Impacto social de la despenalización de la muerte médicamente asistida / The social impact of physician-assisted death legalization

The debate on legalization of physician-assisted death (PAD) has focused on its purely individual aspects, leaving aside equally relevant social dimensions such as a progressive expansion of PAD's causes, strains and changes in the doctor-patient relationship, and unreported PADs. The aim of this work was to explore these aspects through an analysis of the experience of Belgium and the Netherlands, countries where PAD is legal since 2002. The results, obtained through a systematic review of the literature, indicate that in both countries, the acceptance of the concept of "psychological suffering" allowed PAD to be performed in psychiatric patients, in persons with dementia and in older people with geriatric conditions. The acceptance to perform a PAD has a significant emotional burden for the physician who must assume the role of executor of the patient's will, which is aggravated by pressures from patients and their relatives. Moreover, more than 30% of PADs are not reported. All this information was obtained from physicians not willing to incriminate themselves, after the commission of the PADs, therefore hampering the monitoring of law abiding. These results reveal the existence of a social impact of PAD decriminalization that deserves greater consideration and further studies.

Dual role of tumour-infiltrating T helper 17 cells in human colorectal cancer.

BACKGROUND: The immune contexture predicts prognosis in human colorectal cancer (CRC). Whereas tumour-infiltrating CD8+ T cells and myeloid CD16+ myeloperoxidase (MPO)+ cells are associated with favourable clinical outcome, interleukin (IL)-17-producing cells have been reported to correlate with severe prognosis. However, their phenotypes and functions continue to be debated. OBJECTIVE: To investigate clinical relevance, phenotypes and functional features of CRC-infiltrating, IL-17-producing cells. METHODS: IL-17 staining was performed by immunohistochemistry on a tissue microarray including 1148 CRCs. Phenotypes of IL-17-producing cells were evaluated by flow cytometry on cell suspensions obtained by enzymatic digestion of clinical specimens. Functions of CRC-isolated, IL-17-producing cells were assessed by in vitro and in vivo experiments. RESULTS: IL-17+ infiltrates were not themselves predictive of an unfavourable clinical outcome, but correlated with infiltration by CD8+ T cells and CD16+ MPO+ neutrophils. Ex vivo analysis showed that tumour-infiltrating IL-17+ cells mostly consist of CD4+ T helper 17 (Th17) cells with multifaceted properties. Indeed, owing to IL-17 secretion, CRC-derived Th17 triggered the release of protumorigenic factors by tumour and tumour-associated stroma. However, on the other hand, they favoured recruitment of beneficial neutrophils through IL-8 secretion and, most importantly, they drove highly cytotoxic CCR5+CCR6+CD8+ T cells into tumour tissue, through CCL5 and CCL20 release. Consistent with these findings, the presence of intraepithelial, but not of stromal Th17 cells, positively correlated with improved survival. CONCLUSIONS: Our study shows the dual role played by tumour-infiltrating Th17 in CRC, thus advising caution when developing new IL-17/Th17 targeted treatments.

Stapled orthotopic ileal neobladder after radical cystectomy for bladder cancer: Functional results and complications over a 20-year period.

AIMS: To present the long term-results and complications of a large series of stapled ileal orthotopic neobladders. MATERIALS AND METHODS: From 1992 to 2012 we performed 606 radical cystectomies with stapled orthotopic neobladder substitution in male patients. The median patient age was 65 years (interquartile range [IQR]: 58-71). RESULTS: Median operative time was 205 min (IQR: 180-225). The overall survival rates at 5, 10, 15, and 20 yr were 68% (336 of 494), 55% (207 of 376), 38% (98 of 259), and 23% (14 of 62), respectively, and the disease specific survival rates were 75% (371 of 494), 59% (222 of 376), 50% (130 of 259), and 35% (22 of 62), respectively. After a median follow-up of 81 months (IQR: 30-144), a total of 147 early (less than 90 days) complications (38 diversion related, 109 diversion unrelated) occurred in 144 patients (24%); 163 late complications (141 diversion related, 22 diversion unrelated) affected 141 patients (23%). At 60 months, daytime and nighttime continence was complete in 96% and 72% of cases, respectively. Urodynamic studies showed that maximum capacity, residual volume, maximum flow rate, pressure at maximum capacity, and maximum outlet closure pressure were not statistically different at 12 and 60 months postoperatively. CONCLUSIONS: The use of a stapler when performing orthotopic neobladders significantly reduces the operating time, and offers good functional results with acceptable complication rates. Our results could encourage the use of a stapler when performing an ileal neobladder during laparoscopic and robotic radical cystectomies.

