Clinicopathological features and surgical outcomes of intraductal tubulopapillary neoplasm of the pancreas: a systematic review.

BACKGROUND AND AIMS: Intraductal tubulopapillary neoplasms (ITPNs) of the pancreas are rare. The purpose of this study was to collate and analyze published data on ITPNs of the pancreas to determine the clinicopathological features of the tumors and the surgical outcomes of patients. PATIENTS AND METHODS: We searched MEDLINE and Igakuchuo-Zasshi for the period of 1980 to 2015 for case reports on surgical resection for ITPN of the pancreas. We evaluated the clinicopathological data associated with pancreatic ITPNs, the prognosis for each patient, and surgical outcomes described in the case reports. RESULTS: We obtained clinicopathological data for 58 patients (33 men and 25 women) with a mean age of 61 years (range, 35-84 years) who had undergone surgical resection for ITPN of the pancreas, including one patient from our clinic. Although ITPNs of the pancreas have different clinicopathological features to intraductal papillary mucinous neoplasms, the treatment strategy for patients with ITPNs is the same as for patients with other cystic neoplasms of the pancreas. The immunohistochemical features of ITPNs included testing positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. The overall 1-, 3-, and 5-year survival rates after surgery for the 37 cases with available data were 97.3, 80.7, and 80.7 %, respectively. CONCLUSION: Surgical treatment is the only curative management option for patients with ITPN of the pancreas. To determine the best management strategy for this tumor and improve accuracy of prognosis for patients, we will continue to collect and analyze epidemiological and pathological data.

A totally implanted intra-arterial chemotherapy system for advanced maxillary sinus carcinoma.

CONCLUSION: Both reservoir systems for intra-arterial cisplatin and intravenous sodium thiosulfate infusions are low- invasive, safe and effective procedures for treatment of advanced maxillary sinus carcinoma. OBJECTIVES: To use our reservoir system for intra-arterial high-dose cisplatin infusion therapy in patients with advanced maxillary sinus carcinoma. MATERIALS AND METHODS: Eight patients with advanced maxillary sinus carcinomas underwent treatment utilizing intra-arterial cisplatin (CDDP) infusion and radiation therapy followed by planned surgical resection. For intra-arterial infusion of high-dose cisplatin, both intra-arterial and intravenous reservoir systems were used. RESULTS: CDDP was infused 4-6 times (mean 5.1) and the total dose of CDDP was between 690 and 910 mg (mean 771 mg). The response rate was 100 with 50% CR and 50% PR and all patients underwent medial maxillectomy. Only 1 T(4) patient had local recurrence and 1 other patient had bilateral neck metastasis.

Phase I study of a new radiosensitizer containing hydrogen peroxide and sodium hyaluronate for topical tumor injection: a new enzyme-targeting radiosensitization treatment, Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II).

Using a currently employed linear accelerator, our intent was to inactivate peroxidase/catalase in tumor tissue by the application of hydrogen peroxide, which is degraded to produce oxygen, thus re-oxygenizing the tumor tissue. In this way, we can convert radioresistant tumors into radiosensitive ones. On the basis of this strategy, we previously developed a new enzyme-targeting radiosensitization treatment named KORTUC I, which remarkably enhances the radiotherapeutic effect on various types of superficially exposed and locally advanced malignant neoplasms. Based on our clinical experience using KORTUC I, we also developed a new radiosensitizer containing hydrogen peroxide and sodium hyaluronate for injection into various types of tumors that are not superficially exposed (KORTUC II; described herein). KORTUC II was approved by our local ethics committee for advanced skin cancer, including malignant melanoma, bone/soft tissue malignant neoplasms, breast cancer, and metastatic lymph nodes. A maximum of 6 ml of the agent was injected into tumor tissue one to two times per week under ultrasonographic guidance, just prior to each administration of radiation therapy. Eleven patients, including seven with breast cancer, were enrolled in the KORTUC II trial upon fully informed consent. KORTUC II was well tolerated, with a minimum of adverse effects. Nine of the 11 patients showed a complete response (CR), and no severe complications occurred in any of the 11 patients. This new enzyme-targeting radiosensitization treatment may be indicated for various types of locally advanced neoplasms, including soft tissue neoplasms and breast cancers.

