Is there any relation between diabetes therapy and cancer risk?

Type 2 diabetes is associated with increased risk of cancer. This risk is related to HbA1 increase and this influence is present also in prediabetes and in nondiabetics with HbA1c in upper normal range. In last 2 years, it was concluded that that the specific antidiabetic therapy could influence the cancer risk. In this review we show that reduction of HbA1c does not change cancer risk. Most important is the risk reduction of cancer risk by metformin. Insulin therapy and the use ofsulphonylurea related drugs, increases the risk of cancer. This risk can be eliminated in the combination with metformin. Other published results including the suspected effect related to the use of glargine, pioglitazone, sitagliptine and exenatide are inconsistent and analysis of long term effects of these drugs is necessary. The large discussion in many publications shows the important role of FDA and EMA. This agencies do not suspend drugs without consistent evaluation of results.     

Thymidylate synthase expression in resectable and unresectable pancreatic cancer: role as predictive or prognostic marker?

Background and aims Thymidylate synthase (TS) is an important enzyme for DNA synthesis and the target for 5-fluorouracil (5-FU). Its expression may determine the outcome of patients with gastrointestinal cancers. We examined the prognostic and predictive value of TS-protein expression in patients with ductal adenocarcinoma of the pancreas.Methods TS expression from 131 patients with ductal adenocarcinoma of the pancreas was analyzed by immunohistochemistry in paraffin-embedded primary tumour specimens or biopsies.Results The median disease-specific survival among all patients (n=131) was 13 months. The invasion depth, the presence of metastases, grading and Union Internationale Contre le Cancer [International Union Against Cancer] (UICC) stage were associated with survival. Among resected patients (n=98), a difference in median survival was seen in the group receiving postoperative adjuvant treatment (21.1 months) compared with the group treated by surgery alone (12.4 months) (p=0.025). Low- and high-TS immunoreactivity was present in 74 (56%) and 56 (43%) of the cancers, respectively. One sample was not evaluable. No difference in median survival was observed among low- and high-TS-expressing tumours. Among patients undergoing resection and receiving postoperative intra-arterial chemotherapy (n=23), a marked trend to a longer median survival was seen for the group with low-TS-expressing tumours compared with the corresponding high-TS group (25.0 vs 16.0 months) (p=0.3834). There was no difference in survival among all palliative treated patients with low- and high-TS-expressing tumours.Conclusion Especially patients undergoing tumour resection with low-TS values seemed to have taken advantage from an intensified postoperative chemotherapeutic protocol. However due to the heterogeneous group of patients in the present report, larger trials of more homogenous patient populations will be necessary to confirm this hypothesis.     

Is there still a role for neoadjuvant therapy in breast cancer?

The role of neoadjuvant chemotherapy in locally advanced breast cancer is firmly established. There is now also an emerging role for neoadjuvant systemic therapy in the treatment of operable breast cancer. There is good evidence that the chances of breast conserving surgery can be increased with this approach and results of randomised studies indicate that survival is at least as good with neoadjuvant as with adjuvant chemotherapy. Similar clinical data are emerging with neoadjuvant endocrine therapy. For the future, there are important potential advantages in having an in vivo measure of chemosensitivity rather than blindly treating micrometastatic disease in the adjuvant setting. Clinical response to neoadjuvant treatment, and in particular complete pathological response, are predictors of subsequent outcome. Pathological involvement of axillary nodes following neoadjuvant therapy portends a poor prognosis. The potential for biological surrogate markers of response to predict for long-term outcome may allow individualisation of systemic treatment and the rapid assessment of new drugs in early breast cancer.     

Is there an optimal neoadjuvant therapy for locally advanced pancreatic cancer?

Treatment of locally advanced pancreatic cancer is challenging. Despite continuing research, effective treatments continue to be elusive with median survival of only 8-12 months. Treatment options for locally advanced pancreatic cancer include radiation therapy, concurrent chemoradiation or chemotherapy. It is felt that radiation therapy is a suboptimal treatment as most of patients will die of systemic disease. In the past, radiation with 5-FU was the standard treatment for locally advanced pancreatic cancer. But now radiation has been used with combination other chemo agents such as paclitaxel or gemcitabine in order to increase the efficacy. Chemotherapy such as gemcitabine alone or gemcitabine doublet also has been studied in patients with locally advanced pancreatic cancer as well with overall survival being approximately the same magnitude as chemoradiation. The exact role of chemoradiation or chemotherapy in treatment of locally advanced pancreatic cancer is yet to be defined. Hence, this review summarizes and compares of role of radiation, chemoradiation and chemotherapy in treating this disease.     

