EGFR ligands and DNA repair genes: genomic predictors of complete response after capecitabine-based chemoradiotherapy in locally advanced rectal cancer.

Epidermal growth factor receptor (EGFR) activation by radiation leads to increased cell proliferation and acts as a radioresistance mechanism. Neoadjuvant chemoradiation is the standard of care for locally advanced rectal cancer, and to date, no biomarkers of response have been found. We analyzed polymorphisms in the EGFR and its ligands, DNA repair genes and the thymidylate synthase in 84 stages II and III rectal cancer patients treated with neoadjuvant capecitabine plus radiotherapy. The rs11942466 polymorphism in the amphiregulin (AREG) gene region was associated with a pathological complete response (ypCR) (odds ratio: 0.26; 95% confidence interval: 0.06-0.79; P=0.014). The rs11615 C>T polymorphism in the ERCC1 gene also correlated with the ypCR as no patients with a C/C genotype achieved ypCR; P=0.023. This is the first work to propose variants within the AREG and the ERCC1 genes as promising predictive biomarkers of ypCR in rectal cancer.

Dasatinib worsens the effect of cetuximab in combination with fractionated radiotherapy in FaDu- and A431-derived xenografted tumours.

BACKGROUND: Cetuximab is often combined with radiotherapy in advanced SCCHN. Alternative routes bypassing inhibition of EGFR with cetuximab may overshadow the efficacy of this combination. We undertook this study to investigate a possible role of dasatinib in this scenario. METHODS: The SCC5, SCC25, SCC29, FaDu and A431 cell lines were assessed in vitro for cell proliferation under cetuximab and dasatinib treatments. In FaDu and A431 cells, dasatinib plus cetuximab resulted in higher proliferation than cetuximab alone. Then, FaDu and A431 cells were implanted into subcutaneous tissue of athymic mice that were irradiated with 30 Gy in 10 fractions over 2 weeks, and treated with cetuximab and dasatinib. Tumour growth, DNA synthesis and angiogenesis were determined. The EGFR, RAS-GTP activity, phosphorylated AKT, ERK1/2, SRC protein levels and VEGF secretion were determined in vitro. RESULTS: The addition of dasatinib to cetuximab and radiotherapy increased tumour growth, DNA synthesis and angiogenesis that were associated with RAS, AKT and ERK1/2 activation, and SRC inhibition in FaDu and A431 cells. CONCLUSIONS: In xenografts derived from these two cell lines, dasatinib did not improve the efficacy of cetuximab combined with radiotherapy. On the contrary, it worsened tumour control achieved by the combination of these two treatments.

Evaluation of patients with hereditary hemorrhagic telangiectasia with video capsule endoscopy: a single-center prospective study.

BACKGROUND AND STUDY AIMS: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by telangiectasia formation that can lead to small-bowel bleeding. In this study, video capsule endoscopy was used to compare the small-bowel findings observed in patients with HHT with those seen in patients without the condition. PATIENTS AND METHODS: We performed capsule endoscopy studies in 93 consecutive patients who were being evaluated for small-bowel bleeding, 38 patients with known or suspected HHT and 55 patients without HHT. Nine patients were excluded because the capsule failed to reach the cecum. The findings in 32 patients with a final diagnosis of HHT and in 48 patients without HHT were recorded and compared. RESULTS: Capsule endoscopy detected telangiectases evenly distributed throughout the small bowel in 26/32 (81%) patients with HHT, compared with 14/48 (29%) in patients without HHT. When active bleeding was observed in patients with HHT (n = 4), the bleeding was within reach of standard small-bowel push enteroscopy in all cases. The presence of five or more gastrointestinal telangiectases by capsule endoscopy had a sensitivity of 75% and a positive predictive value of 86% for diagnosing HHT. Unexpected findings (small-bowel polyps and mass-like lesions) were seen in both groups of patients (6.2% in patients with HHT and 2.1% in patients without HHT). CONCLUSIONS: Small-bowel telangiectases were seen in the majority of patients with HHT and were evenly distributed throughout the small bowel. Telangiectases were observed in only a minority of patients who did not have HHT. Actively bleeding small-bowel telangiectases were located in the proximal and mid-small bowel in patients with HHT, all within reach of an enteroscope. We propose a cutoff point of at least five gastrointestinal telangiectases to support a diagnosis of HHT.