Benefits and shortcomings of superselective transarterial embolization of renal tumors before zero ischemia laparoscopic partial nephrectomy.

AIMS: To report feasibility, safety and effectiveness of "zero-ischemia" laparoscopic partial nephrectomy (LPN) following preoperative superselective transarterial embolization (STE) for clinical T1 renal tumors. METHODS: We retrospectively reviewed perioperative data of 23 consecutive patients, who underwent STE prior LPN between March 2010 and November 2012 for incidental clinical T1 renal mass. STE was performed by two experienced radiologists the day before surgery. Surgical procedures were performed in extended flank position, transperitoneally, by a single surgeon. RESULTS: Mean patients age was 68 years (range 56-74), mean tumor size was 3.5 cm (range 2.2-6.3 cm). STE was successfully completed in 16 patients 12-15 h before surgery. In 4 cases STE failed to provide a complete occlusion of all feeding arteries, while in 3 cases the ischemic area was larger than expected. LPN was successfully completed in all patients but one where open conversion was necessary; a "zero-ischemia" approach was performed in 19/23 patients (82.6%) while hilar clamp was necessary in 4 cases, with a mean warm-ischemia time of 14.8 min (range 5-22). Mean operative time was 123 min (range 115-130) and mean intraoperative blood loss was 250 mL (range 20-450). No patient experienced postoperative acute renal failure and no patient developed new onset IV stage chronic kidney disease at 1-yr follow-up. CONCLUSIONS: STE is a viable option to perform "zero-ischemia" LPN at beginning of learning curve; however, hilar clamp was necessary to achieve a relatively blood-less field in 17.4% of cases.

Post-surgical lipophagic panniculitis: a specific model of traumatic panniculitis and new histopathological findings.

Aim of this work was to define the histopathological features of post-surgical panniculitis. Dermal and hypodermal changes will be analyzed in detail, to understand the cascade of events that characterize the tissue response to surgical trauma. Cutaneous re-excision specimens of cases of basal cell carcinoma, squamous cell carcinoma, and melanoma consecutively seen from January 1, 2011 to June 30, 2011 at the Department of Dermatology, University of Pavia, were included in this study. Only the cases in which the first surgical procedure included the subcutaneous fat, were considered. In addition, the time elapsed from the first surgical procedure and the re-excision had to be included in a period of time from one to three months. All the specimens were stained with hematoxylin and eosin. Thirty cutaneous re-excision specimens were studied. Histopathologic examination revealed changes of epidermis, ranging from slight atrophy to moderate hyperplasia. In two cases focal ulceration was seen, with transfollicular elimination of foreign body material. The main dermal changes observed were the: 1) scar with well defined vertical orientation along the dermal suture line; 2) rounded cicatricial areas with radial branching septa of scarring tissue; 3) foreign body granuloma formation; 4) alignment of hystiocytes at the dermo-hypodermal border; 5) traumatic neuromas. The subcutaneous fat changes included: 1) lobular panniculitis with consistent presence of foam cells; 2) striking anisocytosis with pseudocystic degeneration and necrosis of adipocytes; 3) eritrocyte extravasation, mainly at the dermo-hypodermal border; 4) deep seated phlebitis. Post-surgical panniculitis is a lobular foam cell panniculitis characterized by simultaneous dermal and hypodermal changes, expression of the multi-faceted tissue response to a surgical trauma. This type of peculiar lipophagic response puts post-surgical panniculitis into the wider chapter of lipophage tissue response seen in atherosclerosis, glomerulosclerosis and some infectious models such as Mycobacterium tuberculosis and Chlamydia pneumoniae infections. Furthermore it may be seen as a reliable and convenient model for laboratory investigation on foam cell tissue response.

Clinical, pathological and immunohistochemical effects of arsenical-ferruginous spa waters on mild-to-moderate psoriatic lesions: a randomized placebo-controlled study.