How reliable is current imaging in restaging rectal cancer after neoadjuvant therapy?

In patients with advanced rectal cancer,neoadjuvant chemo radiotherapy provides tumor downstaging and downsizing and complete pathological response in up to 30%of cases.After proctectomy complete pathological response is associated with low rates of local recurrence and excellent long term survival.Several authors claim a less invasive surgery or a non operative policy in patients with partial or clinical complete response respectively,however to identify patients with true complete pathological response before surgical resection remains a challenge.Current imaging techniques have been reported to be highly accurate in the primary staging of rectal cancer,however neoadjuvant therapy course produces deep modifications on cancer tissue and on surrounding structures such as overgrowth fibrosis,deep stroma alteration,wall thickness,muscle disarrangement,tumor necrosis,calcification,and inflammatory infiltration.As a result,the same imaging techniques,when used for restaging,are far less accurate.Local tumor extent may be overestimated or underestimated.The diagnostic accuracy of clinical examination,rectal ultrasound,computed tomography,magnetic resonance imaging,and positron emission tomography using 18F-fluoro-2’-deoxy-Dglucose ranges between 25%and 75%being less than 60%in most studies,both for rectal wall invasion and for lymph nodes involvement.In particular the ability to predict complete pathological response,in order to tailor the surgical approach,remains low.Due to the radio-induced tissue modifications,combined with imaging technical aspects,low rate accuracy is achieved,making modern imaging techniques still unreliable in restaging rectal cancer after chemo-radiotherapy.     

Breast surgery for young women with early-stage breast cancer: Mastectomy or breast-conserving therapy?

Whether breast-conserving therapy (BCT) should be chosen as a local treatment for young women with early-stage breast cancer is controversial. This study compared the survival benefits of BCT or mastectomy in young women under 40 with early-stage breast cancer and further explored age-stratified outcomes. This study investigated whether there is a survival benefit when young women undergo BCT compared with mastectomy.The characteristics and prognosis of white women under 40 with stage I–II breast cancer from 1988 to 2016 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. These women were either treated with BCT or mastectomy. The log-rank test of the Kaplan–Meier survival curve and Cox proportional risk regression model were used to analyze the data and survival. The analysis was stratified by age (18–35 and 36–40 years).A total of 23,810 breast cancer patients were included, of whom 44.9% received BCT and 55.1% underwent mastectomy, with a median follow-up of 116 months. Patients undergoing mastectomy had a higher tumor burden and younger age. By the end of the 20th century, the proportion of BCT had grown from nearly 35% to approximately 60%, and then gradually fell to 35% into the 21st century. Compared with the mastectomy group, the BCT group had improved breast cancer-specific survival (BCSS) (hazard ratio [HR] 0.917; 95% CI, 0.846–0.995, P = .037) and overall survival (OS) (HR 0.925; 95% CI, 0.859–0.997, P = .041). In stratified analysis according to the different ages, the survival benefit of BCT was more pronounced in the slightly older (36–40 years) group while there was no significant survival difference in the younger group (18–35 years).In young women with early-stage breast cancer, BCT showed survival benefits that were at least no worse than mastectomy, and these benefits were even better in the 36 to 40 years age group. Young age may not be a contraindication for BCT.     

Do clinical criteria reflect pathologic complete response in rectal cancer following neoadjuvant therapy?

Background

Clinical complete response (cCR) in rectal cancer is being evaluated as a tool to identify patients who would not require surgery in the curative management of rectal cancer. Our study reviews mucosal changes after neoadjuvant therapy for rectal cancer in patients treated at our center.

Methods

Pathology reports were retrieved for patients treated with neoadjuvant chemoradiation therapy (CRT) or high-dose rate brachytherapy (HDRBT). The macroscopic appearance of the specimen was compared with pathologic staging.

Results

This study included 282 patients: 88 patients underwent neoadjuvant CRT and 194 patients underwent HDRBT; all patients underwent total mesorectal excision (TME). There were 160 male and 122 female patients with a median age of 65 years (range 29–87). The median time between neoadjuvant therapy and surgery was 50 and 58 days. Sixty patients (21.2%) were staged as ypT0N0, 21.2% had a pathologic complete response (pCR), and only 3.2% had a cCR. Of the 67 patients with initial involvement of the circumferential radial margin (CRM), 44 converted to pathologic CRM?. Two hundred seventy-three patients (96.8%) had mucosal abnormalities. Of the 222 patients with residual tumor, 70 patients had no macroscopic tumor visualized but an ulcer in its place.

