A Prospective Phase I/II Study of Docetaxel, Cisplatin and Continuous Capecitabine in Advanced Oesophago-Gastric Cancer (NWCOG-3).

AIMS: This open-label prospective phase I/II dose-escalation study determined the maximum tolerated dose (MTD) and then evaluated response, safety and feasibility of a novel combination of docetaxel, cisplatinum and capecitabine (DCC) in chemotherapy-naive patients with advanced oesophago-gastric carcinoma. MATERIALS AND METHODS: Patients with adenocarcinoma or squamous cell carcinoma of the oesophagus or stomach, of good performance status, deemed too advanced for curative treatment, were given systematically increasing doses of 3 weekly DCC to ascertain the MTD. Phase II administered up to six cycles of DCC at the MTD, assessing response and toxicity. RESULTS: Between November 2007 and November 2012, 15 patients were recruited into phase I and 41 into phase II. The MDT was a 21 day cycle of docetaxel 60 mg/m2 IV day 1, cisplatinum 60 mg/m2 IV day 1 and oral capecitabine 1000 mg/m2 daily in two divided doses for days 1-21. The most common phase II grade 3-4 toxicities were neutropenia 88% (10% febrile neutropenia), fatigue 15%, sensory neuropathy 10% and non-neutropenic infection 10%. The overall response rate was 51%, median progression-free survival was 7.4 months (confidence interval 6.7-9.4) and median overall survival was 10.9 months (confidence interval 7.7-13.7). CONCLUSION: DCC was tolerable and feasible with promising efficacy, and may be suitable for future investigation in both first-line metastatic and neoadjuvant settings.

Radiation retinopathy secondary to treatment of maxillary sinus carcinoma: a dramatic case. / Retinopatía por radiación secundaria a tratamiento de carcinoma de seno maxilar: un caso dramático.

CLINICAL CASE: A 53-year old male presented with visual impairment in right eye after irradiation of right maxillary sinus carcinoma. Funduscopy shows radiation retinopathy: haemorrhages, exudates, macular oedema, and peripheral retinal ischaemia. A poor outcome was achieved despite laser treatment and intravitreal injections of bevacizumab, resulting in evisceration of the affected eye. DISCUSSION: Radiation retinopathy must be considered in any loss of vision after head and neck irradiation. Ophthalmological long-term follow-up of these patients is essential for an early diagnosis.

Report From the First and Second Spanish Killer Immunoglobulin-Like Receptor Genotyping Workshops: External Quality Control for Natural Killer Alloreactive Donor Selection in Haploidentical Stem Cell Transplantation.

An important factor affecting the success in the setting of related haploidentical hematopoietic stem cell transplantation (HSCT) is the graft-versus-leukemia effect mediated by natural killer (NK) cells when the donor displays NK alloreactivity versus the recipient. NK cell function is regulated by killer immunoglobulin-like receptors (KIR) and it has been described that donor KIR genotype influences transplantation outcome. This has led to a requirement of laboratories to have a quality assurance program for validation and control of their KIR genotyping methods. The goal of the 1st and 2nd Spanish KIR Genotyping Workshops was to provide an external proficiency testing program in KIR genotyping for Spanish immunology and transplant laboratories. These workshops were conducted during the years 2014-2016 and consisted of 17 participating laboratories typing a set of 20 samples. The presence/absence of 16 mandatory KIR loci (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 2DP1, 3DL1, 3DL2, 3DL3, 3DS1, and 3DP1) was evaluated per sample. Methods for KIR genotyping included polymerase chain reaction with the use of sequence-specific primers and sequence-specific oligoprobes. Consensus typing was reached in all samples, and the performance of laboratories in external proficiency testing was satisfactory in all cases. The polymorphism detected in the small sample studied in both workshops is indicative of an ample variety of KIR gene profiles in the Spanish population.

Epiretinal membrane surgery: anatomic and functional outcomes.

