Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway

Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53.     

Is adenocarcinoma/large cell carcinoma the most radiocurable type of cancer of the lung?

Radiation therapy is widely considered the primary treatment for inoperable "non-small" cell carcinoma of the lung. In clinical investigations, distinction has been infrequent among the histopathologic subtypes of non-small cell carcinoma. Studies have shown significant differences between squamous cell carcinoma and adenocarcinoma/large cell carcinoma; adenocarcinoma/large cell carcinoma has a greater propensity for extrathoracic dissemination, especially to the brain, and it is less curable by resection when regional lymph node metastases are present. No differences have been documented between adenocarcinoma and large cell carcinoma. A retrospective study was undertaken to determine the results of definitive radiation therapy by histopathologic subtype of non-small cell carcinoma of the lung. Between July 1977 and April 1983, 134 patients with non-small cell carcinoma of the lung underwent definitive radiation therapy with curative intent. All patients had performance status scores of 80 to 100 (Karnofsky), and received minimum total doses within the tumor of 60 Gy in 6 to 7 weeks, five fractions per week. The median period of observation was 63 months. Ninety patients had squamous cell carcinoma; 44 had adenocarcinoma/large cell carcinoma. The two groups of patients were comparable in respect to age and Stage; there were significantly more women with adenocarcinoma/large cell carcinoma (27%) than with squamous cell carcinoma (13%). The median survival for patients with squamous cell carcinoma was 11.5 months; the 2 and 4 year survival rates were 21 and 7%, respectively. The median survival for patients with adenocarcinoma/large cell carcinoma was 18 months; 2 and 4 year survival rates were 38 and 23%, respectively. Comparison of the overall survival experience did not show a significant difference between the two cell types (p = .12 using Gehan's generalized Wilcoxon test). However, comparison of the proportion of patients with adenocarcinoma/large cell carcinoma surviving 18 months (50%) was significantly higher (p = .02) than that with squamous cell carcinoma (30%). A small body of data from the literature also suggests a better long-term prognosis for adenocarcinoma/large cell carcinoma. This observation requires confirmation from large trials with histopathologic review. If it is confirmed, there are important implications for therapeutic strategies in future clinical investigations of inoperable carcinoma of the lung.     

Increasing the rate of late toxicity by changing the score? A comparison of RTOG/EORTC and LENT/SOMA scores

PURPOSE: The Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue Task Force subjective, objective, management, and analytic (LENT/SOMA) scores were compared in a group of breast cancer patients. The impact of the classification system on grading late effects was evaluated. MATERIALS AND METHODS: Telangiectasia, skin pigmentation, and fibrosis were scored according to both LENT/SOMA and RTOG criteria. The results were compared with respect to up- or downgrading and correlated (Spearman's rho). Other side effects were recorded using LENT/SOMA criteria. Interobserver variability was calculated with Cohen's kappa. Two hundred fifty-nine subsequent relapse-free patients who underwent breast-conserving therapy between 1981 and 1995 were examined. The median dose of radiotherapy to the breast was 55 Gy. Adjuvant chemotherapy was given to 31 patients and tamoxifen to 52 patients. The median follow-up was 8 years. RTOG skin and s.c. tissue scales and LENT/SOMA breast and pigmentation scales were used. Two doctors examined 45 patients jointly. RESULTS: Of all patients, 20% had telangiectasia, 22% pigmentation, 43% fibrosis, 4% breast edema, 77% retraction/atrophy, and 54% pain. In comparison, when LENT/SOMA criteria were used, telangiectasia and pigmentation were upgraded in 34% and 36%, respectively, and telangiectasia was downgraded in 45%. Fibrosis correlated well (Spearman's rho 0.78, p = 0.01). An additional 356 side effects, mainly retraction/atrophy were observed in 226 patients using LENT/SOMA criteria. Interobserver variability was similar for both classification systems and ranged from Cohen's kappa 0.3 (retraction) to 0.91 (telangiectasia). CONCLUSIONS: LENT/SOMA criteria seem to be the better tool in grading and recording late radiation toxicity compared with the RTOG scale. There was some upgrading with the RTOG score when skin toxicity is evaluated. In contrast, fibrosis scores correlated very well. Adjustments of the LENT/SOMA scoring system should be considered to standardize reporting of late radiation morbidity.     

