Risk of stricture after endoscopic submucosal dissection in the cervical esophagus and efficacy of local steroid injection for stricture prevention.

BACKGROUND AND AIMS: There is a high incidence of stricture after endoscopic submucosal dissection (ESD) for cervical esophageal cancer. We aimed to elucidate the risk factors for stricture and evaluate the efficacy of steroid injection for stricture prevention in the cervical esophagus. METHODS: We retrospectively analyzed 100 patients who underwent ESD for cervical esophageal cancer to: (1) identify the factors associated with stricture among patients who did not receive steroid injection; (2) compare the incidence of stricture between patients with and without steroid injection. RESULTS: Among 48 patients who did not receive steroid injection, there were significant differences in tumor size (P = .026), resection time (P = .028), and circumferential extent of the mucosal defect (P = .005) between patients with stricture (n = 5) and without stricture (n = 43). Compared with patients without steroid injection, patients with steroid injection had a significantly lower incidence of stricture when the post-ESD mucosal defect was < 3/4 and ≥ 1/2 (40% versus 8%, P = .039). As for the patients with a post-ESD mucosal defect of ≥ 3/4 (n = 13), local steroid injection was performed for all the patients, and 6 patients (46%) developed stricture. CONCLUSIONS: Patients who underwent ≥ 1/2 circumferential resection were at high risk of cervical esophageal stricture. Steroid injection had a stricture-prevention effect in patients with < 3/4 and ≥ 1/2 circumferential resection, but seemed to be insufficient in preventing stricture in patients with ≥ 3/4 circumferential resection.

Unexpected anti-tumor effect of immune checkpoint inhibitors followed by transcatheter arterial chemoembolization for hepatocellular carcinoma.

The abscopal effect has recently attracted much attention because this effect is enhanced by immune checkpoint inhibitors (ICIs). However, little is known about the association between induction of the abscopal effect and local treatment against hepatocellular carcinoma (HCC). We describe a patient with advanced HCC who underwent selective transcatheter arterial chemoembolization (TACE) after treatment with an ICI that was found to remarkably regress in lesions in areas outside that targeted by selective TACE. An 82-year-old man had multiple recurrences in both lobes of the liver despite of repeated TACE and radiofrequency ablation, after resection of an HCC five years previously. After chemotherapy with atezolizumab and bevacizumab, his des-gamma-carboxy prothrombin (DCP) increased. CT during hepatic arteriography revealed multiple recurrent HCCs in both lobes of the liver. TACE with selective embolization at the level of the medial segmental arteries was performed against an approximately 50 mm-diameter tumor in the right lobe. Hepatic arterial phase imaging of contrast-enhanced CT performed 6 days after TACE showed hypo-enhancement of tumors in segment II and III in the left lobe. This case highlights that abscopal effects can be induced by local treatment against HCCs in combination with treatment with ICIs.

The Diagnostic Utility of IDH2 R172 Immunohistochemistry in Tall Cell Carcinoma With Reversed Polarity of the Breast.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic type of low-grade breast cancer, consisting of tall columnar cells with reversed nuclear polarity and characterized by frequent IDH2 mutations. We herein report 3 cases of TCCRP with sequencing analyses of the IDH2 gene and immunohistochemical examination using monoclonal antibodies (11C8B1) against IDH2 R172. IDH2 R172 mutations were detected in all 3 resected tumors (R172S in 2 tumors and R172T in 1 tumor), and the presence of these mutations was confirmed by IDH2 R172 immunohistochemistry. Tumor cells of TCCRP showed strong and diffuse staining for the antibody against IDH2 R172. In 1 case, tumor tissue from 2 core needle biopsy samples collected on different days were also immunohistochemically positive for IDH2 R172. These results indicate that IDH2 R172 immunohistochemistry is suitable for the detection of TCCRP in both resection and biopsy samples. In addition, a literature review revealed that R172S and R172T account for 76% of IDH2 mutations in TCCRP, suggesting that 11C8B1, which reacts with R172S and R172T, was likely most sensitive for IDH2 -mutated TCCRP among many available antibodies for IDH2 R172. Furthermore, the combination of 2 or more antibodies against IDH2 R172 could be more effective for detecting TCCRP mutation. However, it is important to note that IDH2 R172 immunohistochemistry is not absolute, because IDH2 wild type is found in a small proportion (10%) of cases, and a few cases of IDH2 -mutated TCCRP may harbor rare subtypes of R172 that are not covered by available antibodies.