[A case of small cell undifferentiated carcinoma of the esophagus successfully treated by chemoradiotherapy].

Small cell carcinoma of the esophagus is rare, with a poor prognosis, and there is currently no standard therapy. Here we report a case of small cell carcinoma of the esophagus with right supraclavicular lymph node metastasis which was successfully treated by chemoradiotherapy. A 55-year-old man was admitted to our hospital with a right-sided neck tumor. The neck tumor was diagnosed as a small cell carcinoma by aspiration cytology. Endoscopy revealed an irregular tumor in the middle thoracic esophagus, 31 cm from the upper incisor teeth, but malignant cells were not detected from an esophageal biopsy. Right supraclavicular lymph node metastasis was detected by computed tomography and positron emission tomography computed tomography, and aspiration cytology revealed small cell undifferentiated carcinoma cells. The patient was diagnosed with a small cell carcinoma of the esophagus with supraclavicular lymph node metastasis, stage III: T2N3M0. Concurrent chemoradiotherapy using 5-fluorouracil and cisplatin was started. Lymph node reduction occurred from day 3, and endoscopy two months after chemoradiotherapy showed only a scar. We diagnosed the patient in complete remission, and he continues to do well with a recurrence-free status of 14 months after initial chemoradiotherapy.

Radiological imaging features of invasive micropapillary carcinoma of the breast and axillary lymph nodes.

Invasive micropapillary carcinoma of the breast is of growing clinical significance. The purpose of this study was to identify the radiological imaging features for this type of breast carcinoma and the axillary lymph nodes. The study population consisted of 30 breast cancer patients (8 invasive micropapillary carcinomas and 22 other types of invasive ductal carcinoma). The breast lesions were evaluated with mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (MRI) prior to neoadjuvant chemotherapy. The pathological outcome of the axillary lymph nodes in 27 patients was correlated with the sonographic findings. Only contrast-enhanced MRI showed characteristic findings for invasive micropapillary carcinoma. Although invasive micropapillary carcinoma is commonly irregular in shape (7/8) compared with other types of invasive carcinoma (6/22) (p=0.012, chi(2) test), a careful interpretation of radiological imaging to identify lesion borders helped the complete clearance of cancer cells from 6/8 patients with invasive micropapillary carcinoma in one-time breast conservative surgery. The positive and negative predictive values of sonography in diagnosing axillary lymph node metastases in cases of invasive micropapillary carcinoma were 100 and 50%, respectively. In conclusion, contrast-enhanced MRI reveals the irregular shape of invasive micropapillary carcinoma and helps conservative breast surgery to be performed safely. The pathological analysis of axillary nodes in cases of invasive micropapillary carcinoma may prove to be indispensable due to the relatively low negative predictive value of sonography.

Perforating branches of the internal thoracic artery in women with breast cancer: an anatomical study for breast-conservation surgery.

Breast reconstruction after breast-conservation surgery is an important issue for breast cancer patients. Various factors are associated with complications, of which blood flow is one of the more important. The perforating branches of the internal thoracic artery (ITA) are key contributors to blood flow in the anterior chest wall. The present study examined the distributions and depths of the perforating branches of the internal thoracic artery using a multi-detector row-computed tomography (MDCT) angiography. The subjects in this prospective study comprised of 38 women with suspected breast cancer who underwent MDCT angiography. The images were analyzed on computer using transverse MDCT source data and volume renderings. A total of 47 perforating branches were found, with 27 (57.4%) originating in the second, 6 (12.8%) in the third and fourth, 5 (10.6%) in the first and 2 branches (4.3%) originating in the fifth intercostal space, with one branch (2.1%) originating opposite the first intercostal space. A strong correlation was identified between the distance from the skin to the branch and adipose thickness at the shallowest and deepest points (P<0.001). The distributions and depths of the perforating branches of ITA identified in this study may be helpful in immediate breast reconstruction following mastectomy or breast-conserving surgery.