Inhibition of the Rho/ROCK pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1α in human ovarian cancer cells

Rho, a Ras-related small GTPase, and Rho-associated coiled coil-containing protein kinase (Rho kinase, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus cell motility. Rho/ROCK kinases also play roles in proliferation, differentiation, apoptosis and oncogenic transformation. In the present study, we have shown that Rho/ROCK pathway inhibition by fasudil, an orally administered inhibitor of Rho kinases, enhanced cisplatin-induced growth inhibition and apoptosis in human ovarian cancer cell lines. Fasudil inhibited hypoxia inducible factor (HIF)-1α protein expression. Knockdown of RhoA, ROCK1 or ROCK2 also attenuated the expression of HIF-1α. Furthermore, knockdown of HIF-1α using small interfering RNA enhanced cisplatin-induced growth inhibition and apoptosis as did inhibition of the Rho/ROCK pathway by fasudil, the Rho/ROCK inhibitor Y27632, or by Rho/ROCK knockdown. Therefore, the Rho/ROCK pathway may modulate HIF-1α signal transduction and blockade of Rho/ROCK enhances the efficacy of cisplatin by inhibiting HIF-1α in ovarian cancer cells. Our findings suggested that the Rho/ROCK pathway may be a new target for molecular targeting therapies against ovarian cancer.     

Paget’s disease of the breast: the experience of the European institute of oncology and review of the literature

Background Paget’s disease of the breast is an uncommon presentation of breast malignancy, accounting for 1–3% of all the breast tumors and presents in different histopathologic patterns: in association with an underlying invasive or non invasive carcinoma, or without any underlying neoplasia. In the literature, different methods are used for the treatment. Mastectomy with or without axillary dissection has been considered as the standard treatment procedure for many years. Several studies have already shown that breast conservation with radiation therapy is an oncologically safe option. Regarding the axillary approach, several studies have documented the presence of positive sentinel lymph node even in Paget’s disease alone. The objective of this study was to retrospectively analyze outcome of patients affected by Paget’s breast disease and to define our institutional experience. Patients and methods Between May 1996 and February 2003, 114 patients with confirmed Paget’s disease of the breast were retrieved and underwent surgery at the European Institute of Oncology of Milan, Italy. The median age of the patients was 54 years at the time of the diagnosis. In our study, the histopathological examination of the operated specimen revealed one hundred seven patients with Paget’s disease associated with an underlying invasive or non invasive carcinoma, and seven patients without underlying carcinoma. Patients underwent either conservative breast surgery or mastectomy, with or without sentinel lymph node biopsy and/or axillary surgery. Each patient was evaluated after surgery at a multidisciplinary meeting to selecting systemic therapy. Results Seven patients had “pure” Paget’s disease of the breast and one hundred seven had the disease associated with an underlying carcinoma. As surgical techniques 71 mastectomies and 43 breast conserving surgeries have been performed. Complete axillary dissection was done in patients with clinically positive lymph node and/or sentinel lymph node biopsy positive. Sentinel lymph node biopsy was performed in nineteen patients with invasive component and five were positive and underwent axillary dissection. Eleven sentinel lymph node biopsies were done in patients with non invasive component and none of them was positive. Adjuvant systemic therapies were based on the final tumor, node and metastasis stage: thirty patients received adjuvant chemotherapy alone, fourteen received endocrine treatment alone, twenty-six patients were evaluated to receive both chemo and endocrine therapy. The median duration of follow up was 73 months and was updated in the last 6 months. Five patients developed local recurrence, one had regional recurrence, another two had loco-regional recurrences and fourteen had distant metastasis as a first event. Malignancy-related deaths were censored in the statistical analyses cancer for and due to another tumor in eleven patients. Additionally, deaths were not related to malignancy totally in thirteen patients. Conclusions Screening examination and imaging techniques are fundamental. Breast conserving surgery combined with breast irradiation for patients with invasive and non invasive breast carcinoma has become the treatment of first choice. All surgical conservative approaches should include the complete nipple–areolar complex and margins of resected specimen free of tumor. Thanks to the evolution of the conservative approach, good cosmetic result can be obtained. To be informed about the axillary lymph node status and to avoid the patient to have a second surgical approach, sentinel lymph node biopsy should be performed.     

Do the risks of Lynch syndrome-related cancers depend on the parent of origin of the mutation?

Familial Cancer - Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the...     

New Cancer Drugs at the Cost of Bankruptcy: Will the Oncologist Tell the Patients the Benefit in Terms of Days/Weeks Added to Life?