OBJECTIVE: To study the influence of anatomic preoperative characteristics (based on the parameter, foveal central thickness, measured by optical coherence tomography) and functional characteristics (based on the parameter, best corrected visual acuity, [BCVA]) on functional recovery after epiretinal membrane (ERM) surgery. METHODS: A total of 88 eyes (of 86 patients), on whom a vitrectomy due to ERM was performed during a 3 years period were reviewed in this longitudinal, prospective study. An analysis was made of, ERM aetiology, BCVA, presence or absence of metamorphopsia, lens status, and central foveal thickness. Data relating to surgery and local complications, changes in BCVA, and changes in foveal central thickness were collected during the follow-up period. RESULTS: An improvement was in observed in BCVA in 82%, as well as a decrease in foveal thickness in 79% of the eyes which underwent surgery, both of these being statistically significant (P<.01). However, most of the patients showed different grades of oedema and/or macular thickening in the postoperative period. A significant correlation was found between preoperative and postoperative BCVA (P=.001), and also between preoperative and postoperative central foveal thickness (P=.004), but not between BCVA and foveal thickness. CONCLUSIONS: There is functional recovery in terms of BCVA in more than 80% of the patients after ERM surgery. Most of the eyes showed persistent macular thickening, but this did not seem to have influenced the final BCVA. The best determinant of postoperative functional recovery (postoperative visual acuity) is, in our experience, the preoperative BCVA, and not the macular thickness.

Evolution of soluble forms of CD86, CD95 and CD95L molecules in liver transplant recipients.

Co-stimulatory factors such as CD86 and apoptotic molecules such as CD95 and CD95L required to start and to turn off the allogenic immune response may also be present as soluble proteins. To determine the role of the soluble forms of CD86 (sCD86), CD95 (sCD95) and CD95L (sCD95L) in the outcome of liver transplants, we analyzed the circulating levels of these molecules in patients subjected to liver transplantation in the pre-operative period and during the first month post-transplantation. Serum samples were obtained from sixty-nine first orthotopic liver transplants (OLT). The patients were classified into acute rejection (AR=24) and not acute rejection (NAR=45), or considering the presence of chronic active hepatitis B or C (VP=30) or other primary liver diseases (VN=39). The levels of sCD86, sCD95 and sCD95L were analyzed by solid phase sandwich enzyme-linked immunoabsorbent assays. Our results first showed that the pre-transplantation serum levels of sCD86 in the AR group were significantly higher than in the NAR group (1007±82U/mL vs. 739±46U/mL, p=0.006), and in the post-transplantation period these levels decreased sharply. Second, the levels of sCD95L and sCD95 in the pre-transplantation period did not point to statistically significant differences between the AR and NAR groups. Considering primary liver disease, the pre-transplantation levels of sCD86 and sCD95L in the VP group were significantly higher than those of the VN group (VP, 977±69U/mL vs. VN, 722±51U/mL, p<0.002, and VP, 482±78pg/mL vs. VN, 221±31pg/mL, p=0.002, respectively). Multivariate analysis revealed that only the pre-transplantation levels of sCD86 were independently associated with the development of episodes of acute rejection (p=0.005, OR=2.1, IC 95%=1.27-3.47). In conclusion, the present work shows that primary liver disease could influence the pre-transplantation levels of sCD86 and sCD95L. High pre-transplantation serum levels of sCD86 could favor the development of episodes of acute rejection.

[Intravitreal triamcinolone acetonide use in diffuse persistent diabetic macular edema]. / Uso de triamcinolona intravítrea en el tratamiento del edema macular diabético difuso persistente.