Conclusion

Most patients undergoing neoadjuvant therapy for rectal cancer have residual mucosal abnormalities which preclude to a cCR as per published criteria from Brazil. Further studies are required to optimize clinical evaluation and MRI imaging in selected patients.

     

The utilization and impact of adjuvant therapy following neoadjuvant therapy and resection of pancreatic adenocarcinoma: does more really matter?

BackgroundAlthough neoadjuvant therapy is increasingly administered to patients with pancreatic ductal adenocarcinoma (PDAC), the impact of additional adjuvant therapy (AT) following resection is not well defined.MethodsThe National Cancer Database (NCDB) was queried for patients who received neoadjuvant therapy followed by R0 or R1 resection for PDAC. Factors influencing survival, including the receipt of AT were evaluated.ResultsOf patients receiving neoadjuvant therapy and resection 680 (33.8%) received AT and 1331 (66.2%) did not. For R0 resected patients (n = 1800), lymphovascular invasion (HR 1.24, p = 0.034) and increasing N classification (N1: HR 1.27, p = 0.019; N2: HR 1.51, p = 0.004) were associated with increased risk of death while AT was not associated with improved overall survival (OS) (HR 0.88, p = 0.179). Following R1 resection (n = 211), AT was associated with reduced risk of death (HR 0.57, p = 0.038). Within propensity matched cohorts, median OS for patients receiving and not receiving AT was 32.1 and 30.0 months after R0 resection (p = 0.184), and 23.6 and 20.5 months after R1 resection (p = 0.005).ConclusionThis analysis demonstrated that AT did not yield OS benefit for patients who had neoadjuvant therapy and R0 resection and a statistically significant, although relatively short, improvement in OS for patients who underwent R1 resection.     

��-catenin and Her2/neu expression in rectal cancer: association with histomorphological response to neoadjuvant therapy and prognosis

Background

Neoadjuvant treatment strategies have been developed to improve survival of patients with advanced rectal cancer. Since mainly patients with major histopathological response benefit from this therapy, predictive and prognostic markers are needed. We examined the association of ??-catenin and Her2/neu protein expression with histopathologic response to neoadjuvant radiochemotherapy and prognosis in patients with locally advanced rectal cancer.

Methods

Fifty-four patients (33 male; 21 female; median age 60.4?years) with locally advanced rectal cancer were included in this study. All patients received a neoadjuvant radiochemotherapy (50.4?Gy, 5-FU) followed by surgical resection. Histomorphologic regression was evaluated by Dworak and Cologne staging system. Major response was defined by Dworak classification when resected specimens contained less than 50% vital tumor cells (n?=?14) and by Cologne grading system when resected specimens contained less than 10% vital tumor cells (n?=?15). Intratumoral ??-catenin (nuclear/membranous) and Her2/neu (cytoplasmatic/membranous) expression was determined by immunohistochemistry in pre- and post-therapeutic specimens and correlated with clinicopathologic parameters.

Results

A significant association was detected between pre-therapeutic membranous ??-catenin levels and response: patients with a lower ??-catenin protein expression showed significantly more often a major response compared with patients having high intratumoral protein levels (p?=?0.011). In addition, patients with a higher Her2/neu protein expression showed a significant survival benefit compared with patients having low intratumoral protein levels (5-year survival rate: 81% vs. low 41%; p?=?0.023).

Conclusions

The pre-therapeutic ??-catenin and Her2/neu protein expression seem to be valuable predictive and prognostic markers in the multimodality treatment of advanced rectal cancer.     

Evaluating the response of neoadjuvant chemotherapy for treatment of breast cancer: are tumor biomarkers and dynamic contrast enhanced MR images useful predictive tools?

Objective

In order to evaluate the therapeutic response to neoadjuvant chemotherapy (NAC) for breast cancer, this research focused on the changes in expression of tumor biomarkers and the correlations associated with changes of magnetic resonance imaging (MRI) pre- and post-NAC. We also compared the accuracy of MRI and pathology in terms of residual tumor extent after NAC.

