Survival of Lung Cancer Patients Dependent on the LOH Status for DMP1, ARF, and p53.

Lung cancer is the leading cause of cancer deaths in the world, and accounts for more solid tumor deaths than any other carcinomas. The prognostic values of DMP1, ARF, and p53-loss are unknown in lung cancer. We have conducted survival analyses of non-small cell lung cancer (NSCLC) patients from the University of Minnesota VA hospital and those from the Wake Forest University Hospital. Loss of Heterozygosity (LOH) for hDMP1 was found in 26 of 70 cases (37.1%), that of the ARF/INK4a locus was found in 33 of 70 (47.1%), and that of the p53 locus in 43 cases (61.4%) in the University of Minnesota samples. LOH for hDMP1 was associated with favorable prognosis while that of p53 predicted worse prognosis. The survival was much shorter for ARF-loss than INK4a-loss, emphasizing the importance of ARF in human NSCLC. The adverse effect of p53 LOH on NSCLC patients' survival was neutralized by simultaneous loss of the hDMP1 locus in NSCLC and breast cancer, suggesting the possible therapy of epithelial cancers with metastatic ability.

Stabilization of the p53-DNA Complex by the Nuclear Protein Dmp1α.

We recently reported the existence of a physical interaction between the Myb-like transcription factor Dmp1 (Dmtf1) and p53 in which Dmp1 antagonized polyubiquitination of p53 by Mdm2 and promoted its nuclear localization. Dmp1 significantly stabilized p53-DNA complexes on promoters that contained p53-consensus sequences, which were either supershifted or disrupted with antibodies to Dmp1. Lysates from mice injected with doxorubicin showed that Dmp1 bound to p21Cip1, Bbc3, and Thbs1 gene regulatory regions in a p53-dependent fashion. Our data suggest that acceleration of DNA-binding of p53 by Dmp1 is a critical process for Dmp1 to increase the p53 function in Arf-deficient cells.

Oral 5-aminolevulinic acid mediated photodynamic diagnosis using fluorescence cystoscopy for non-muscle-invasive bladder cancer: A randomized, double-blind, multicentre phase II/III study.

BACKGROUND: Photodynamic diagnosis (PDD) of non-muscle-invasive bladder cancer (NMIBC) following transurethral administration of a hexalated form of 5-aminolevulinic acid (5-ALA), 5-ALA hexyl ester, is widely performed in Western countries. In this study, effectiveness and safety of the oral administration of 5-ALA is assessed in a phase II/III study of PDD for NMIBC in comparison to those of conventional white-light endoscopic diagnosis. METHODS: Patients with NMIBC were allocated to two groups that were orally administered 10 and 20 mg/kg of 5-ALA under the double-blind condition. Effectiveness was evaluated by setting the primary endpoint to sensitivity. Safety was also analyzed. Moreover, clinically recommended doses of 5-ALA was also investigated as an investigator-initiated multicenter cooperative clinical trial in which five medical institutions participated. RESULTS: All 62 enrolled patients completed the clinical trial. The sensitivities of PDD were higher (84.4 and 75.8% in the 10 and 20 m g/kg-groups, respectively) than those of conventional endoscopic diagnosis (67.5 and 47.6%, respectively) (p = 0.014 and p < 0.001, respectively). Five episodes of serious adverse events developed in four patients; whereas a causal relationship with the investigational agent was ruled out in all episodes. CONCLUSION: This investigator-initiated clinical trial confirmed the effectiveness and safety of PDD for NMIBC following oral administration of 5-ALA. Both doses of 5-ALA may be clinically applicable; however, the rate of detecting tumors only by PDD was higher in the 20 mg/kg-group suggesting that this dose would be more useful.

[Incomplete self-castration by the patient with gender identify disorder: a case report].

A 29-year-old man with gender identify disorder presented to our hospital complaining of scrotal pain. Two hours before the consultation, he tried to do self-castration by himself, but he stopped due to bleeding and scrotal pain. His testes were not removed, and his scrotal wound was closed at the emergency operation under spinal anesthesia. After the operation, he never repeated the same act.