PURPOSE: To determine the efficacy of intravitreal triamcinolone injections (iv TA) for diffuse persistent diabetic macular oedema (DMO) based on the functional parameter of modification in best corrected visual acuity (BCVA) and the anatomic parameter of quantitative changes in central macular thickness, as determined by optical coherence tomography (OCT). The secondary outcome is to analyse the safety of the procedure. METHODS: In this retrospective study, 16 patients (22 eyes) were included over a period of six months. Type and time of evolution of diabetes mellitus, previous treatments, BCVA, lens status, intraocular pressure (IOP) and central macular thickness, were analysed. During the follow-up period were collected: number of injections, changes in BCVA, IOP, central macular thickness, and complications observed. RESULTS: Improvement in BCVA was recorded in 30.77%, 47.37% and 52.63%, at one, three and six months, respectively (P<.05 at 3 months). The IOP increased in 57.69% at one month, and 75 and 47.05%, at 3 and 6 months, respectively (P<.05 at 3 months). Progression of cataracts was found in 22.72%. No cases of endophthalmitis were observed. CONCLUSIONS: Intravitreal TA is a good therapeutic option for patients with persistent DMO, increasing BCVA and decreasing central macular thickness in the short term, with a percentage of clinical resolution of more than 70%. However, due to the transient effect, and potential adverse effects, it should be administered to selected refractory cases with caution.

Improving the chemotherapy process and service to cancer patients.

The North Wales Cancer Treatment Centre (NWCTC) has to deal with an increasing demand in the number of patients who require chemotherapy, with the escalating use of second line, third line, and additional treatment for many cancers. As a result, there is growing pressure on the chemotherapy unit to deliver treatment quickly, efficiently, and safely. Following guidelines from the Department of Health's Manual for Cancer Services, we are constantly looking for ways to improve and develop the level of care provided at our center, and the process of receiving chemotherapy has been identified as an area of high risk. Therefore, a team was established to review and explore current practices at the NWCTC with the goal of implementing an improved process to minimize the risks of chemotherapy treatment.

[Cerebrovascular stroke as a sign of atrial myxoma in childhood]. / Accidente cerebrovascular como manifestación de mixoma auricular.

Primary cardiac tumors are uncommon with an estimated incidence of between 0.0017 % and 0.19 %. Most are benign. Whereas myxomas are the most common primary tumor in adults, in children they are exceptionally rare. Cardiac myxomas usually develop in the left atrium, 20 % occur in the right atrium and the remainder develops in the ventricles and rarely in the heart valves. Cerebrovascular strokes secondary to myxoma are rare in childhood. The diagnostic test of choice is transesophageal echocardiogram and early excision is the most effective treatment in preventing serious complications. We report a case of cerebral stroke as the only manifestation of an atrial myxoma in an 11-year-old-girl. The patient presented vertigo, right hemiparesis of the body and dysarthria without loss of consciousness. After diagnostic tests (computerized tomography, magnetic resonance imaging and cerebral angioresonance) she was diagnosed with an ischemic lesion in the left middle cerebral artery. Various investigations were performed to find the cause of the stroke, among them cardiologic study, and a mass in the left atrium suggestive of myxoma was found. The tumor was removed and the diagnosis of myxoma was confirmed by histopathological examination. Outcome was satisfactory. The presence of a cerebral ischemic episode, with or without concomitant heart disease, suggests the need to look for cardiac etiology.

CD28/CTLA-4 and CD80/CD86 costimulatory molecules are mainly involved in acceptance or rejection of human liver transplant.

CD28/CTLA-4 interactions with their specific B7-ligands (CD80 and CD86) have decisive roles in antigenic and allogenic responses. Recently, experimental transplant studies demonstrated that donor-specific tolerance is achieved by blocking these interactions. The present study analyzes the expression of these co-stimulatory molecules in peripheral blood cells from 74 liver recipients and in 16 liver biopsies, which were classified into acute-rejection (AR, n = 27) and nonacute-rejection (NAR, n = 47) groups, as well as their influence on the in vitro response of in vivo allosensitized cells. The results clearly indicate that in human liver transplant too, B7 and CD28/CTLA-4 expression on B and CD4(+) peripheral lymphocytes respectively, contributes to graft acceptance or rejection, and appears to be of crucial importance in modulating the host alloresponse and specific-CTL generation. In the NAR-group, costimulatory molecule expression remained at basal levels after transplant, whereas in the AR-group these molecules were significantly upregulated on days of AR. CTLA-4 was observed in the infiltrating lymphocytes in most of the biopsies, but CD80 or CD86 were not. Moreover, specific cytotoxicity from the in vivo primed cells was clearly suppressed in the NAR-patients with low co-stimulatory molecule expression, whereas this activity was not modified but rather stimulated in the AR-group. Together, these findings indicate that intervention of CD28/CTLA-4/B7 signaling could be therapeutically useful in clinical transplantation.