Methods

MRI was performed before and after four courses of cyclophosphamide, epirubicin and paclitaxel (CET) NAC on 114 patients treated in Huashan Hospital (Fudan University) from December 2009 to January 2013. All patients were pathologically diagnosed with invasive breast cancer via core needle biopsy. A series of tumor biomarkers, including P-glycoprotein (P-gp) and Ki-67, was tested by immunohistochemistry in both core needle biopsy and surgical specimens. The changes in tumor biomarker expression and the shrinkage of tumor on MRI were observed. The residual tumor extent after NAC was compared in terms of MRI and histopathology, and the accuracy of MRI was evaluated by both residual tumor extent and by NAC therapeutic effect. Together, these methods enabled a prognostic estimate of NAC.

Results

The P-gp expression before NAC was used to evaluate the therapeutic effect of NAC. The up-regulation of P-gp expression after NAC was associated with poor therapeutic effect (P=0.0011). The expression of Ki-67 was significantly down-regulated (P<0.0001) but it had no association with NAC response (P=0.9645). The mean extent of residual tumor after NAC as seen on MRI was 20.83 mm (±4.14 mm, 95% CI) and that of surgically removed specimens, 18.89 mm (±3.71 mm, 95% CI). The sensitivity of MRI was 95.1%, the specificity was 28.6%, the positive predictive value was 79.6%, and the negative predictive value was 66.7%.

Conclusions

P-gp status was an important factor affecting the pathological complete response (pCR) rate. The change in P-gp expression, from negative to positive following NAC treatment, indicated the emergence of drug resistance resulting from chemotherapy. The down-regulation of Ki-67 was associated with the decline of tumor proliferation. However, compared to the pre-NAC P-gp status, the pre-NAC Ki-67 status had little prognostic value. Additionally, the evaluation of the efficacy of NAC by either MRI or histopathology was inconclusive.     

Histone deacetylase inhibitors and pancreatic cancer: Are there any promising clinical trials?

Pancreatic cancer,although not very frequent,has an exceptionally high mortality rate,making it one of the most common causes of cancer mortality in developed countries.Pancreatic cancer is difficult to diagnose,allowing few patients to have the necessary treatment at a relatively early stage.Despite a marginal benefit in survival,the overall response of pancreatic cancer to current systemic therapy continues to be poor,and new therapies are desperately needed.Histone deacetylase(HDAC) enzymes play an important role in the development and progression of cancer and HDAC inhibitors(HDACIs) have been shown to induce differentiation and cell cycle arrest,activate the extrinsic or intrinsic pathways of apoptosis,and inhibit invasion,migration and angiogenesis in different cancer cell lines.As a result of promising preclinical data,various HDACIs are being tested as either monotherapeutic agents or in combination regimens for both solid and hematological malignancies.Vorinostat was the first HDACI approved by the Food and Drug Administration for patients with cutaneous T-cell lymphoma.The use of HDACIs in clinical trials,in pretreated and relapsed patients suffering from advanced pancreatic cancer is discussed.Unfortunately,clinical data for HDACIs in patients with pancreatic cancer are inadequate,because only a few studies have included patients suffering from this type of neoplasm and the number of pancreatic cancer patients that entered HDACIs phase Ⅱ/Ⅲ trials,among others with advanced solid tumors,is very limited.More studies recruiting patients with pancreatic cancer remain to determine the efficiency of these therapies.     

Breast cancer treatment and adverse cardiac events: what are the molecular mechanisms?

Cardiotoxicity associated with breast cancer treatment is an important concern in the oncology clinic. Different types of anti-cancer therapies have recorded high rates of cardiac dysfunction in treated patients. Cardiac dysfunction linked to anthracyclines--one of the most common conventional chemotherapies--has extensively been described and several mechanisms have been proposed, although their mode of action is not fully understood even in cancer cells. The mediation of cardiac damage by reactive oxygen species stress is a recent hypothesis that has attracted a lot of interest, since it might explain the tissue-specific toxic effects of anthracyclines in the heart. Regarding molecular targeted tyrosine kinase inhibitors used in patients with human epidermal growth factor receptor type 2+ tumours (e.g., trastuzumab, lapatinib), it is the blockage of survival pathways required for a normal heart development and function that seems to lead to cardiac pathology. Both types of breast cancer treatment appear to trigger cardiotoxicity synergically, being patients under adjuvant therapy closely monitored. Given the complex nature of heart failure and of the pathways altered by anti-cancer drugs, global gene expression regulation is key in the heart disease process. MicroRNAs have been demonstrated to be small molecules with big roles as essential gene expression modulators. The great potential of microRNAs as biomarkers in the cardio-oncology field needs to be further explored before new microRNA-based diagnostic and therapeutic tools can be developed.     

