.

Perioperative challenges associated with a pancreaticoduodenectomy and distal pancreatectomy for pancreatic cancer in patients with situs inversus totalis: Report of two cases

Situs inversus totalis is a rare anatomic variant of a complete mirror-image transposition of the thoracic and abdominal viscera. The performance of a pancreaticoduodenectomy and distal pancreatectomy in patients with situs inversus totalis is both rare and challenging. We herein present two cases of pancreatic cancer with situs inversus totalis. The abdominal anatomy was preoperatively assessed by multidetectorrow computed tomography, three-dimensional reconstruction, and angiography. We herein report that a pancreaticoduodenectomy and distal pancreatectomy with standard regional lymphadenectomy are feasible in patients with situs inversus totalis. Due to the transposition of the viscera and major blood vessels in such cases, preoperative knowledge of the exact anatomy, mapping of anomalies, and meticulous forward planning are essential for performing these technically difficult and complex hepatobiliary-pancreatic surgeries.

Current status of immunotherapy for the treatment of biliary tract cancer

Biliary tract cancer (BTC) is one of the most aggressive malignancies. Although various promising regimens of chemotherapeutic and/or molecular targeted agents have been developed, further treatment modalities, including immunotherapies, still remain to be established for refractory patients who are unresponsive to or relapse after currently available therapeutic options for BTC. Recently, several clinical trials of immunotherapies, including peptide-based vaccines and dendritic cell (DC)-based vaccines, have been reported with promising results. Here we summarize the data from phase I or phase II clinical trials of immunotherapies for BTC. In particular, we introduce our novel immunotherapeutic approach called personalized peptide vaccine (PPV), in which HLA-matched peptides were selected and administered based on the pre-existing host immunity before vaccination, for the treatment of advanced BTC. Further clinical trials would be recommended to prove clinical benefits of these novel immunotherapeutic approaches. Recently concomitant treatments, such as chemotherapies and immune checkpoint blockade, have been reported to enhance the therapeutic effects of cancer immunotherapies through multiple coordinated immune mechanisms. Additional therapies in combination with immunotherapies could produce synergistic effects in the treatment of advanced BTC.

Evaluation of prognostic significance of granulocyte-related factors in cancer patients undergoing personalized peptide vaccination

Since cancer vaccines do not always elicit beneficial effects in treated patients, identification of biomarkers for predicting clinical outcomes would be highly desirable. We previously reported that abnormal granulocytes present in peripheral blood mononuclear cells (PBMC) may contribute to poor prognosis in advanced prostate cancer patients receiving personalized peptide vaccination (PPV). In the current study, we examined whether soluble factors derived from granulocytes, such as matrix metalloproteinase 9 (MMP-9), myeloperoxidase (MPO), and arginase 1 (ARG1), and inhibitory cytokine TGFβ in pre-vaccination plasma were useful for predicting prognosis after PPV in advanced cancer patients. In biliary tract cancer (n=25), multivariate Cox regression analysis demonstrated that patients with higher plasma MMP-9 levels had a significantly worse overall survival (OS) [hazard ratio (HR) = 4.637, 95% confidence interval (CI) = 1.670 - 12.877, P = 0.003], whereas MPO, ARG1, or TGFβ levels were not correlated with OS. Similarly, patients with higher MMP-9 levels showed worse prognosis than those with lower MMP-9 levels in other types of advanced cancers, including non-small cell lung cancer (n=32, P = 0.037 by log-rank test), and pancreatic cancer (n=41, P = 0.042 by log-rank test). Taken together, plasma MMP-9 levels before vaccination might be potentially useful as a biomarker for selecting advanced cancer patients who would benefit from PPV.

The Safety and Efficacy of Combination Therapy of Sorafenib and Radiotherapy for Advanced Hepatocellular Carcinoma: A Retrospective Study

Objective Sorafenib is a standard therapy for advanced hepatocellular carcinoma (HCC), whereas radiotherapy is effective for local control of extrahepatic spread (EHS) or macrovascular invasion (MVI). This study investigated the safety and efficacy of this combined therapy to treat advanced HCC. Methods This retrospective study reviewed 62 patients with advanced-stage HCC with EHS or MVI who received sorafenib therapy, excluding the patients with only lung metastases. Results Of the 62 patients, 15 were treated using the combined therapy of sorafenib and radiotherapy (group RS), and 47 were treated with sorafenib monotherapy (group S). In group RS, patients were treated using three-dimensional conformal radiotherapy with a total irradiation dose of 30-60 Gy (median, 50 Gy). Irradiation was targeted at the bone, lymph nodes, adrenal gland, and MVI in 6, 5, 1, and 4 patients, respectively. The overall incidence of adverse events was 93.3% in group RS and 91.5% in group S (p=N.S.). Incidences of thrombocytopenia, leukopenia, and skin reaction were significantly higher in group RS (73.3%, 40.0%, and 66.7%, respectively) than in group S (36.2%, 10.6%, and 27.7%, respectively, p=0.02, 0.02, and <0.01, respectively). The incidence of severe adverse events, however, was comparable in the 2 groups: 20% in group RS and 19.2% in group S. The median progression-free survival (PFS) of EHS or MVI, PFS of whole lesions, and overall survival were longer in group RS (13.5, 10.6, and 31.2 months, respectively) than in group S (3.3, 3.5, and 12.1 months, respectively) (p<0.01 for all). Conclusion Sorafenib in combination with radiotherapy is a feasible and tolerable treatment option for advanced HCC.