In addition to considerations of possible cancer treatments reducing quality of life, the cost effectiveness of such treatments must also be a factor when determining treatments. Some patients have opted for expensive new treatments, leading to high financial risk but only modest results. Oncologists must explain to patients the expected benefits of treatments in terms of absolute values to allow patients to make informed decisions.“All is fine, doctor, chemotherapy for my husband has been planned; however, we are worried how to arrange money for trastuzumab. We have been advised that this drug, if added to chemotherapy, can significantly improve the survival. We have decided to sell our house to get the money,” she informed me. I recalled her husband’s case: he was suffering from metastatic gastric cancer—image guided cytological examination had confirmed multiple liver metastases. I got worried. Why were they selling their house? What would happen to their children? And what was this significant improvement? I remembered that the well-known Trastuzumab for Gastric Cancer Trial had shown a benefit of 2.7 months in the overall median survival (13.8 months versus 11.1 months; hazard ratio 0.74, 95% confidence interval 0.60–0.91; p value .0046) [1]. Do they know this absolute value of the so-called significant improvement in survival? Is this gain of 3 months worth problems that this lady and her children would suffer for a lifetime?We read with great interest the article titled “Quality of life in the Trasuzumab for Gastric Cancer Trial” by Satoh et al. [2] published in July issue of The Oncologist. The authors have correctly identified the basic panacea of treatment in advanced cancer; gain of a few days or weeks must not be at the cost of deterioration in quality of life. We strongly believe there is another dimension too; the money spent/expended. Is this marginal gain of a few days or weeks worth the money spent? Even in developed countries, cost effectiveness of treatments is being discussed vigorously. The evidence review group report, published in 2011, does not find merit in the efficacy of combination chemotherapy (trastuzumab, cisplatin, capecitabine/fluorouracil) compared with current National Health Service standard therapy for a certain incremental cost-effective ratio based on available literature [3]. Kantarjian et al. [4] raised the issue of the high cost of cancer drugs involved in modest prolongation of progression-free survival in metastatic solid cancers. They supported their argument with an example of anti-vascular endothelial growth factor inhibitors, which provide a median survival advantage of 1.4 months over the standard of care in metastatic colon cancer at a monthly cost of $5,000–$11,000 per month. Is this modest benefit worth of such a high price? The fact that the illness and medical bills contribute to a large and increasing share of bankruptcies in United States of America [5] further highlights the gravity of the situation. The scenario in developing countries gets gloomier as patients suffer out-of-pocket expenditures for cancer care most of the time [6]. It cannot be overemphasized that a high percentage of out-of-pocket payments and low health insurance coverage results in exposure to high financial risk and ultimately pushes the patients and their families into catastrophic poverty [7].While writing a commentary for the spiraling cost of cancer care, in particular the cost of cancer therapeutics that achieve only marginal benefits, Tito Fojo and Christine Grady raised very pertinent questions [8]: What counts as a benefit in cancer treatment? How much should cost factor into deliberations? Who should decide? The time has come when oncologists need to face these questions and must come out with clear answers. We believe that oncologists must tell each and every patient explicitly the expected benefit of a new cancer treatment modality in terms of “absolute values” (for example, the likely benefit of 2.7 months in the overall median survival if trastuzumab is added to standard chemotherapy [1]). One must not use the statistical jargon—significant improvement in survival—while informing the patient about benefits of a new drug or therapy. And one must allow the patients to make informed decisions without compromising their right to avail the standard therapies or best supportive care.     

Potentiation of the antitumor activity of 5-trifluoromethyl-2′-deoxyuridine by the use of depot forms of the parent compound