Adjuvant therapy for stage II colorectal cancer: Who and with what?

Opinion statement The role of adjuvant chemotherapy for patients with stage II colon adenocarcinoma remains controversial. The high surgical cure rate for patients with "low-riskrd stage II colon cancer, ranging from 75% to 80%, and the available clinical trials and metaanalyses provide conflicting recommendations for or against adjuvant chemotherapy for this group of patients. For fit "high-riskrd stage II patients with clinical obstruction or perforation at presentation, in which the 5-year survival rate is 60% to 70%, there is little controversy, as these patients are routinely treated with adjuvant chemotherapy. Other potential high-risk factors, including high histologic grade, microsatellite instability, and loss of 18q, have yet to be validated in prospective trials. Patients with fewer than 12 regional lymph nodes identified in the surgical specimen have a statistically unclear risk of lymph node involvement. These patients may have stage III disease and should receive adjuvant therapy. The decision to use adjuvant chemotherapy to treat low-risk stage II colon cancer patients (no obstruction or perforation) should be an informed decision weighing the magnitude of a net 2% to 5% survival benefit, a 0.5% to 1.0% risk of mortality with chemotherapy in addition to 6 months of chemotherapy-related toxicities, other coexisting patient morbidities, and the anticipated life expectancy of each patient. As adjuvant chemotherapy is therapy addressing local or metastatic microscopic disease, and the effectiveness of systemic and biologically targeted therapy for advanced macroscopic colon cancer continues to improve rapidly, it remains to be determined by clinical trials whether therapies including newer agents such as cetuximab and bevacizumab administered in the adjuvant setting may affect survival for stage II cancer patients.     

Lung cancer screening: has there been any progress? Computed tomography and autofluorescence bronchoscopy

PURPOSE OF REVIEW: Advances in imaging technologies are currently being explored in the attempt to reduce lung cancer morbidity and mortality by achieving stage shift. We reviewed recent important publications on lung cancer screening. RECENT FINDINGS: Autofluorescence bronchoscopy has established its important role in the intervention of early central airway lesions. Multidetector computed tomography (CT) and CT-positron emission tomography may facilitate diagnosis of early parenchymal lung lesions. Practical implications of screening are reaching far beyond early diagnostic efforts per se as lead-time, length-time, overdiagnosis biases combined with low specificity of screening tests undermine its cost-effectiveness in the era of healthcare budget constraints. SUMMARY: Advanced imaging technologies may allow early detection and prudent intervention in some individuals that harbour asymptomatic early lung cancer, but disproportional expenses may be required to sieve out many more individuals at risk to attain stage shift. Confounding co-morbidities and practical hurdles may reduce screening's efficacy as it is plausible that for the majority of smokers, lung cancer may not be the ultimate cause of suffering since 90% of them will not develop lung cancer. This fact remains true despite increased use of noninvasive and minimally invasive technologies for the maximum preservation of quality of life irrespective of whether early intervention is a success or failure.     

Cancer and HIV infection: any association?

PURPOSE: Morbidity and mortality related to neoplasia are increasing in HIV-infected patients. CURRENT KNOWLEDGE AND KEY-POINTS: The incidence of AIDS opportunistic infections dramatically decreased since the introduction of highly active antiretroviral therapy (HAART). Among AIDS-cancers, the incidences of Kaposi sarcoma and of cerebral lymphoma decreased in a same way than AIDS infections but the incidences of systemic non-Hodgkin lymphoma and of cervical cancer decreased less than the others and remain higher than in the general population. This suggests that other factors than the quantitative immune reconstitution could be implicated. The most recent and large studies have also shown a 1.7 to 3 fold increased risk of developing non-AIDS cancers in HIV-infected patients when compared to the general population without significant impact of HAART on incidence curves. These malignancies include Hodgkin disease, lung, anal, head and neck cancers, hemopathies, and conjunctival cancers. PERSPECTIVES: Epidemiologic survey will help to define priorities in terms of prevention and screening in this specific population and to evaluate interventions which should be systematically proposed (alcohol and tobacco cessation programs, viral coinfection). The own roles of HIV itself and of antiretrovirals as prooncogenic factors need to be assessed.