Long-term effects of multimodal treatment for patients with resectable carcinoma of the pancreas.

The treatment of pancreatic carcinoma remains one of the most formidable challenges in oncology. Curative resection, currently the only available treatment option, provides no significant impact on long-term survival. The recent development of multimodal treatment options for pancreatic cancer has provided clinical benefits and improved patient survival. In this study, we retrospectively evaluated our experiences with multimodal therapy, including radiotherapy and chemotherapy with gemcitabine, for the treatment of resectable pancreatic cancer. Fifty-eight patients with ordinary pancreatic carcinoma who underwent surgical resection at Kochi Medical School were studied. The clinical and pathological factors and multimodal treatment for pancreatic carcinoma that influenced patient survival were analyzed. Cumulative 1-, 3- and 5-year survival rates after surgery for ordinary pancreatic carcinoma were 62.2, 20.3 and 20.3%, respectively. The overall 4-year survival rate of patients subjected to adjuvant chemotherapy with gemcitabine after curative resection for ordinary pancreatic carcinoma is 39.1%. Adjuvant chemotherapy with gemcitabine provided a significantly better prognosis for patients following curative surgical resection than curative surgical resection alone (P=0.035). Although the rate of survival was greater for patients who underwent radiotherapy than those who did not, the difference was not statistically significant (P=0.054). Postoperative local recurrence around the nerve plexus of celiac and superior mesenteric arteries was better controlled in patients who underwent radiotherapy than those who did not. Adjuvant chemotherapy with gemcitabine after curative resection provides a significant survival benefit for patients with pancreatic carcinoma. Our results suggest that the postoperative recurrence of ordinary pancreatic carcinoma will be reduced by multimodal treatment using radiotherapy and adjuvant chemotherapy with gemcitabine.

New radiosensitization treatment (KORTUC I) using hydrogen peroxide solution-soaked gauze bolus for unresectable and superficially exposed neoplasms.

We developed a new radiosensitization treatment using a hydrogen peroxide solution (Oxydol)-soaked gauze named KORTUC I (Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas) for superficially exposed and unresectable neoplasms, such as malignant melanoma and malignant fibrous histiocytoma (MFH), based on our experimental results which demonstrated hydrogen peroxide as a strong radiosensitizer for the highly radioresistant osteosarcoma cell line, HS-Os-1. Five patients entered our clinical trial, one of whom had unresectable malignant melanoma; one, unresectable MFH; one, unresectable extramammary Paget's disease; one, locally advanced breast cancer and one with locally recurrent skin cancer. These patients were treated with radiation therapy using a high-energy electron beam from a linear accelerator. The total dose was 48 Gy, and each fraction size was 4 Gy. Radiation therapy for these patients was performed three times per week. Each time the radiation therapy was carried out, the superficially exposed tumors of these patients were covered with hydrogen peroxide solution (Oxydol)-soaked gauze, and the lesion was gently massaged for several minutes so as to allow the hydrogen peroxide solution to soak deeply into the tumor. In the treatment results, two of these five patients showed a clinically complete response (cCR) two to three months following the end of the KORTUC I radiosensitization treatment. The other three patients showed a clinically partial response (cCR) showing a decrement of more than half of the pretreatment volume. KORTUC I was completed without any severe complications, excluding mild radiation-induced dermatitis/mucositis (Grade I). In conclusion, this newly developed radiosensitization treatment using hydrogen peroxide solution (Oxydol)-soaked gauze for superficially exposed unresectable/radioresistant neoplasms appears to be an effective and valuable method of radiosensitization in terms of the blockade of anti-oxidative enzymes such as peroxidases, resulting in local oxygen production. Moreover, the KORTUC I radiosensitization treatment is relatively inexpensive and the method can therefore be utilized worldwide for many patients suffering from superficially exposed and locally advanced radioresistant neoplasms such as malignant melanoma, malignant fibrous histiocytoma (MFH) and various types of sarcomas.