Axitinib controlled metastatic renal cell carcinoma for 5 years.

We present two patients with a long-term response to axitinib for cytokine-refractory metastatic renal cell carcinoma. One patient has had a continuing partial response for 58 months with cytokine-intolerant metastatic renal cell carcinoma and the other patient has had continuing stable disease accompanied by a mixed response for 57 months with cytokine-refractory and intolerant metastatic renal cell carcinoma. The condition of hypertension as an adverse event markedly depended on whether or not axitinib was administered. The patients responded to axitinib with an elevation of diastolic blood pressure to 90 mmHg or higher until 2 weeks after starting axitinib. To get a long-term response to axitinib, it may be important to control well the balance between treatment effect and adverse events while using drug withdrawal.

Temsirolimus controlled metastatic advanced renal cell carcinoma for over 4 years: a case study.

We present a case report of long-term response with temsirolimus in cytokine refractory metastatic renal cell carcinoma (RCC). A 74-year-old Japanese man was diagnosed with advanced RCC in November 2007 and enrolled in a phase II study to examine the safety and efficacy of temsirolimus in East Asian patients with metastatic RCC. He achieved a partial response 12 months after starting treatment with temsirolimus followed by stable disease for 39 months. The most notable toxicity was grade 3 pericardial effusion, which gradually increased 2 years after treatment start until discontinuation of the trial resulting in pericardial tamponade, grade 3 hypoxia associated with chronic obstructive pulmonary disease (COPD), which he had before the trial, and latent interstitial pneumonia. The cease of temsirolimus led to improvement of interstitial pneumonia while the target lesion progressed. He died of progressive COPD and latent interstitial pneumonia 4 months after discontinuing temsirolimus. To our knowledge, he lived the longest in East Asian populations since starting temsirolimus.

[Bilateral adrenal hemorrhage due to adrenal metastasis of lung cancer].

A 58-year-old man presented with nausea and left flank pain. The patient was referred to our hospital based on clear detection of anemia and computed tomography findings of bilateral adrenal tumors with hemorrhage and a mass in the apex of the left lung. Right adrenal artery embolization had no effect on enlargement of the right adrenal hematoma or advanced anemia. Right adrenalectomy was then performed in an attempt to control hemorrhaging and make a definitive diagnosis, and the patient's anemia improved following the operation. Histopathological diagnosis suggested adrenal metastasis of lung adenocarcinoma, which was subsequently diagnosed given similarities in transbronchial biopsy findings to those in the right adrenal gland. Adrenal hemorrhage due to metastasis of lung cancer is an extremely rare condition; indeed, to our knowledge, the present case is only the 26th reported worldwide. However, prognosis for this mortal condition may be improved should patients receive adrenalectomy followed by an appropriate treatment regimen.

[Salvage therapy for castration-refractory prostate cancer resistant to docetaxel].

OBJECTIVES: To evaluate the treatment for castration-refractory prostate cancer (CRPC) resistant to docetaxel MATERIALS AND METHODS: Among 45 patients with CRPC treated with docetaxel (70-75 mg/m2) every 3 to 4 weeks at Hamamatsu University Hospital from January 2004 to July 2012, 19 patients underwent salvage treatments. We retrospectively analyzed the medical records of 14 patients except for 5 patients who were enrolled in clinical trials. RESULTS: The median age and serum prostate-specific antigen (PSA) level at starting salvage treatments was 71 years (range 45 to 79) and 241.1 ng/mL (range 3.06 to 1,643.0), respectively. All patients maintained castration status. Salvage treatments include DTX (30 mg/m2) + cisplatin (CDDP) (70 mg/m2)/carboplatin (Area under the curve = 4), etoposide + CDDP, paclitaxel + CDDP, cyclophosphamide, S-l, tegaful-uracil. The reasons why 14 patients moved to salvage treatments after DTX were progressive disease in 12 patients and adverse events in 2. Eight patients had a PSA response, 3 patients>50% and 5 patients<50%. Six patients had a PSA progression. The median overall survival was 10.4 months (range 4.1 to 27.3). All patients died of cancer, 13 patients with prostate cancer and one patient with lung adenocarcinoma. Most adverse events were mild. Transitory grade 3 leukopenia was observed in 2 patients, and grade 3 anemia in 2. No grade 4 toxicities were noted. CONCLUSIONS: All salvage treatments without grade 4 toxicities described in this study may be acceptable in the patients with CRPC progressing after docetaxel although the effect would be limited.