Thermalism and spa treatments are traditionally considered effective in a number of dermatologic inflammatory conditions, yet there is scarce evidence about spring water effectiveness on psoriasis in a daily setting. We enrolled 34 patients with mild-to-moderate psoriasis in a double-blind, randomized, placebo-contralaterally-controlled trial, to evaluate Levico and Vetriolo arsenical-ferruginous water effectiveness on psoriatic lesions by daily 20-minute wet packing for 12 consecutive days. Clinical, histopathologic and immunohistochemical parameters were considered. A statistically significant difference between spa water-treated lesions and placebo-treated lesions in the same patients was demonstrated for histopathologic and immunohistochemical parameters. Since iron ions have an antiproliferative effect on epithelia, and magnesium ions have an anti-inflammatory effect, Levico and Vetriolo water effectiveness on psoriasis could be addressed to their content of these ions.

Olfactory and toxic impact of industrial odour emissions.

This paper describes the approach adopted for the evaluation both of the odour impact and of the non-carcinogenic health effects relevant to odours in the city of Terni, Italy. The first part of the study focused on the quantification of emissions by means of dynamic olfactometry and chemical analyses. Dispersion modelling was then applied for the evaluation of citizens' exposure both to odours and to their non-carcinogenic toxicity. The results show that, on one hand, the odour impact is considerable, actually affecting almost the whole city of Terni. On the other hand, the toxic impact, expressed in terms of the Hazard Index (HI), is about three orders of magnitude lower than the level that is expected to bring adverse effects, over a lifetime exposure, for human health.

Evaluating the dispersion of toxic odour emissions from complex sources.

This article describes an original approach for evaluating exposure to toxic odour emissions, based on methods commonly used for assessing the impact of odour, adopted in this specific case to examine the non-carcinogenic health effects of odours in the city of Terni, Italy. First the hazardous volatile organic compounds emitted from the main odour sources were identified and quantified by chemical analysis. The Hazard Index (HI) was used to assess the toxicity associated with the emissions. The HI is the sum of the concentrations of the hazardous compounds weighted with their Reference Concentration (RfC). A RfC is the estimated continuous inhalation concentration at which people are unlikely to risk any deleterious effects during their lifetime. Atmospheric dispersion modelling was based on the Toxicity Emission Rate (TER) which, like the Odour Emission Rate (OER) conventionally used to quantify odour emissions, relates the HI with the air flow of an emission source; it is as a simple but effective method for the general characterization of toxic odour emissions in complex scenarios. The results indicated that citizens' exposure to the non-carcinogenic toxic compounds involved in odour emissions was below the level expected to have adverse effects on human health. Classical risk assessment techniques should now be employed to define the pollutants and their effects better and to validate this approach.

Endovascular treatment of in-stent restenosis using excimer laser angioplasty and drug eluting balloons.

In-stent restenosis after endovascular treatment of stenotic and occlusive disease of the infrainguinal arteries is still a clinical challenge. In this paper an overview of the current status of drug-eluting balloon technology and results of clinical trials with drug-eluting balloon angioplasty is given. Furthermore a case series of 10 patients with in-stent restenosis that were treated with excimer laser angioplasty and drug eluting balloons is described. In this case series the mean lesion length treated was 115 mm, and the mean time to occurrence of restenosis after initial treatment was 7.2 months. At a mean follow-up (of all patients) of 7.6 months no target vessel revascularization was seen. In 7 patients that had Duplex and/or angiographic control (mean follow-up 7 months) no signs of neointimal hyperplasia were demonstrated. These short-term data compare favorable to results obtained with standard balloon angioplasty and cutting-balloon angioplasty. Long-term follow-up is necessary to define the role of combined excimer laser and drug-eluting balloon angioplasty in the treatment of in-stent restenosis further.

Erythema nodosum in kidney transplant recipient: a rare complication of pneumonia treatment.

Erythema nodosum (EN) is a cutaneous inflammatory reaction, usually reported in young women, but it is rarely observed among transplant patients. Localization in the lower extremities is typical, mostly involving the anterior surfaces of the legs. Several viral, bacterial, mycotic, and non-infectious etiologies, such as autommune disorders, drugs, inflammatory bowel diseases, sarcoidosis, pregnancy, and malignancies, have been found. We describe the case of a young woman kidney transplant recipient developing bilateral, erythematous, warm nodules localized on the anterior surface of her legs after antibiotic treatment for pneumonia with levofloxacin. Her immunosuppression was sirolimus and mycophenolate mofetil. EN was diagnosed by skin biopsy; microscopic examination showed septal panniculitis with granulomas. As a complete remission of the lesions was obtained in our patient after interruption of levofloxacin therapy, we suspect that levofloxacin was involved in the pathogenesis of EN. In fact, the management of EN is based on the treatment of underlying or associated conditions.