Giant Cell Tumor With Atypical Imaging Implying Osteosarcoma.

Giant cell tumor (GCT) of bone is benign and typically shows osteolytic changes on x-ray, whereas osteosarcoma is malignant and generally shows osteolytic and osteoblastic mixed images. We experienced a rare case of GCT with atypical radiological findings. The tumor found in the right knee of a 15-year-old girl comprised a wide range of osteoblastic and osteolytic lesion in medial femur. Technetium uptake, however, was detected only in osteoblastic part, and immunohistochemical staining of biopsy showed diffusely positive for antihistone G34W and almost negative for Ki-67. These results strongly suggest the tumor was GCT.

[Hypopituitarism associated with autoimmune pancreatitis: a case report].

We herein report the case of a 64-year-old male patient with hypopituitarism associated with autoimmune pancreatitis (AIP). The patient was previously diagnosed with AIP based on the presence of a swollen pancreas, elevated serum immunoglobulin G4, and narrowing of the pancreatic duct by imaging. Magnetic resonance imaging revealed a pituitary stem tumor, and loading test showed a decrease in the function of the anterior lobe suggesting severe failure of growth hormone secretion. Treatment with steroids was effective in reducing the pituitary lesion and improving the function of the anterior lobe. The present case illustrates the importance of pituitary function evaluation before steroid treatment in patients with AIP.

[Three Poor Performance Status(PS)Cases of Metastatic Breast Cancer Controlled with Adjustment of Dosing Interval and Dosage of Bevacizumab and Paclitaxel].

A standard symptomatic therapy regimen of bevacizumab(BV)plus paclitaxel(PTX)was planned for use in 3 cases of metastatic breast cancer. Due to poor patient performance status(PS)because of malignant pleural effusion and ascites, the initial standard regimen was determined to be unsuitable. However, adjustment and fine-tuning of the BV plus PTX interval and dosage were found to be effective in improving symptoms, and consequently obtained good efficacy. Adverse effects were managed with drug withdrawal and symptomatic therapy. The 3 clinical cases all included females aged 62-76 years old, with a median age of 67.6. One case was classified as PS 3, and 2 were classified as PS 4. The main deciding factors for initiating the regimen of BV plus PTX were 2 cases of malignant pleural effusion and 1 case of malignant ascites, which contributed to worsening of the overall PS. With adjustment and fine-tuning of the BV plus PTX interval and dosage, we were able to safely achieve symptomatic improvement in 3 metastatic breast cancer cases, in which the overall PS grade was unsuitable for standard chemotherapy.

A case of pancreatic intraepithelial neoplasia-3 with autoimmune pancreatitis.

We report a case of pancreatic intraepithelial neoplasia-3 (PanIN-3) with autoimmune pancreatitis (AIP). The patient, a 75-year-old man, had been diagnosed to have AIP with stenosis of the main pancreatic duct. After six years, computed tomography demonstrated dilatation of the main pancreatic duct in the mid-pancreas. Although we could not confirm the presence of any pancreatic tumor on the basis of imaging modalities alone, cytological examination of the pancreatic juice obtained by endoscopic retrograde pancreatography revealed atypical cells. Therefore, we performed pancreatoduodenectomy and obtained a pathologic diagnosis of PanIN-3 with AIP. The present case is informative in the context of pancreatic carcinogenesis in AIP.

[A case of hepatocellular carcinoma complicated by pleural effusion mixed with bile after radiofrequency ablation].

An 84-year-old Japanese man was admitted with hepatocellular carcinoma (HCC). He underwent transcatheter arterial chemoembolization and percutaneous radiofrequency ablation (RFA). Three weeks later, he developed sudden-onset right pleural effusion mixed with bile. Drip infusion cholangiography-computed tomography revealed leakage of the contrast agent, which passed from the HCC to the pleural cavity through a perforation in the diaphragm. The patient's condition improved after thoracic and endoscopic nasobiliary drainage. The occurrence of pleural effusion mixed with bile is a rare complication of RFA. This case provides important information about the morbidity, prevention, and treatment of this complication.

Effects of TiO2 nanoparticles on cytotoxic action of chemotherapeutic drugs against a human oral squamous cell carcinoma cell line.