Diagnostic accuracy of mammography, ultrasonography and magnetic resonance imaging in the detection of intraductal spread of breast cancer following neoadjuvant chemotherapy.

The purpose of this study is to evaluate the accuracy of mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging for the diagnosis of intraductal spread of breast cancer following preoperative neoadjuvant chemotherapy. We evaluated a total of 168 areas of normal breast tissue outside the mass in 42 consecutive female patients with breast cancer using each imaging modality both before and after neoadjuvant chemotherapy. Neoadjuvant chemotherapy comprised two to four cycles of adriamycin-based CAF regimen. Multivariate analysis indicated that calcification on mammography and size of hypoechoic structures on ultrasonography prior to neoadjuvant chemotherapy shows a correlation with intraductal spread on pathologic study. Our study reveals that mammography and ultrasonography are useful in avoiding residual cancer cells caused by intraductal spread following conservative breast surgery.

Clinical effects of chemoradiotherapy in pursuit of optimal treatment of locally advanced unresectable pancreatic cancer.

OBJECTIVE: The treatment of locally advanced unresectable pancreatic cancer remains extremely challenging, particularly as the efficacy of concurrent chemoradiotherapy (CRT) remains unclear. METHODS: We studied 93 patients (8.0%) with locally advanced unresectable pancreatic cancer without distant metastases from among a total group of 1168 patients who were diagnosed with pancreatic cancer from March 2005 to November 2015 at the Kochi Health Sciences Center, Kochi, Japan. We therefore evaluated the clinical efficacy of CRT in patients with locally advanced unresectable pancreatic cancer. RESULTS: Of the 93 patients with locally advanced unresectable pancreatic cancer, 35 patients (37.6%) were subsequently classified as having resectable disease following CRT. The median overall survival of patients who received CRT alone for locally advanced unresectable pancreatic cancer was 8.0 months, and all died within 3 years. On the other hand, the overall 1-, 3- and 5-year survival rates in patients who were reclassified as having resectable tumour after CRT were 71.3%, 39.2% and 23.5%, respectively. Our pathological assessments after surgical resection suggested that CRT might be associated with a significant reduction in the risk of lymph node metastases in patients with locally advanced unresectable pancreatic cancer. CONCLUSION: The results of this study suggested that CRT is clinically effective in improving survival, particularly in association with the resultant possibility of curative resection. Advances in knowledge: The best treatment strategy for patients with locally advanced unresectable pancreatic cancer is the subject of considerable debate, and CRT is only recommended if cancer has only grown around the pancreas without any distant metastases.

Sentinel node biopsy in breast cancer patients treated with neoadjuvant chemotherapy.