Improving survival and local control in rectal cancer in Catalonia (Spain) in the context of centralisation: A full cycle audit assessment.

BACKGROUND: Rectal cancer surgery in Catalonia has been involved in a process of centralisation. We assessed the impact of this health policy strategy on quality of care and clinical results. METHODS: We compared patterns of care and clinical outcomes of all rectal cancer patients receiving radical surgery for the first time in public hospitals in two time periods, before (2005 and 2007) and after (2011-2012) centralisation, analysing indicators of care quality according to the regional clinical practice guidelines. Clinical outcomes at two years were also assessed. RESULTS: A total of 3780 patients were included. From 2005 to 2012, the proportion of patients treated surgically for the first time in centres whose annual surgical caseload was more than 11 increased from 84.0% to 90.4%. The rate of locoregional recurrence at two years fell from 4.5 to 3.06/100 person-years (p = 0.005). The crude mortality rate at three months, one and two years was reduced by 55%, 40% and 34% (p < 0.001). CONCLUSION: Improvements in quality of care might be associated with the centralisation of surgery and with the selective focus effect derived from the process of auditing. Our results support the continuation of clinical auditing and surveillance of authorised centres.

Radiotherapy for supratentorial low-grade gliomas: results and prognostic factors with special focus on tumour volume parameters.

From 1973 to 1990, 67 patients with a diagnosis of low-grade glioma were treated in our hospital. Overall survival was analysed as well as the influence of patient, tumour- and treatment-related factors with special focus on tumour volume parameters. Our study group included 49 patients treated by surgery and post-operative radiotherapy (RT) (40 patients) or post-biopsy irradiation alone (9 patients). Total or almost total resection was performed in 16 patients; partial excision was done in 24. With the available pre-surgery and pre-RT CT-scan and/or MRI images we were able to calculate tumour volumes by measuring the largest tumour dimensions in the three axes D1, D2, D3 and by assuming an ellipsoidal growth (i.e., tumour volume = D1D2D3 pi/6). RT was delivered to involved regions: either the residual tumour volume or the tumour bed. The median RT dose was 56 Gy (45-60, range). The 60- and 90-month overall survival (Kaplan-Meier) was 79% and 67%, respectively. Female sex, > 70% Karnofsky (Kf) score, oligodendroglioma and < 71 cm3 (approximately 5 cm diameter sphere) tumour residuals before RT were associated with better overall survival rates (p < 0.05, log-rank). However, a Cox proportional hazards model showed that only the histological subtype and Kf significantly determined the patients' outcome: 60-month overall survival of 100%, 62%, 83% and 64% for oligodendrogliomas, mixed oligo-astrocytomas and grade-I and grade-II astrocytomas, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of oesophageal cancer with preoperative chemoradiotherapy may increase operative mortality.

AIMS: This phase II multicentric study evaluates a modified preoperative chemoradiotherapy schedule. METHODS: Patients <75 years with potentially resectable neoplasm were eligible. Treatment included an initial course of CDDP 100 mg/m2 (Day 1) and 5-FU CI 5000 mg/m2 (Days 1-5) followed by 45 Gy (Days 28-63) and 5-FU CI 5000 mg/m2 (Days 28-33), CDDP 75 mg/m2 (Day 56) and 5-FU CI 3750 mg/m2 (Days 56-61). Regional lymph nodes were irradiated. RESULTS: Nineteen patients were studied. Oesophagectomy was performed in 17. Clear margins were achieved in 16 of these. Eight patients showed a pathologic complete response (pCR). One patient died of infection during the preoperative treatment and four died due to acute surgical complications. The study was closed prematurely because of excessive mortality. Median follow-up was 19 months. Local and regional relapse occurred in one and three patients, respectively. Median time and actuarial 3-year of overall survival and progression free rates were 18.6 months and 28%, and 12.7 months and 10.4%, respectively. CONCLUSIONS: This schedule showed a high pCR, resectability and local control rate. Treatment-related mortality limits its clinical applicability, but further investigations are warranted.