Dmp1 physically interacts with p53 and positively regulates p53's stability, nuclear localization, and function.

The transcription factor Dmp1 is a Ras/HER2-activated haplo-insufficient tumor suppressor that activates the Arf/p53 pathway of cell-cycle arrest. Recent evidence suggests that Dmp1 may activate p53 independently of Arf in certain cell types. Here, we report findings supporting this concept with the definition of an Arf-independent function for Dmp1 in tumor suppression. We found that Dmp1 and p53 can interact directly in mammalian cells via the carboxyl-terminus of p53 and the DNA-binding domain of Dmp1. Expression of Dmp1 antagonized ubiquitination of p53 by Mdm2 and promoted nuclear localization of p53. Dmp1-p53 binding significantly increased the level of p53, independent of the DNA-binding activity of Dmp1. Mechanistically, p53 target genes were activated synergistically by the coexpression of Dmp1 and p53 in p53(-/-);Arf(-/-) cells, and genotoxic responses of these genes were hampered more dramatically in Dmp1(-/-) and p53(-/-) cells than in Arf(-/-) cells. Together, our findings identify a robust new mechanism of p53 activation mediated by direct physical interaction between Dmp1 and p53.

Characteristics of aggressive variants in T1a renal cell carcinoma.

PURPOSE: To explore factors associated with metastasis and prognosis in T1a renal cell carcinoma (RCC). METHODS: We retrospectively reviewed 451 cases of sporadic T1aRCC among 1,060 patients admitted to the Department of Urology at Hamamatsu University Hospital and affiliated hospitals between 1978 and 2007. Clinicopathological factors were analyzed for metastatic and prognostic risks. RESULTS: We identified 32 RCC patients with metastatic disease, 22 with synchronous and 10 with metachronous metastatic RCC. Patients with metastatic disease had a significantly higher incidence of symptomatic cancer, as well as greater tumor size, C-reactive protein (CRP) level, sarcomatoid component ratio, histological grade 3 and microvascular invasion than those without metastasis. Among the 32 patients with metastasis, there is no significant difference in clinicopathological factors. The most common site of metastasis was bone. Among patients with metastatic T1aRCC, findings at diagnosis of a symptomatic cancer, CRP level of 0.4 mg/dL or more, tumor size of 3.0 cm or greater, histological grade 3, a sarcomatoid component and microvascular invasion appeared to be significant and independent risk factors. Significant independent risk factors with metachronous metastatic RCC were a symptomatic cancer and a sarcomatoid component at diagnosis. A CRP level of 0.4 mg/dL or more was also an independent prognostic factor for overall survival. CONCLUSION: RCC patients with findings at diagnosis of a symptomatic cancer, a sarcomatoid component and CRP level of 0.4 mg/dL or more require intensive follow-up.

Should ipsilateral solitary adrenal involvement in renal cell carcinoma be staged as M1?