A sentinel node biopsy (SNB) has been proved to be an accurate method to estimate the axillary lymph node status as a replacement for axillary lymph node dissection (AxLND) in patients with early breast cancer who have not been treated with neoadjuvant chemotherapy (NAC). We examined the feasibility and accuracy of performing SNB after NAC. Seventy breast cancer patients treated with NAC were enrolled in the current study during the period between March 2001 and June 2005. NAC performed preoperatively consisted of three to four times of CAF chemotherapy. Moreover, intra-arterial (subclavian artery and internal mammary artery) infusion of epirubicin and 5-fluorouracil was performed in addition to systemic CAF chemotherapy once to three times in patients with large breast tumors or bulky axillary lymph node metastases. The sentinel nodes were successfully identified in 63 out of 70 patients (identification rate: 90%). The mean number of sentinel nodes removed per patient was 1.5 (range 1-6). Of the 43 patients in whom AxLND was performed after the sentinel nodes were identified, 19 (44.2%) had positive sentinel nodes. In 8 of those 19 patients, the sentinel node was the only cancer positive lymph node. Among the 24 patients who had negative sentinel nodes it was found that one patient had a confirmed false negative result, thus yielding a false negative rate of 5%, and a sensitivity of 95%. There was no false negative patient who had a clinically negative lymph node status (N0) before NAC (17 patients), whereas the false negative rate was 6.3% in the subgroup of patients with a clinically positive lymph node status (N1, N2) before NAC (26 patients). As a result, SNB after NAC is thus considered to be able to effectively predict the axillary lymph node status in patients with a clinically negative lymph node status before NAC.

Development of a Novel Enzyme-Targeting Radiosensitizer (New KORTUC) Using a Gelatin-Based Hydrogel Instead of a Sodium Hyaluronate.

We recently developed Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas (KORTUC) as a strategy to increase intratumoral oxygen concentrations and degrade antioxidant enzymes such as peroxidase and catalase. We then developed KORTUC II, which uses sodium hyaluronate containing hydrogen peroxide as a radiosensitizer. KORTUC II requires twice-weekly administration to sustain its effects, but decreasing the frequency of radiosensitizer injections to once-weekly would reduce the burden on the patients and the physicians. The goal of this study was thus to develop a new formulation of KORTUC (New KORTUC) that only requires once-weekly administration. We performed experimental studies using a mouse tumor model and biodegradable hydrogel. C3H/He mice were allocated to control, KORTUC, or hydrogel groups. At 72 h after injection, each tumor was irradiated with a 6 MeV electron beam to a total dose of 30 Gy. During a 62-day observation period, changes in tumor volume and survival rates were assessed in each group. Tumor growth rate was slowest in the hydrogel groups. These data suggest that hydrogel could represent a useful adjunct as a long-acting radiosensitizer in place of sodium hyaluronate. New KORTUC, which contains hydrogen peroxide and hydrogel, exerted a radiosensitizing effect that persisted beyond 72 h following injection of the agent. Use of this new formulation allows radiosensitizer injections to be performed once-weekly with good effect.

Computed Tomography Demonstration of the Production and Distribution of Oxygen Gas Following Intratumoral Injection of a New Radiosensitizer (KORTUC) for Patients with Breast Cancer-Is Intratumoral Injection Not an Ideal Approach to Solve the Major Problem of Tumor Hypoxia in Radiotherapy?

We previously developed a new enzyme-targeting radiosensitization treatment named Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate for injection into various types of tumors. For breast cancer treatment, the radiosensitization agent was injected into the tumor tissue twice a week under ultrasonographic guidance, immediately prior to each administration of radiation therapy. At approximately three hours after the second or third injection, computed tomography (CT) was performed to confirm the production and distribution of oxygen gas generated from the KORTUC radiosensitization agent by catalysis of peroxidases contained mainly in tumor tissue. The purpose of this study was to demonstrate that tumor hypoxia could be overcome by such a procedure and to evaluate the method of intratumoral injection in terms of confirming oxygen distribution in the target tumor tissue and around the tumor to be visualized on dedicated CT imaging. Three-dimensional reconstructed maximum intensity projection imaging of contrast-enhanced breast magnetic resonance imaging was used to compare the position of the tumor and that of the generated oxygen. Distributed oxygen gas was confirmed in the tumor tissue and around it in all 10 patients examined in the study. A region of oxygen gas was measured as an average value of -457.2 Hounsfield units (HU) as a region of interest. A slightly increased HU value compared to the density of air or oxygen was considered due to the presence of tumor tissue in the low-density area on 5-mm-thick reconstructed CT imaging. The results of this study showed that intratumoral oxygen was successfully produced by intratumoral KORTUC injection under ultrasonographic guidance, and that tumor hypoxia, which is considered a main cause of radioresistance in currently used Linac (linear accelerator) radiation therapy for malignant neoplasms, could be resolved by this method.