Histologic sectioning produces TUNEL reactivity. A potential cause of false-positive staining.

OBJECTIVE: To determine if the DNA strand breaks caused by tissue sectioning result in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) reactivity. METHODS: The incidence and location of TUNEL-positive nuclei were determined in 5- and 15-micron sections of human stomach. Five- and 15-micron sections of tonsil were stained as a positive control. RESULTS: In 5-micron gastric sections, 69% of nuclei were labeled; in 15-micron sections, only 30% were labeled. In the latter sections, almost all labeled nuclei were located at the cut surface of sections. Labeled nuclei did not have apoptotic morphology. Apototic bodies and tingible body macrophages were labeled throughout 15-micron sections of tonsil. CONCLUSIONS: Tissue sectioning creates TUNEL reactivity. The morphologic findings on routine stains should be considered the gold standard for the detection of apoptosis on tissue sections.

Endometrial cancer stages I and II. Analysis of survival and prognostic factors.

BACKGROUND: Endometrial cancer is the most frequent gynaecologic neoplasia in women. Stages I and II account for 75% of endometrial cancers. METHODS: Diagnostic features, treatment and outcome based on therapy with surgery and/or irradiation of 185 endometrial cancer patients in Stage I and II were analysed retrospectively. RESULTS: There were 148 patients (80%) in Stage I and 37 (20%) in Stage II. Twenty-nine patients (16%) relapsed and 18 have died of cancer. The 5 and 10 year specific actuarial survival was 89% and 81% respectively. The 5 and 10 years disease free survival was 82% and 78% respectively. In our analysis of prognostic factors we observed a significantly worse survival for postmenopausal and Stage II patients, high grade tumors (grade III) and greater myometrial penetration (outer 2/3). CONCLUSIONS: Endometrial cancer has a relatively good prognosis partly because of its early diagnosis. There is general consensus that surgery is the optimal treatment in Stages I and II. While it is well documented that complementary irradiation improves survival in Stage II, there is no general agreement regarding the value of complementary irradiation in Stage I. Further studies are needed to delimit Stage I patients who would benefit from complementary irradiation.

[Perfusion tomographic scintigraphy and coronary angiography as complementary studies for the therapy decision for patients with ischemic cardiopathy]. / La tomogammagrafía de perfusión y la coronariografía como exploraciones complementarias en la decisión terapéutica de pacientes con cardiopatía isquémica.

BACKGROUND: The aim of the present study was to assess the value of tomographic perfusion scintigraphy as a complement to coronary arteriography in the therapeutic management of patients admitted to the hospital for treatment of unstable ischaemic heart disease. METHODS: A review was carried out of the discharge report of 100 consecutive patients (mean age 58 years, 19 females) in which there was a mention of having taken a therapeutic decision on the basis of coronary angiography and tomographic perfusion scintigraphy with 99m-technetium isonitriles under exercise and/or dipyridamole. In 90% of instances the study was performed during drug therapy after the patient had remained stable for at least 3 days. The indication of the studies and the type of therapy was made by the attending physician. Concordance between both studies was said to exist when both pointed to the same type of therapeutic approach, either medical treatment (nonsevere stenosis on coronary arteriography with mild ischaemia on scintigraphy) or revascularization (severe stenosis with moderate or severe ischaemia in tomographic scintigraphy). Discordance was said to be present when ischaemia was mild with severe stenosis on coronary angiography. RESULTS: In 80 patients there was concordance between both studies regarding the subsequent therapeutic approach (medical treatment in 32 and revascularization in 48 [25 coronary angioplasty and 23 bypass surgery]). In the patients with discordance (n:20) medical treatment was decided in 14 patients on the basis of mild ischaemia with significant angiographic stenosis, and in only 6 patients revascularization (angioplasty in 5 and bypass surgery in 1) was indicated, based on the severity of coronary stenosis even if the ischaemia apparent on the scintigraphy was mild. CONCLUSIONS: Therefore, in 80% of patients admitted for unstable coronary artery disease there was a concordance between the results of tomographic scintigraphy and coronary angiography, when both studies were indicated to select the most appropriate therapeutic modality. In the 20% of discordant cases the attending physician decided on a conservative strategy in most cases, as no significant enough perfusion defect was shown on scintigraphy in spite of severe coronary artery stenosis.