OBJECTIVE: In 2009, the TNM classification of malignant tumors was revised, and the renewal of the T2-4 stage in renal cell carcinoma was adopted. To date, however, the staging of ipsilateral solitary adrenal involvement in renal cell carcinoma has not been sufficiently evaluated. METHODS: We retrospectively reviewed the adrenal involvement in renal cell carcinoma among 1033 patients admitted to the Department of Urology at Hamamatsu University Hospital, Japan, and affiliated hospitals between 1978 and 2007. RESULTS: We identified 23 of the 1033 patients (2.2%) with adrenal involvement in renal cell carcinoma. In renal cell carcinoma patients with adrenal involvement, a tendency for a high histological grade of tumor and lower overall survival (P< 0.0001) was observed. Ipsilateral solitary adrenal involvement was detected in 4 of the 23 patients (15%), whereas 2 of the 23 (9%) had direct invasion of the adrenal gland. All tumors in the 14 patients without ipsilateral solitary adrenal involvement and recurrent adrenal tumors were classified as Stage IV. The TNM classification of the four renal cell carcinoma patients with ipsilateral solitary adrenal involvement was determined to be either pT3N0M0 or pT1-3N0M1. Among the four patients with ipsilateral solitary adrenal involvement, three patients had recurrent tumors, despite complete surgical resection. Two of these patients died of metastatic renal cell carcinoma after 2 and 10 years of radical nephrectomy, respectively, whereas one was still alive with cancer 3 years after the initial radical nephrectomy. The fourth had no recurrence of renal cell carcinoma, but did develop synchronous gall bladder cancer (pT2N0M0) and bile duct cancer (pT2N0M0). CONCLUSIONS: Adrenal involvement in primary renal cell carcinoma was observed more frequently in patients with advanced tumor stages. In the TNM classification system, we propose that ipsilateral solitary adrenal involvement in renal cell carcinoma should be staged as M1.

Natural history of renal cell carcinoma: a case with 18 years follow-up.

A 53-year-old woman presented to our hospital with a non-metastatic 4 cm renal mass in the right kidney. The patient rejected treatment, but consented to follow-up observation of her condition. The patient underwent a series of computed tomography scans to monitor the progression of the disease. We were able to observe not only an increase in renal mass size, but also involvement of para-aortic lymph nodes, inferior vena cava, and metastasis to the lung. Eighteen years after diagnosis, the subject was hospitalized and died as a result of complications of the disease. Autopsy showed the pathologic diagnosis of the renal mass to be a grade 2 clear cell carcinoma. The literature contains several papers that describe the natural history of renal masses and carcinomas over short periods; however, prior to our case, no reports existed that detailed long-term progression of renal cell carcinoma (RCC) from initial diagnosis to death. It is necessary to clarify the course that RCC takes due to its unpredictable, indolent nature. This will provide clinicians with better insight into how to manage the disease, decide on treatment options, and improve overall survival.

Critical roles of DMP1 in human epidermal growth factor receptor 2/neu-Arf-p53 signaling and breast cancer development.

Human epidermal growth factor receptor 2 (HER2) overexpression stimulates cell growth in p53-mutated cells while it inhibits cell proliferation in those with wild-type p53, but the molecular mechanism is unknown. The Dmp1 promoter was activated by HER2/neu through the phosphatidylinositol-3'-kinase-Akt-NF-κB pathway, which in turn stimulated Arf transcription. Binding of p65 and p52 subunits of NF-κB was shown to the Dmp1 promoter and that of Dmp1 to the Arf promoter on HER2/neu overexpression. Both Dmp1 and p53 were induced in premalignant lesions from mouse mammary tumor virus-neu mice, and mammary tumorigenesis was significantly accelerated in both Dmp1+/- and Dmp1-/- mice. Selective deletion of Dmp1 and/or overexpression of Tbx2/Pokemon was found in >50% of wild-type HER2/neu carcinomas, although the involvement of Arf, Mdm2, or p53 was rare. Tumors from Dmp1+/-, Dmp1-/-, and wild-type neu mice with hemizygous Dmp1 deletion showed significant downregulation of Arf and p21Cip1/WAF1, showing p53 inactivity and more aggressive phenotypes than tumors without Dmp1 deletion. Notably, endogenous hDMP1 mRNA decreased when HER2 was depleted in human breast cancer cells. Our study shows the pivotal roles of Dmp1 in HER2/neu-p53 signaling and breast carcinogenesis.

Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance.