Is a surgical approach justified for octogenarians with pancreatic carcinoma? Projecting surgical decision making for octogenarian patients.

BACKGROUND: In recent years, more elderly patients have undergone surgery for pancreatic cancer, although the safety and efficacy of performing complex pancreatic resections in patients older than 80 years remain controversial. METHODS: Patients with pancreatic cancer who underwent curative surgical treatment were divided into 2 subgroups: the younger group (<80 years) and the octogenarian group (≥80 years). RESULTS: From March 2005 to December 2013, 194 consecutive surgically curable patients with diagnosed pancreatic cancer were studied, among which 34 (17.5%) were of 80 years or older. There were no significant differences in postoperative severe complication rates for younger and octogenarian groups (16% vs 20%, respectively) or perioperative mortality rates (1.3% vs .0%). The incidence of postoperative delirium in the octogenarian group was greater than that in the younger group (23.5% vs 3.8%). CONCLUSIONS: Octogenarian pancreatic cancer patients should not be denied a priori the opportunity for surgery, particularly if the patient represents an ideal candidate and if the co-operation of the family can be obtained.

Therapeutic response to a novel enzyme-targeting radiosensitization treatment (Kochi Oxydol-Radiation Therapy for Unresectable Carcinomas) in patients with recurrent breast cancer.

Linear accelerator-based radiotherapy has little effect on the majority of locally advanced neoplasms. Thus, the novel radiosensitizer Kochi Oxydol Radiation Therapy for Unresectable Carcinomas, Type II (KORTUC II), which contains hydrogen peroxide and sodium hyaluronate, was developed. The effectiveness of KORTUC II for the treatment of chemotherapy-resistant supraclavicular lymph node metastases has been previously demonstrated. The present study evaluated the safety and effectiveness of KORTUC II in patients with recurrent breast cancer. A total of 20 patients (age range, 39-84 years) were enrolled in the study. The majority of patients underwent positron emission tomography (PET)-computed tomography (CT) examinations prior to and 1-7 months following KORTUC II treatment, and every 6 months thereafter when possible. The radiotherapy regimen was 2.75 Gy/fraction, 5 fractions/week, for 16-18 fractions, with a total radiation dose of 44.00-49.50 Gy (X-ray irradiation), or 4.00 Gy/fraction, 3 fractions/week, for 10-12 fractions, with a total radiation dose of 40.00-48.00 Gy (electron beam irradiation). The injection of 3-6 ml of the KORTUC II agent was initiated at the fifth radiotherapy fraction, and was performed twice/week under ultrasonographic guidance. The therapeutic effects were evaluated by PET-CT examinations prior and subsequent to KORTUC II treatment, which was observed to be well tolerated with minimal adverse effects. Of the 24 lesions presented by the 20 patients, 18 exhibited complete response, 5 partial response, 0 stable disease and 1 progressive disease. The overall survival rate was 100% at 1 year and 95% at 2 years. The mean duration of follow-up at the end of June 2014 was 51 months. Based on the results of the PET-CT studies conducted, KORTUC II treatment demonstrated marked therapeutic effects, with satisfactory treatment outcomes and acceptable adverse events.

CYP17 polymorphism as a risk factor of tamoxifen-induced hepatic steatosis in breast cancer patients.