Summary 5-Trifluoromethyl-2-deoxyuridine (CF₃dUrd), an antitumor agent, is known to be short-lived in human plasma. Since its rapid elimination from the blood-stream seems to have descouraged the clinical evaluation of this drug, we explored the potential use of masked derivatives of CF₃dUrd as depot forms of the parent compound. First, we observed that the toxicity of CF₃dUrd against HeLA cells in culture was 10⁴ times greater for a 24-h treatment as compared with a 1-h treatment at identical concentrations of the drug, which suggests the importance of using a prolonged treatment period. In fact, the divided dosing of CF₃dUrd to L1210-bearing mice was markedly more effective than its single administration. 5-O-Hexanoyl-,N ³-p-butylbenzoyl-, 5-O-benzyloxymethyl-, and 3-O-benzyl-CF₃dUrd were found to be effective in maitaining the CF₃dUrd concentration in plasma. The oral doses of these agents required to achieve 50% growth inhibition (ED₅₀) in mice bearing sarcoma 180 tumors were 19, 34, 10, and 13 mg kg^–1 day^–1, respectively, whereas that of CF₃dUrd was 63 mg kg^–1 day^–1. The ED₅₀ values for these compounds were inversely correlated with the residence time of CF₃dUrd in plasma. The therapeutic indices of these compounds, calculated as the dose producing a 50% inhibition of body-weight gain (IB₅₀) divided by the ED₅₀ value (1.89, 1,21, 1.40, and 2.15, respectively), were significantly higher than that of CF₃dUrd (0.78). Consequently, these depot forms of CF₃dUrd, particularly 3-O-benzyl-CF₃dUrd, are expected to be more useful than the parent compound as antitumor agents.Abbreviations CF₃dUrd 5-trifluoromethyl-2-deoxyuridine - CF₃dUMP 5-trifluoromethyl-2-deoxyuridine-5-monophospate - S180 sarcoma 180 - L1210 L1210 leukemia - k_el elimination rate constant - T1/2 half-life time - AUC area under the curve - ILS increase in life span - TS thymidylade synthase - FdUMP 5-fluoro-2-deoxyuridine-5 monophosphate - FUra 5-fluorouracil     

Dissection of the RET/β-catenin interaction in the TPC1 thyroid cancer cell line

The RET receptor tyrosine kinase is a member of the cadherin superfamily and plays a pivotal role in cell survival, differentiation and proliferation. Currently, 12 ret/ptc chimeric oncogenes, characterized by the fusion between the intracellular domain of RET and different activating genes, which can cause ligand-independent dimerization and constitutive activation, have been described. β-catenin is usually involved in the maintenance of cell-to-cell adhesion and mediates the Wnt/β-catenin pathway important during embryogenesis and in cellular malignant transformation. Recently, a novel mechanism of RET-mediated function through the β-catenin pathway has been reported in multiple endocrine neoplasia type 2 and in sporadic thyroid carcinomas. Here, we investigated the effects of the ZD6474, a small molecule RET-inhibitor, on RET/β-catenin interaction. We confirmed the ZD6474 mediated-inhibition of recombinant RET kinase and of growth of cells expressing RET/PTC. Interestingly, we firstly observed reduced cellular mobility and changed morphology of TPC1 treated cells suggesting that RET-inhibitor could affect β-catenin cellular distribution as resulted in its co-immunoprecipitation with E-cadherin. We further investigated this hypothesis showing that TPC1 treated cells displayed predominantly β-catenin cytosolic localization. Surprisingly, RET and β-catenin co-immunoprecipitated in both ZD6474-treated and untreated TPC1 cells, suggesting that RET/β-catenin interaction might not be affected by RET kinase inactivation. All together these results suggest that RET kinase activation is crucial for β-catenin stabilization (pY654), localization and its signaling pathway activation but not for β-catenin/RET physical interactions, in human papillary thyroid carcinomas. In conclusion, ZD6474, by inhibiting RET kinase, down-modulates β-catenin pathway leading its recruitment to the membrane by E-cadherin.     

Measurement of Microcirculation of the Gastric Conduit

IntroductionThe standard reconstruction after esophagectomy isthe formation of a gastric tube with cervical or intratho-racic esophagogastrostomy.This type of reconstructionis associated with a considerable morbidity and mortal-ity due to anastomotic leakage of the esophagogastrosto-my.Although several etiological factors have beendiscussed to contribute to this clinically relevant com-     

The impact of changing the prevalence of overweight/obesity and physical inactivity in Australia: An estimate of the proportion of potentially avoidable cancers 2013–2037

Globally, 39% of the world's adult population is overweight or obese and 23% is insufficiently active. These percentages are even larger in high-income countries with 58% overweight/obese and 33% insufficiently active. Fourteen cancer types have been declared by the World Cancer Research Fund to be causally associated with being overweight or obese: oesophageal adenocarcinoma, stomach cardia, colon, rectum, liver, gallbladder, pancreas, breast, endometrium, ovary, advanced/fatal prostate, kidney, thyroid and multiple myeloma. Colon, postmenopausal breast and endometrial cancers have also been judged causally associated with physical inactivity. We aimed to quantify the proportion of cancer cases that would be potentially avoidable in Australia if the prevalence of overweight/obesity and physical inactivity in the population could be reduced. We used the simulation modelling software PREVENT 3.01 to calculate the proportion of avoidable cancers over a 25-year period under different theoretical intervention scenarios that change the prevalence of overweight/obesity and physical inactivity in the population. Between 2013 and 2037, 10–13% of overweight/obesity-related cancers in men and 7–11% in women could be avoided if overweight and obesity were eliminated in the Australian population. If everyone in the population met the Australian physical activity guidelines for cancer prevention (i.e. engaged in at least 300 min of moderate-intensity physical activity per week), an estimated 2–3% of physical inactivity-related cancers could be prevented in men (colon cancer) and 1–2% in women (colon, breast and endometrial cancers). This would translate to the prevention of up to 190,500 overweight/obesity-related cancers and 19,200 inactivity-related cancers over 25 years.     