Training of vascular surgeons by interventional radiologists.

This paper will discuss the potential role of interventional radiologists in teaching of endovascular skills to vascular surgical trainees. Prerequisites and advantages of such a training will be discussed, as well as the secondary effect this kind of training program may have on developing multidisciplinary teams.

The surgical and endovascular management of deep venous thrombosis of the lower extremity.

This paper will discuss the clinical sequelae of deep venous thrombosis of the lower extremity and will deal briefly with conservative therapy. The (endo)vascular modalities that are currently used will be described more in detail, and includes systemic thrombolysis, surgical thrombectomy, catheter directed thrombolysis and other catheter based therapies like ultrasound assisted thrombolysis, pharmacomechanical thrombolysis and percutaneous mechanical thrombectomy. Results, advantages and disadvantages of each technique will be dealt with.

Relevance of CD38 expression on CD8 T cells to evaluate antiretroviral therapy response in HIV-1-infected youths.

Surrogate markers for monitoring immuno-virological discordant responders, in addition to plasma viral load and CD4 cells, are still lacking. We assessed the diagnostic utility of CD38 expression on CD8 T cell assay, alone or in association with lymphocyte proliferation to mycotic antigens, in evaluating antiretroviral response. 28 vertically HIV-infected youths, 21 HAART- and seven 2 nucleotide reverse transcriptase inhibitors-treated, were enrolled in a retrospective study. Responders (57.1%) and non-responders (42.9%) to stable antiretroviral therapy for a minimum of 6 months, on the basis of viral load and CD4 T cells, comprehensively evaluated by CD38 expression on CD8 T lymphocytes [measured as CD38 antibody bound per CD8 T cell (CD38 ABC) and %CD38+ of total CD8 T cells (%CD38/CD8)] and lymphocyte proliferation to P. jiroveci, C. albicans, C. neoformans, A. fumigatus at a single time point after treatment, were selected. CD38 expression > or =2401 CD38 ABC and > or =85% CD38/CD8 cut-off points, accurately discriminates responders versus non-responders, both measures resulting in 75.0% (CI 42.8-94.5) sensitivity (identification of non-responder) and 93.8% (CI 69.8-99.8) specificity (identification of responder), when considered as single assays. The association '> or =2401 CD38 ABC or > or =85% CD38/CD8' improved sensitivity to 83.3% (CI 51.6-97.9), while the association '<2401 CD38ABC (or <85% CD38/CD8) and lymphoproliferative response positive to > or =2 tested organisms' improved specificity to 100% (CI 79.4-100). In conclusions, CD38 expression and mycotic antigen-specific T-cell proliferation may be used as additional parameters to existing criteria to evaluate antiretroviral response in immuno-virological discordant patients.

Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study.

BACKGROUND: The aim of the study was to evaluate tolerance and efficacy of preoperative treatment with capecitabine in combination with radiation therapy (RT) in patients with locally advanced, resectable, rectal cancer. PATIENTS AND METHODS: Fifty-three patients with potentially resectable T3, N0-2 (87%) and T4, N0-2 (13%) rectal cancer were treated with capecitabine (825 mg/m2, twice daily for 7 days/week) and concomitant RT (50.4 Gy/28 fractions). Patients underwent surgery after 6-8 weeks followed, upon physician's indications, by 4-months adjuvant capecitabine. The primary end point was to determine the rate of pathologic complete response. Secondary end points were to assess the rate of clinical response and the safety profile. RESULTS: All patients but two completed the RT programme and 47 (89%) received 81%-100% of the capecitabine dose (100% of dose in 72% patients, 81%-95% in 17% patients and 48%-74% in 11% of patients). No patient had grade 4 toxicity. Grade 3 toxicity occurred in six patients (11%) and consisted mainly of leucopenia (4%) and hand-foot syndrome (4%). Mild or moderate toxicity was common and included leucopenia (72%), diarrhea (40%), proctitis (34%) and skin toxicity (20%). The overall clinical response rate was 58% and the downstaging rate was 57%, with a pathologic complete response rate of 24%. Among 34 patients with low-lying tumors (

HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients.