Oral administration of tamoxifen, an endocrine therapy for breast cancer, often induces hepatic steatosis (THS, tamoxifen-induced hepatic steatosis) as a complication, which can progress to non-alcoholic steatohepatitis (NASH). The development of this complication is strongly associated with three clinical risk factors; specifically, insulin resistance, central obesity, and hypertriglyceridemia, however a genetic predisposition to THS has yet to be investigated. The aim of this study is to determine whether genetic polymorphism of the P450c17alpha enzyme coded for by the CYP17 gene, responsible for regulating serum estrogen, has an association with THS. After obtaining informed consent from 180 eligible breast cancer patients treated with tamoxifen, DNA was collected and analyzed by restriction fragment length polymorphism assay and classified into alleles defined as A1 and A2. The absence or presence and extent of THS was evaluated by calculating the liver/spleen (L/S) ratio based on Hounsfield units with a CT scanner. Administration of tamoxifen led to THS (L/S ratio <0.9) in 57 (31.7%) of 180 patients while the remaining 123 (68.3%) patients did not develop THS. A significant difference in the distribution of CYP17 genotypes was observed between patients who developed THS and those who did not (P=0.021). A significantly higher frequency of the A2 allele was seen in the THS group (odds ratio, 1.90; 95% confidence interval, 1.21-2.99). Our study provides the first evidence that CYP17 polymorphism participates in the development of THS, and sheds light on the genetic causes of this side effect and genetic differences between tamoxifen-treated individuals.

CYP17 polymorphism and tamoxifen-induced hepatic steatosis.

Hepatic steatosis is a frequent complication, which sometimes develops nonalcoholic steatohepatitis (NASH), in breast cancer patients treated with tamoxifen, a potent antagonist of estrogen. Recently we reported the impairment of fatty acid beta-oxidation and the enhancing fatty infiltration to hepatocytes in aromatase deficiency (ArKO) mice as the estrogen deficiency models. This experimental observation let us speculate strong link between estrogen and hepatic steatosis. In this study, we investigated whether a polymorphism in the cytochrome P450c17alpha gene (CYP17), which is associated with circulating estrogen levels, influences the development of tamoxifen-induced hepatic steatosis. This consecutive study included 180 breast cancer patients undergoing tamoxifen treatment. Genomic DNA extracted from the peripheral blood of each patient was analyzed by restriction fragment length polymorphism (defined as the A1 and A2 alleles). The extent of hepatic steatosis was assessed by computed tomography (CT) as the liver/spleen (L/S) ratio. While receiving adjuvant tamoxifen, 57 of 180 patients developed hepatic steatosis (L/S ratio <0.9) without obvious changes in body mass index (BMI). We observed a significant association between the A2/A2 genotype and the development of hepatic steatosis compared with the A1/A1 genotype [odds ratio (OR), 3.60; 95% confidence interval (C.I.)=1.42-9.10]. The A1/A2 genotype was at an intermediately increased risk of hepatic steatosis (OR, 2.24; 95% C.I.=0.99-5.08). The presence of the A2 allele possibly increased the progression of hepatic steatosis with a gene dosage effect (P=0.06). Our results suggest that functional polymorphism in CYP17 may be involved in determining susceptibility of tamoxifen-induced hepatic steatosis.

In vivo imaging of hepatic fatty acid metabolism in patients with nonalcoholic steatohepatitis using semiquantative (123)I-BMIPP liver scan.

Recent progress of studies in NASH displays multi-disciplinary characters of the pathogeneses. Despite these advances, the strategic use of imaging modalities such as CT, US, and MRI, remains a relatively low priority in clinical situations, because these can only visualize the presence of fatty infiltration to the hepatic parenchyma, impossible to figure out the dynamic function of NASH liver. Morphological alteration such as CT value, MR signal intensity and echo-grade do not distinguish NASH from simple fatty liver. In this presentation, from a radiologic viewpoint, we show the feasibility of in vivo fatty acid imaging with (123)I-beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP). BMIPP is an (123)I labeled fatty acid analog for imaging damaged myocardium, using conventional nuclear imaging equipment. Under normal conditions, the energy source for myocardial utilization is dependent on the beta-oxidation of fatty acids. For energy production in ischemic myocardium, the drastic switch from reduced beta-oxidation of fatty acids to glucose metabolism is well known. BMIPP can detect the area of reduced fatty acids metabolism on myocardial imaging and the data can be converted into semiquantitative analysis. Therefore, we speculate that the use of BMIPP to in vivo hepatic imaging in NASH could highlight a lot of matters of NASH. Details of this presentation include: (1) Hepatic imaging with BMIPP; (2) Clearance of BMIPP from NASH liver; (3) semiquantitative analysis of hepatic BMIPP clearance and clinical features of NASH; (4) Profiles of NASH categorized by BMIPP imaging and (5) Preliminary data of BMIPP clearance in patients with Tamoxifen-induced NASH. The core of our stance in this presentation is searching for valuable advice on clinical use of BMIPP in patients with NASH from specialists in the field of HEPATOLOGY.