[Morphologic classification of hypertrophic cardiomyopathy with myocardial single photon emission tomography. Comparison with echocardiographic classification]. / Clasificación morfológica de la miocardiopatía hipertrófica mediante tomogammagrafía miocárdica. Comparación con la clasificación ecocardiográfica.

INTRODUCTION AND OBJECTIVES: The aim of this study was to compare different morphologic types of hypertrophic cardiomyopathy obtained by single photon emission tomography to those obtained by echocardiogram. MATERIALS AND METHODS: In 76 (64%) out of 119 patients with hypertrophic cardiomyopathy the echocardiogram permitted an optimal visualization of all left ventricular segments in the short axis view and consequent classification to one of the six morphological types: type I (septal anterior hypertrophy), type II (septal anterior and septal posterior hypertrophy), type III (septal and antero-lateral hypertrophy), type IV (antero-lateral and/or septal posterior hypertrophy), type V (concentric hypertrophy) and type VI (apical hypertrophy). Without knowledge of echo data, two experienced observers included the short axis of single photon emission tomography images at rest (99mTc-tetrofosmin) to one of those types. RESULTS: Global concordance between echocardiogram and single photon emission tomography was 75%. Type III was the most frequent both in echo (76%) and in single photon emission tomography (74%) and type III produced the majority of discrepancies. SPET identified 4 patients with a predominant septal and inferior hypertrophy, that did not correspond to any of the 6 types of echocardiographic classification and had been previously classified as type III by echo in 3 cases and as type V in 1 case. CONCLUSIONS: There was agreement between echo and single photon emission tomography in the morphological classification of most of the patients (75%) with hypertrophic cardiomyopathy. Nevertheless, some discrepancies were observed for the type III echocardiogram.

[Influence of ergometric parameters on the results of myocardial perfusion tomographic scintigraphy]. / Importancia de los parámetros ergométricos en los resultados de la tomogammagrafía de perfusión miocárdica.

BACKGROUND: The percentage of peak predicted heart rate that is accepted to consider as sufficient a given exercise test is 85%. However, the optimal value of such rate and other exercise parameters for the purposes of myocardial single-photon emission tomography is not well established. PATIENTS AND METHODS: With the aim of establishing the minimal levels of maximal heart rate, product heart rate x systolic blood pressure and ventilatory oxygen uptake to obtain an adequate diagnostic efficacy of myocardial perfusion scintigraphy, 159 patients with coronary artery disease or suspicion of this without previous myocardial infarction were studied with stress test single photon emission tomography with 99mTc-methoxi-isobutil-isonitrile. All the patients were coronary angiography tested. RESULTS: Sensitivity and negative predictive value were significantly higher at levels of heart rate > 80% (93 vs 78%; p = 0.002 and 94 vs 56%; p = 0.0004), product heart rate x systolic blood pressure > 18,000 (88 vs 78%; p = 0.04 and 84 vs 52%; p = 0.004) and > 5 METs (85 vs 77%; p = 0.002 and 74 vs 69%; p = 0.03). CONCLUSIONS: Sensitivity and negative predictive value of stress test single photon emission tomography with 99mTc-methoxi-isobutil-isonitrile are low if levels higher than 80% of heart rate, 18,000 of product of heart rate x systolic blood pressure and 5 METs have not been achieved.

Survival of cancer of the pancreas. Bases for new strategies in diagnosis and therapy.