No data are available on the role of HER2 overexpression in predicting the efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients. We retrospectively evaluated this role in patients enrolled in a phase III study comparing standard FEC21 (5-fluorouracil, epirubicin, and cyclophosphamide, administered every 3 weeks) vs dose-dense FEC14 (the same regimen repeated every 2 weeks). HER2 status was determined for 731 of 1214 patients. Statistical analyses were performed to test for interaction between treatment and HER2 status with respect to event-free survival (EFS) and overall survival (OS); EFS and OS were compared within each HER2 subgroup and within each treatment arm. Median follow-up was 6.7 years. Among FEC21-treated patients, both EFS (HR=2.07; 95% CI 1.27-3.38) and OS (HR=2.47; 95% CI 1.34-4.57) were significantly worse in HER2 + patients than in HER2 - patients. Among FEC14-treated patients, differences in either EFS (HR=1.21; 95% CI 0.65-2.24) or OS (HR=1.85; 95% CI 0.88-3.89) between HER2 + and HER2 - patients were not statistically significant. Interaction analysis suggested that the use of dose-dense FEC14 might remove the negative prognostic effect of HER2 overexpression on EFS and OS. Our data suggest a potential role of HER-2 overexpression in predicting the efficacy of dose-dense epirubicin-containing chemotherapy and the need to confirm this hypothesis in future prospective studies.

The NK1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on neuroblastoma and glioma cell lines.

We have carried out an in vitro study to investigate the ability of substance P to activate cell growth and the NK1 receptor antagonist L-733,060 to inhibit cell growth in the SKN-BE(2) neuroblastoma and GAMG glioma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)2-(4-sulfophenyl)-2H-tetrazolium], inner salt, colorimetric method to evaluate cell viability in this cytotoxicity assay. Nanomolar concentrations of substance P increased, and micromolar concentrations of L-733,060 inhibited the growth of both cell lines studied, with and without previous administration of substance P. In addition, we have demonstrated by immunoblot analysis that NK1 receptors are present in both cancer cell lines studied here. Thus, this study demonstrates that substance P acts as a mitogen in the SKN-BE(2) neuroblastoma and GAMG glioma cell lines, and that the antitumoural action of L-733,060 on both human cell lines occurs through the NK1 receptor. This action suggests that the NK1 receptor is a new and promising target in the treatment of human neuroblastoma and glioma.

Weekly paclitaxel as first-line chemotherapy in elderly advanced breast cancer patients: a phase II study of the Gruppo Italiano di Oncologia Geriatrica (GIOGer).

BACKGROUND: First-line chemotherapy regimens suitable for elderly advanced breast cancer patients are still not defined. PATIENTS AND METHODS: Women with stage III or IV breast cancer aged > or =70 years were enrolled in a phase II study aimed to evaluate both activity and toxicity of weekly paclitaxel. Among 46 planned patients, at least 18 responses and not more than seven unacceptable toxic events are required for a favourable conclusion. Paclitaxel 80 mg/m(2) was administered weekly for 3 weeks every 28 days. RESULTS: Unacceptable toxicity occurred in seven out of 46 patients evaluated for toxicity [15.2%; exact 95% confidence interval (CI) 7.6% to 28.2%] and was represented by one case of febrile neutropenia, one case of severe allergic reaction and five cases of cardiac toxicity. Among 41 patients evaluated for response, a complete response occurred in two (4.9%) patients and a partial response in 20 (48.8%), with an overall response rate of 53.7% (exact 95% CI 38.7% to 67.9%). The median progression-free survival was 9.7 months (95% CI 8.5-18.7) and median survival was 35.8 months (95% CI 19-not defined). CONCLUSIONS: Weekly paclitaxel is highly active in elderly advanced breast cancer patients. Data on cardiovascular complications, however, indicate the need for a careful monitoring of cardiac function before and during chemotherapy.

Adjuvant sequential methotrexate --> 5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer.

The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m(-2) i.v. bolus preceded by LV 100 mg m(-2) i.v. bolus on days 1-5, or 6 monthly cycles of sequential MTX 200 mg m(-2) i.v. days 1 and 15 and FU 600 mg m(-2) i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h x 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1-3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX --> FU and FU+LV (77 vs 77% at 5 years; P = 0.90), as were 5-year disease-free survivals (67 vs 63%; P = 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX --> FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.