The use of biomarkers ensures breast cancer patients receive optimal treatment. Established biomarkers such as estrogen receptor (ER) and progesterone receptor (PR) have been playing significant roles in the selection and management of patients for endocrine therapy. HER2 is a strong predictor of response to trastuzumab. Recently, the roles of ER as a negative and HER2 as a positive indicator for chemotherapy have been established. Ki67 has traditionally been recognized as a poor prognostic factor, but recent studies suggest that measurement of Ki67-positive cells during treatment will more effectively predict treatment efficacy for both anti-hormonal and chemotherapy. p53 mutations are found in 20-35% of human breast cancers and are associated with aggressive disease with poor clinical outcome when the DNA-binding domain is mutated. The utility of cyclin D1 as a predictor of breast cancer prognosis is controversial, but cyclin D1b overexpression is associated with poor prognosis. Likewise, overexpression of the low molecular weight form of cyclin E1 protein predicts poor prognosis. Breast cancers from BRCA1/2 carriers often show high nuclear grades, negativity to ER/PR/HER2, and p53 mutations, and thus, are associated with poor prognosis. The prognostic values of other molecular markers, such as p14(ARF), TBX2/3, VEGF in breast cancer are also discussed. Careful evaluation of these biomarkers with current treatment modality is required to determine whether their measurement or monitoring offer significant clinical benefits.

The Arf-inducing transcription factor Dmp1 encodes a transcriptional activator of amphiregulin, thrombospondin-1, JunB and Egr1.

Dmp1 (Dmtf1) encodes a Myb-like transcription factor implicated in tumor suppression through direct activation of the Arf-p53 pathway. The human DMP1 gene is frequently deleted in non-small cell lung cancers, especially those that retain wild-type INK4a/ARF and/or p53. To identify novel genes that are regulated by Dmp1, transcriptional profiles of lung tissue from Dmp1-null and wild-type mice were generated using the GeneChip Microarray. Comparative analysis of gene expression changes between the two groups resulted in identification of numerous genes that may be regulated by Dmp1. Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated. These target genes were chosen for further analyses since they are involved in cell proliferation, transcription, angiogenesis/metastasis, apoptosis, or DNA methylation, and thus could account for the tumor suppressor phenotype of Dmp1. Dmp1 directly bound to the genomic loci of Areg, Tsp-1, JunB and Egr1. Significant upregulation or downregulation of the novel Dmp1 target genes was observed upon transient expression of Dmp1 in alveolar epithelial cells, an effect which was nullified by the inhibition of de novo mRNA synthesis. Interestingly, these genes and their protein products were significantly downregulated or upregulated in the lungs from Dmp1-heterozygous mice as well. Identification of novel Dmp1 target genes not only provides insights into the effects of Dmp1 on global gene expression, but also sheds light on the mechanism of haploid insufficiency of Dmp1 in tumor suppression.

MMTV mouse models and the diagnostic values of MMTV-like sequences in human breast cancer.

Mouse mammary tumor virus (MMTV) long terminal repeat (LTR)-driven transgenic mice are excellent models for breast cancer as they allow for the targeted expression of various oncogenes and growth factors in neoplastic transformation of mammary glands. Numerous MMTV-LTR-driven transgenic mouse models of breast cancer have been created in the past three decades, including MMTV-neu/ErbB2, cyclin D1, cyclin E, Ras, Myc, int-1 and c-rel. These transgenic mice develop mammary tumors with different latency, histology and invasiveness, reflecting the oncogenic pathways activated by the transgene. Recently, homologous sequences of the env gene of MMTV have been identified in approximately 40% of human breast cancers, but not in normal breast or other types of cancers, suggesting possible involvement of mammary tumor virus in human breast carcinogenesis. Accumulating evidence demonstrates the association of MMTV provirus with progesterone receptor, p53 mutations and advanced-stage breast cancer. Thus, the detection of MMTV-like sequences may have diagnostic value to predict the clinical outcome of breast cancer patients.

Impact of thymidine phosphorylase-expressing macrophages for surgical margin in partial nephrectomy.