Prediction of post-progression survival in patients with advanced hepatocellular carcinoma treated with sorafenib by using time-dependent changes in clinical characteristics

Aim: Sorafenib has been shown to improve time to tumor progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC); however, post-progression survival (PPS) has not been well characterized in these patients. This study aimed to evaluate the predictors of PPS by using time-dependent and dynamic changes in radiologic progression patterns, liver function, and performance status (PS) in patients with advanced HCC receiving sorafenib treatment. Methods: We retrospectively analyzed the clinical characteristics of 128 advanced HCC patients with Child-Pugh scores ≤ 7 at the initiation of sorafenib treatment. Results: The median TTP, OS, and PPS were 3.8, 15.6, and 9.9 months, respectively. At the time of confirmation of radiologic progressive disease (PD), a total of 46 (35.6%) patients showed impairments in their PS of ≥ +1 points over time. For the Child-Pugh score, 27 (21.1%) and 26 (10.9%) patients exhibited an impairment of ≥ +1 and ≥ +2 points, respectively. Multivariate analysis identified the following independent predictors of PPS: impairment in the PS score of ≥ +1 point [hazard ratio (HR) 1.81, 95% confidence interval (CI) 1.16-2.82], impairment in the ChildPugh score of ≥ +2 points (HR 3.70, 95% CI 1.68-8.15), radiologic pattern of progression (target lesion growth and emergence of a new lesion) (HR 2.91, 95% CI 1.79-2.91), a TTP < 4 months (HR 1.87, 95% CI 1.21-2.91), second-line treatment after radiologic confirmation of PD (HR 0.16, 95% CI 0.08-0.32), and continuous sorafenib treatment after radiologic confirmation of PD (HR 1.76, 95% CI 1.06-3.00). Conclusion: PPS in patients with advanced HCC can be characterized by using time-dependent dynamic changes in clinical parameters.

Abstract LB-134: Personalized peptide vaccination as the second line therapy for patients with chemotherapy-resistant advanced pancreatic cancer.

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Since the prognosis of advanced pancreatic cancer remains poor, development of novel therapeutic approaches, including cancer vaccine, would be highly desirable. We conducted a phase II study of personalized peptide vaccine (PPV) in chemotherapy-resistant advanced pancreatic cancer patients. Methods: Forty-one advanced pancreatic cancer patients (7 Stage IVa, 24 Stage IVb, 10 recurrence) who failed to respond to the first line chemotherapy were enrolled. Median duration of chemotherapy prior to the enrollment was 8 months. A maximum of four HLA-matched vaccine peptides showing higher antigen-specific immune responses were selected based on the titers of IgG against each of 31 different peptide candidates, and employed for subcutaneous vaccination. In order to identify potentially prognostic biomarkers for overall survival (OS), pre-vaccination clinical findings and laboratory data were retrospectively assessed and evaluated by multivariate Cox proportional hazards model in 36 patients who completed at least one cycle of 6 vaccinations. Results: Median OS from the first vaccination was 7.9 M with a one-year survival rate of 24%. Notably, median OS from the first line chemotherapy was 19.2 M. The main toxicity of PPV was skin reactions at the injection sites, but no vaccine-related serious adverse events were observed. Among the pre-vaccination factors examined, high level of serum amyloid A (SAA) and high titer of the IgG against 31 vaccine peptide candidates were significantly unfavorable for OS [hazard ratio (HR) = 1.019, P = 0.006; HR = 0.999, P = 0.0001; respectively] by the Cox multivariate analysis. The clinical stage was also associated with OS, as expected (HR = 0.496, P = 0.014). Conclusions: Even in chemotherapy-resistant advanced pancreatic cancer patients, PPV might improve the prognosis. Further randomized clinical trials of PPV would be recommended in advanced pancreatic cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-134. doi:1538-7445.AM2012-LB-134