Relationship between hormonal receptors, HER-2, p53 protein, Bcl-2, and MIB-1 status and the antitumor effects of neoadjuvant anthracycline-based chemotherapy in invasive breast cancer patients.

PURPOSE: The purpose of this study was to evaluate the predictive value of six different biological factors for neoadjuvant chemotherapy (NAC) in breast conservation treatment (BCT) for invasive breast cancer. MATERIALS AND METHODS: Thirty invasive breast cancer patients (31 breasts) who received NAC as BCT and needle biopsy before chemotherapy were included in this study. Breast cancer tissue was obtained with an 18G core needle with ultrasound guidance. Patients received two to five courses of CAF (cyclophosphamide 600 mg/m(2), pirarubicin 20-40 mg, 5-fluorouracil 600 mg/m(2)). Tissue sections from formalin-fixed paraffin-embedded blocks were stained for the presence of estrogen receptor (ER), progesterone receptor (PgR), HER (human epidermal growth factor receptor)-2, p53 protein, Bcl-2, and MIB-1 (Ki-67). Tumor reduction rate was assessed by MRI before and after chemotherapy. RESULTS: The tumor reduction rate did not differ according to the number of courses of chemotherapy administered. In both the univariate and multivariate analyses, HER-2-negative status was the only significant predictive factor of response (P<0.05). There was no correlation between response and hormone receptors, MIB-1, p53 protein, or Bcl-2 expression. CONCLUSION: This study suggests that breast cancer cells that overexpress HER-2 may be resistant to low-doses of anthracycline-based chemotherapy.

Reduction of fibroproliferative changes in irradiated rat lung with soluble transforming growth factor-ß receptor.

The present study investigated whether established fibroproliferative changes in the irradiated rat lung are histopathologically reduced by an adenovirus­mediated soluble transforming growth factor (TGF)­ß type II receptor. Replication­defective adenoviral vectors expressing a type II human TGF­ß receptor (AdTß­ExR) were prepared. Male Fisher­344 rats were divided into the C, R and R + T groups. The rats in the C group did not receive irradiation or treatment. The rats in the R and R + T group each received 30 Gy irradiation to the right lung. Eight weeks following irradiation, the rats in the R and R + T group were treated with saline or AdTß­ExR, respectively. To analyze the TGF­ß expression, myofibroblast proliferation and macrophage/monocyte infiltration, sections of the lung were immunohistochemically stained at 16 weeks following irradiation. Silver staining was performed for semi­quantitative evaluation of the fibroproliferative changes. Definitive TGF­ß expression, myofibroblast proliferation and macrophage/monocyte infiltration were observed in the lungs of the R group, but were significantly lower in the lungs of the R + T group. With respect to the fibroproliferative changes, the proportion of red­stained areas in the R + T group was markedly lower than that in the R group. These data indicate that fibroproliferative changes induced by radiation are reversible and that TGF­ß has a critical role in fibroproliferative changes in the irradiated lung. The present results suggest that gene therapy with an adenoviral vector expressing a soluble TGF­ß receptor may be effective in reducing the established pulmonary fibrosis caused by radiation.