OBJECTIVES: We investigated the relationship between the surgical margin in partial nephrectomy (PN) and thymidine phosphorylase (TP)-expressing macrophages in peritumoral tissue of renal cell carcinoma (RCC). METHODS: In 46 patients who underwent radical nephrectomy, we measured TP protein levels in tumor tissue, peritumoral tissue and normal tissue, and conducted immunohistochemical staining for TP and macrophages. In addition, we prospectively conducted PN with a 5-mm margin in 11 patients with pT1a RCC. RESULTS: The TP protein level and TP-positive macrophages were correlated with T classification, histological grade, mode of infiltration and venous invasion. However, for pT1 RCC, TP-positive macrophages in pT1a were significantly lower than in pT1b (p = 0.0140), while there was no significant difference in TP protein levels between pT1a and pT1b. No surgical margin was positive in 11 patients who underwent PN with a 5-mm margin, and no patient had local recurrence or distant metastasis during follow-up. CONCLUSIONS: The TP protein level and TP-positive macrophages in the peritumor area are thought to be associated with tumor progression in RCC, while a similar relationship was not found in pT1a RCC. These data suggest that a 5-mm margin might be safe to reduce the risk of local recurrence when PN is performed for treatment of solitary pT1a RCC.

Efficacy of adjuvant interferon-alpha therapy following curative resection in renal cell carcinoma: before the molecular targeting therapy era.

OBJECTIVE: Although present treatment programs for renal cell carcinoma (RCC) typically involve molecular-targeting drugs, interferon-alpha (IFN-alpha) remains an important therapeutic drug for this cancer. METHODS: We evaluated the effect of adjuvant therapy in 508 patients with RCC following curative surgery. Patients were classified into one of the two categories based on the duration and the total dose of IFN-alpha treatment. RESULTS: Median follow-up time was 65.5 months. Overall survival rates at 5, 10, 15 and 20 years were 88.8%, 80.5%, 69.6% and 54.1%, respectively. Cause-specific survival rates at 5, 10, 15 and 20 years were 95.0%, 89.1%, 83.0% and 83.0%, respectively. Cox's proportional hazard model revealed that C-reactive protein, T classification, histological grade and age were significantly independent factors indicative of a poor prognosis. Our examination of the 253 patients diagnosed as pT1-2N0M0 who underwent adjuvant IFN-alpha therapy following surgery found that the therapy was not significantly associated with either cause-specific or disease-free survival. With regard to effects of duration of therapy and total dose of IFN-alpha, patients with a total IFN-alpha exposure of > or = 180 x 10(6) international units (IU) had a better prognosis than those exposed to <180 x 10(6) IU. CONCLUSIONS: Adjuvant therapy using large doses of IFN-alpha may improve the prognosis of patients with RCC following curative resection, and the new possibility of IFN-alpha therapy merits further investigation.

High levels of thymidine phosphorylase as an independent prognostic factor in renal cell carcinoma.

BACKGROUND: We investigated whether thymidine phosphorylase (TP) protein level in renal cell carcinoma (RCC) correlates with clinicopathological characteristics and clinical outcomes. METHODS: TP protein level was measured in 116 RCC specimens and in 90 non-neoplastic kidney tissues using a sandwich-type enzyme-linked immunosolvent assay. RESULTS: The median TP protein level in RCC tissues was 9.76-fold (range, 3.2-933.9) higher than those in non-neoplastic kidney tissues (P < 0.0001). TP protein level was correlated with T classification, histological grade and mode of infiltration. TP as a prognostic variable was studied using a logistic regression model. TP at higher levels (128 U/mg protein or greater) would play a role as an independent prognostic factor (odds ratio, 13.73; 95% confidence interval, 2.09-90.41; P = 0.0064). CONCLUSION: TP at high levels can be regarded as an unfavorable independent prognostic factor. These results may pave a way for a novel approach to effective treatment of RCC.

[Interferon-based cytokine therapy for advanced renal cell carcinoma].

Among 126 patients diagnosed with metastatic renal cell carcinoma at Hamamatsu University or its affiliated hospital between 1978 and 2004, pretreatment features associated with a shorter survival in the multivariate analysis were in symptomatic status at diagnosis and in multiple organ metastasis. The 1- and 3-year survival rate in patients with these two prognostic factors were 22.3 and 0.3%, respectively. The style of treatment did not influenced survival in these patients. Therefore, an accurate assessment of their survival benefits both them and physician while it is urgent that we develop novel agents and strategy.