BACKGROUND: Despite the rapid development of nanotechnology, the biological significance of TiO2 nanoparticles (NPs), possibly released from dental materials, is not well-understood. We investigated the effect of TiO2 NPs on the sensitivity of human oral squamous cell carcinoma (OSCC) cell line (HSC-2) to five popular chemotherapeutic agents. MATERIALS AND METHODS: Viable cell number was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The aggregation and cellular uptake of TiO2 NPs were assessed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), respectively. Adsorption of TiO2 NPs to anticancer drugs was assessed by the antitumor activity recovered from the TiO2 NP-free supernatant. RESULTS: When mixed with culture medium, TiO2 NPs instantly aggregated, and some particles were incorporated into the cells, exclusively in the vacuoles. TiO2 NPs showed no cytotoxicity nor hormetic growth stimulation at lower concentrations. Doxorubicin, melphalan, 5-fluorouracil and gefitinib were cytotoxic, whereas docetaxel was cytostatic with or without TiO2 NPs. TiO2 NPs, at wide concentration ranges (0.2-3.2 mM), did not significantly affect the adsorption of NPs to any of these anticancer drugs, nor affected their cytotoxic or cytostatic activity. CONCLUSION: This experimental study demonstrated for the first time that TiO2 NP do not affect the antitumor potential of chemotherapeutic agents against the HSC-2 OSCC cell line.

Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule.

T cell activation is regulated by two distinct signals, signals one and two. Concanavalin A (ConA) is an antigen-independent mitogen and functions as signal one inducer, leading T cells to polyclonal proliferation. CD28 is known to be one of major costimulatory receptors and to provide signal two in the ConA-induced T cell proliferation. Here, we have studied the implication of other costimulatory pathways in the ConA-mediated T cell proliferation by using soluble recombinant proteins consisting of an extracellular domain of costimulatory receptors and Fc portion of human IgG. We found that T cell proliferation induced by ConA, but not PMA plus ionomycin or anti-CD3 mAb, is significantly inhibited by herpes virus entry mediator (HVEM)-Ig, even in the presence of CD28 signaling. Moreover, the high concentration of HVEM-Ig molecules almost completely suppressed ConA-mediated T cell proliferation. These results suggest that HVEM might play more important roles than CD28 in ConA-mediated T cell proliferation.

Detection of parasternal metastatic lymph nodes by sentinel lymph node methods in a patient with recurrence in the conserved breast.

We herein report a case of second sentinel lymph node biopsy (SLNB). A 57-year-old woman underwent breast-conserving surgery including axillary clearance at Aichi Cancer Center on October 20, 2003. Recurrent tumor in the conserved breast was diagnosed in March 2006. She received SLNB using radioactive tracer. Preoperative lymphoscintigraphy detected 2 parasternal lymph nodes as hot spots. No abnormal lymph nodes were revealed on preoperative computed tomography. Salvage mastectomy was performed along with dissection of the Rotter and infraclavicular lymph nodes and biopsy of the detected parasternal lymph nodes. Micrometastases were discovered in both parasternal lymph nodes detected as sentinel lymph nodes. No more metastases were seen in the other lymph nodes. Reoperative SLNB offers the possibility of detecting metastasis in residual lymph nodes and determining whether chemotherapy should be used.

Reproductive history and breast cancer risk.

The fact that reproductive factors have significant influence on the risk of breast cancer is well known. Early age of first full-term birth is highly protective against late-onset breast cancers, but each pregnancy, including the first one, increases the risk of early-onset breast cancer. Estradiol and progesterone induce receptor activator of NF-kappa B ligand (RANKL) in estrogen receptor (ER)- and progesterone receptor (PgR)-positive luminal cells. RANKL then acts in a paracrine fashion on the membranous RANK of ER/PgR-negative epithelial stem cells of the breast. This reaction cascade is triggered by chorionic gonadotropin during the first trimester of pregnancy and results in the morphological and functional development of breast tissue. On the other hand, the administration of non-steroidal anti-inflammatory drugs in the early steps of weaning protects against tumor growth through reduction of the acute inflammatory reaction of post lactation remodeling of breast tissue. This is experimental evidence that may explain the short-term tumor-promoting effect of pregnancy. The protective effect of prolonged breast feeding may also be explained, at least in a part, by a reduced inflammatory reaction due to gradual weaning. Delay of first birth together with low parity and short duration of breast feeding are increasing social trends in developed countries. Therefore, breast cancer risk as a result of reproductive factors will not decrease in these countries in the foreseeable future. In this review, the significance of reproductive history with regard to the risk of breast cancers will be discussed, focusing on the age of first full-term birth and post lactation involution of the breast.

Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer.

Endocrine therapy is the most important treatment of choice for estrogen receptor (ER)-positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve ER-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERalpha-positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERalpha, ERbeta, progesterone receptor (PgR), androgen receptor (AR), amplified in breast cancer 1 (AIB1), aromatase, epidermal growth factor receptor, human epidermal growth factor receptor type 2, Ki67, cyclin D1, p53, Bcl2, signal transducer and activator of transcription 5 (Stat5), and insulin-like growth factor binding protein 5 (IGFBP5), and phosphorylations of ERalpha serine (Ser) 118, ERalpha Ser167, Akt Ser473, and p44/42 MAPK threonine (Thr) 202/tyrosine (Tyr) 204, were examined by immunohistochemistry on pretreatment tumor biopsies and post-treatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, seven responded and nine retained stable disease. High-level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERalpha, ERbeta, PgR, aromatase, Ki67, cyclin D1, and p53, and phosphorylations of ERalpha Ser118, ERalpha Ser167, and p44/42 MAPK Thr202/Tyr204, were decreased, whereas expressions of Stat5 and IGFBP5 were increased in post-treatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen-dependent growth-signaling pathways may be useful in identifying patients responsive to exemestane.

Prognostic significance of insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 expression in breast cancer.

BACKGROUND: Expression of estrogen-regulated genes has been considered as potential predictive markers for endocrine therapy. We focused on two insulin-like growth factor binding proteins (IGFBPs): IGFBP-4, which is an early-responsive estrogen-induced gene, and IGFBP-5, which is an estrogen-repressed gene. Investigation of IGFBP-4 and IGFBP-5 expression would provide important information for predicting prognosis and endocrine responsiveness. METHODS: The levels of IGFBP-4 and IGFBP-5 mRNA expression in 162 human breast cancer tissues were analyzed using quantitative real-time reverse transcriptase-PCR. The association between IGFBP-4 and IGFBP-5 expression and clinicopathological factors was then analyzed. RESULTS: The levels of IGFBP-4 and IGFBP-5 mRNA expression were positively correlated with estrogen receptor (ER) and progesterone receptor (PgR) status and were negatively correlated with HER2 overexpression. Patients with a high level of IGFBP-4 mRNA expression had better disease-free and overall survival than those with a low expression. Multivariate analysis showed that IGFBP-4 mRNA expression is an independent prognostic factor for disease-free survival. When analyzed in 116 patients with ER-positive breast cancer, patients whose tumor expressed higher levels of IGFBP-4 mRNA or lower levels of IGFBP-5 mRNA had better disease-free survival. CONCLUSION: IGFBP-4 mRNA expression was an independent prognostic factor in breast cancer, and patients with ER-positive breast cancer whose tumor expressed higher levels of IGFBP-4 and lower levels of IGFBP-5 had a better prognosis than those without such findings.

Clinical usefulness of oral combination chemotherapy of 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide for metastatic breast cancer.

BACKGROUND: It has been reported that 5'-deoxy-5-fluorouridine (5'-DFUR), the pro-drug of 5-FU, is effective treatment for breast cancer that express thymidine phosphorylase (dThdPase). Since oral cyclophosphamide (CPA) induces dThdPase, a synergistic effect can be expected by combining CPA with 5'-DFUR. We evaluated the usefulness of combination chemotherapy using CPA and 5'-DFUR in patients with relapsed breast cancer in this prospective phase II study. METHODS: Patients with relapsed, advanced breast cancer with evaluable lesions were given 5'-DFUR at 800 mg/day/body and CPA at 100 mg/day/body for 2 weeks, then underwent 2 weeks of drug withdrawal. This was considered one course of treatment. It was repeated until progressive disease (PD) was confirmed. The lesions were evaluated according to UICC criteria and compared with regard to the clinical status. RESULTS: Sixty-four patients with relapsed, advanced breast cancer were registered. Complete response (CR) was seen in 7 patients, partial response (PR) in 12 patients, no change (NC) in 25 patients, of whom 11 achieved long NC with the effect lasting for more than 6 months, and PD was seen in 20 patients. The response rate was 29.7%. The total number of CR, PR, and long NC cases was 30, which comprise-46.9% of the total 64 cases (the clinical benefit rate). As for adverse events, hematological toxicities were seen in 9 patients, with grade 3 toxicits was seen in 1 patient. All other adverse events were grade 1 or 2. CONCLUSION: For those patients who achieved an effect more than NC, it was possible to continue the therapy for an average of 53 weeks. This treatment method is worth considering for patients who have metastatic breast cancer, that is not life threatening.