OBJECTIVE: The ominous prognosis of pancreatic carcinoma (PC) has led to a nihilistic attitude among physicians, and to the need to develop better tools for diagnosis, staging and treatment. The aim of this study was to analyze a series of patients with PC in order to determine stage-related survival, and to try to improve diagnostic and therapeutic strategies. METHODS: This was a retrospective study of 167 patients diagnosed from 1987 to 1993. The diagnosis was based on cytological pathology findings or on a clinical course compatible with PC. TNM stage and survival were calculated. We also analyzed age, sex, time elapsed until diagnosis, diagnostic tests, size and location, cytologic pathology confirmation, number of patients undergoing surgery, and procedures used. RESULTS: Age: 67 +/- 12 years, 82 men and 85 women. Time elapsed until diagnosis: 3 +/- 15.7 months. Pathologic diagnosis: 74.8%. LOCATION: head 75%, body 13.9%, tail 7.2%, diffuse 2.4%, not reported 1.2%. Size: 4.6 +/- 2 cm. TNM staging: stage I 13%; stage II 25%; stage III 20%; stage IV 42%. Stage-related survival: stage I 14 months; stage II 6 months; stage III 4 months; stage IV 1 month. Total survival: 3 months. Surgery was done in 66.5% and resection in 10%; curative surgery in 6.5%; bypass in 81% and diagnostic laparotomy in 9%. In 55% of the patients surgery revealed a higher stage of disease than had been diagnosed preoperatively. Postoperative mortality was 18%. Survival at 1 and 5 years after curative surgery was 80% and 20%, respectively. CONCLUSIONS: Diagnosis was made at a late stage in many patients. Few patients were candidates for radical surgery. Early diagnosis, preoperative staging and postoperative management should be improved in these patients, and surgery should be associated with complementary chemotherapy and/or radiotherapy.

Recent advances in cancer therapy: an overview.

The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.

[The non-mydriatic camera as a screening method in diabetics in Tarragona]. / Resultados de la implantación de la càmara no midriática como método de screening en pacientes diabéticos en Tarragona.

OBJECTIVE: The aim of the study is to present the results of the first year of using a non-mydriatic fundus camera. We performed an evaluation of its usefulness and problems. METHODS: During the first year of using the non-mydriatic fundus camera we evaluated 3,272 type II diabetic patients who were not being controlled in the hospital. RESULTS: The diabetic retinopathy was observed in 164 patients (5.01%), the mild form in 70 patients (2.14%). Diabetic macular oedema was observed in 41 patients (1.25%). In 119 patients (3.63%) the retinography could not be interpreted and were referred to the hospital; 113 patients also were referred due to other pathologies; the largest group of these patients had age-related macular disease or age-related macular degeneration (42 patients). Finally, 458 patients (13.99%) required mydriatic eye-drops. CONCLUSIONS: The non-mydriatic fundus camera is a useful technique for assessing the presence of diabetic retinopathy, particularly in patients with poor ophthalmic control. This technique may enable us to diagnose these patients who need laser treatment.

Safety and efficacy of aspartame-based liquid versus sucrose-based liquids used for dilution in oral sodium phosphate solutions for colonoscopy preparations.

The aim of this study was to investigate whether an oral sodium phosphate solution (OSPS) mixed with aspartame-based clear liquids as the diluent would yield improved colon cleansing results compared to an OSPS mixed with sucrose-based liquids as the diluent. Fifty-one patients undergoing colonoscopy were prospectively randomized into two groups to receive different OSPS colonoscopy preparations, with sucrose-based or aspartame-based liquids used as diluents. The primary end point was the quality of the colonoscopy preparation and secondary end points were serum electrolytes before and after preparations. No significant difference in colonoscopy preparation quality was seen between the two OSPS diluent groups (Mantel-Haenzel chi (2) = 0.795, P = 0.484). There were no significant differences in mean electrolyte shifts of sodium, potassium, blood urea nitrogen (BUN), creatinine (Cr), or BUN/Cr ratios between the two groups. There was a statistically significant increase in serum phosphorous in the aspartame-based group compared to the sucrose-based diluent group (P = 0.021). In conclusion, there was no clinically detectable difference in colonoscopy preparation quality between the two OSPS diluent groups. This study suggests that passive fluid transport by aquaporins may well be the major mediator of fluid shifts in the study subjects. This result suggests the potential importance of aquaporins and minimizes the importance of sodium glucose cotransporter SGLT1 in fluid and electrolyte transport in the human gastrointestinal tract. Aspartame or its constituent amino acids may enhance phosphate absorption across the human small intestine.