Study of the Value of Combined Multiorgan Resection in Surgical Treatment of Carcinoma of the Gastric Cardia

OBJECTIVE:To determine the value of resection of combined visceral organs in surgical treatment of gastric cardiac carcinoma. METHODS:We retrospectively analyzed 217 random patients with car- cinoma of the gastric cardia who underwent a gastric cardiac resection.The patients had been treated as fol ows:186 with partial gastrectomy,31 with total gastrectomy,97 with a combined-visceral resection,of which 82 under- went a splenectomy plus partial pancreatectomy,10 with splenectomy alone and 5 with partial hepatectomy and diaphragmatectomy. RESULTS:The total patients were divided into 3 groups:128 with a gas- trectomy alone,10 with gastrectomy and splenectomy,and 82 with gastrec- tomy and splenectomy plus pancreatectomy.The operating times for these 3 groups were respectively 3.0 h,3.1 h and 3.8 h.The hospitalization times were respectively 23.8 d,31.2 d and 25.9 d.No differences in post-operative complications were found between these 3 groups.There were 92 patients who underwent a gastrectomy combined with a splenectomy and(or)the pancreatectomy,in which 92 No.10 lymph nodes were eliminated,with an average of one in each patient.Among the 125 patients not receiving a sple- nectomy but with elimination of lymph nodes,82 underwent a gastrectomy combined with partial pancreatectomy,of which 107 lymph nodes were elimi- nated for the No.11 group,with an average of 1.3 in each patient.There was a statisticaly significant difference between the 2 groups.The overal survival rates were similar in the 3 groups showing no statistical differences, but was higher in the Stage III patients with a combined resection of multi- organs.For patients in the Stage IV without resection of multi-organs,the survival rate was higher,but there was no significant difference between the 2 groups. CONCLUSION:It is difficult to determine precisely the involvement of para-tumorous organs with the eye during an operation.Combining a sple- nectomy with a pancreatectomy does not increase the post-operative compli- cations following surgical treatment for carcinoma of the gastric cardia.The combination of a splenectomy and partial pancreatectomy results in a higher survival rate and has an important significance for eliminating the lymph nodes of group 10 and 11,especially for patients in Stage III.In the applica- tion of a resection combining multi-organs,the doctor should make every effort to decrease the trauma and the complications based on the condition that the cancerous tissue is totally resected.     

Multi-Analysis of Non-Thyrogenous Masses of the Neck

OBJECTIVE To systematically analyze and summarize non-thyroge-nous masses of the neck(NTMN)by consideration of new areas,a large sample size and multiple-aspect analysis.METHODS Our research involved 3,125 NTMN cases.We summarized the proportion of various NTMN and the distribution of the neck diseases based on the new international classification.The clinical traits such as sexual proportion and age,etc,were analyzed along with the unknown pri-mary cervical metastatic carcinomas(UPCMC),multiple nodular NTMN and tubercular lymphadenitis.RESULTS There were 68 different diseases identified.Among all the NTMN,the percentage of metastatic carcinomas was 63.3%.The neck masses with a focus above the clavicle comprised 62.3% of the metastatic carcinomas whose focuses were clear.Moreover,other results almost sup-ported the “rule of 80%”.There was an obvious distribution of traits at every sub level.For example,there were 23 different diseases in level III,of which the most common was lymphoma.UPCMC made up 12.3% of all metastatic carcinomas.Multiple NTMN were composed of lymphoma,metastatic car-cinoma and tubercular lymphadenitis,etc.For tubercular lymphadenitis pa-tients,the patients without tubercular toxic symptoms comprised 77.1% of all tubercular lymphadenitis patients.CONCLUSION NTMN are complex and various,with a definite distribu-tion in each neck level.Data relating the sex ratio,UPCMC,multiple nodular NTMN and tubercular lymphadenitis to the clinical traits of NTMN will provide support for clinical applications.