p53 protein accumulation predicts resistance to endocrine therapy and decreased post-relapse survival in metastatic breast cancer.

INTRODUCTION: Endocrine therapy is the most important treatment option for women with hormone receptor-positive breast cancer. The potential mechanisms for endocrine resistance involve estrogen receptor (ER)-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine resistance are still poorly identified. MATERIALS AND METHODS: The expression of HER2, p53, and Ki67 was examined by immunohistochemistry in primary breast tumour specimens from 73 metastatic breast cancer patients who received first-line treatment with endocrine therapy on relapse, and analysed to determine whether expression of these molecular markers affected the response to endocrine therapy. RESULTS: Of the 73 invasive ductal carcinomas, 12.3%, 21.9%, and 35.6% were positive for HER2 overexpression, p53 protein accumulation, and Ki67 expression, respectively. All patients received endocrine therapy as first-line treatment for metastatic breast cancer; 34 patients (46.6%) responded. Patients with primary breast tumours that had p53 protein accumulation and Ki67 expression showed significantly more resistance to endocrine therapy (P = 0.0049 and P = 0.024, respectively). There were also tendencies for HER2 overexpression to correlate with resistance to endocrine therapy, but this did not reach significance. p53 protein accumulation and HER2 overexpression significantly reduced post-relapse survival (P < 0.0001 and P = 0.001, respectively), and these factors were also statistically significant in a multivariate analysis. CONCLUSION: These data suggest that p53 protein accumulation is helpful in selecting patients who may benefit from endocrine therapy and is a prognostic marker in hormone receptor-positive metastatic breast cancer.

Low expression of the snail gene is a good prognostic factor in node-negative invasive ductal carcinomas.

BACKGROUND: While Snail is a zinc-finger transcription factor that triggers the epithelial-mesenchymal transition, it has also been reported to be indirectly regulated by estrogen receptor alpha (ERalpha) and to be involved in the transcriptional repression of the aromatase gene. The aim of the present study was to examine the role of Snail expression in node-negative invasive ductal carcinomas. METHODS: We analyzed Snail mRNA expression levels in 86 node-negative invasive ductal carcinomas by real-time quantitative RT-PCR and studied whether Snail mRNA expression correlates with clinicopathological factors. RESULTS: No correlation was found between Snail mRNA expression and ERalpha protein expression levels. However, we observed that none of the 34 patients showing low Snail mRNA expression developed distant metastasis while 6 of 52 (12%) showing high expression of Snail mRNA did. The level of Snail mRNA expression was not found to be significantly correlated with clinicopathological factors. No inverse correlation was found between the Snail and aromatase mRNA expression levels in our series. CONCLUSION: Our data show that low expression of Snail mRNA is a good prognostic factor in node-negative invasive ductal carcinomas. Snail expression is suggested to be involved in distant metastasis in node-negative invasive ductal carcinomas.

NCOR1 mRNA is an independent prognostic factor for breast cancer.

The transcriptional function of estrogen receptor alpha (ERalpha) can be modulated by co-regulatory proteins. In the present study, therefore, the level of expression of one of the co-regulator Nuclear Receptor Co-repressor 1 (NCOR1) mRNA has been assessed by quantitative real-time RT-PCR in 160 cases of invasive breast carcinoma. It was found that NCOR1 mRNA was expressed at significantly higher levels in patients over 50 years of age, without axillary lymph node involvement, with tumor size less than 2 cm, with low or intermediate histological grade, with ERalpha/PgR-positive and with HER2 negative tumors. Patients with high levels of expression of NCOR1 mRNA have a better prognosis than those with low expression. Univariate and multivariate prognostic analysis demonstrated that NCOR1 mRNA is an independent prognostic factor for breast cancer.