[Presence of fetal fibronectin in cervico-vaginal secretion as predictor of premature labor]. / Presencia de fibronectina fetal en secreción cérvico-vaginal como predictor de parto pretérmino.

The objective of this article is to correlate a new biochemical method called fetal fibronectin (fFN) found in cervico-vaginal secretions (CVS) in pregnant woman with the presence or not of preterm labor. In this paper the patients studied had pregnancies of 24 up to 37 weeks of pregnancy. The were free of symptoms and without risk factors for preterm labor. The cervico-vaginal specimen was taken with special equipment designed for this purpose (Adeza Biomedical Collection Kit). The laboratory processed this for immunoassay. A positive fFN was considered above 0.05 microgram/dl. There were 263 patients enrolled for this study. Of these 232 had fFN negative (89%) and 31 were positive (12%). The weeks of gestation at birth were 38.6 for the negative group and 34.4 for the positive group (p < 0.0001). Only 5 neonates from the negative group were born before 37 weeks of gestation (2.2%) and in the positive fFN group this occurred in 22 case (71%) (p < 0.0001). The average weight at birth for the negative fibronectin group was 3152 g. for the positive group (p < 0.0001). The neonatal morbidity was more frequent and respiratory distress syndrome was more severe in the positive fibronectin group in comparison with the negative fFN with a significant p. The same tendency was observe with the Apgar score < 7 at 1 and 5 minutes (more frequent in the positive group) (p < 0.0001). The was one neonatal death in the negative group (0.43%) and 5 in the positive group (16%) p = 0.0001. The sensibility and positive predicitive value of positive fFN for the prediction of preterm labor was 81.4 and 71 respectively and the specificity and negative predictive value for negative fFN was 96.1 and 97.8. Finally the RR for prematurity when the fFN was positive on SCV was 32.9. The presence fFN in cervical-vaginal secretion between 24 and 37 weeks of gestation seems to be a good indicator of preterm labor. In this study positive results correlate with less weeks of pregnancy and lees weight at birth. Also with higher with more morbidity and mortality. These findings give the obstetrician a better chance of an opportune diagnosis with adequate treatment and improve perinatal results.

Effect of partial HLA class I match on acute rejection in viral pre-infected human liver allograft recipients.

BACKGROUND: Acute rejection in liver transplants is one of the commonest causes of liver dysfunction in the early postoperative period. However, the factors involved in liver graft rejection are still unknown. Our study was aimed at ascertaining whether the degree of HLA class I and class II compatibility or pretransplant viral infection have any influence on early acute liver graft rejection. METHODS: We reviewed clinical and laboratory data in 190 consecutive patients who underwent a liver transplant. HLA-A, HLA-B, and HLA-DR typing for the establishment of an HLA match score was performed by a standard microcytotoxicity method. The existence of pretransplant viral infection was investigated in sera and biopsy tissue by serologic (hepatitis B virus, hepatitis C virus) and polymerase chain reaction (cytomegalovirus) techniques, respectively. The influence of these two factors in acute rejection and the interaction between them was also analyzed. RESULTS: A strong association between viral infection and acute rejection in the group with partial class I matching was found (odds ratio=7.75; P<0.0009), whereas no correlation was observed in the group with zero class I matching (odds ratio=0.98; P=0.81). The rejection percentage in the group in which partial class I match and viral infections coexisted was 60%, whereas in the partially class I-matched group without pretransplant viral presence it was 16%. CONCLUSIONS: These findings suggest a participation of partial HLA class I compatibility in triggering acute rejection in recipients suffering preoperative viral infections and support the idea that HLA class I antigen matching could play a role as a linking element between the MHC-restricted T cell-mediated response to viral infection and the allogenic response in liver transplantation.

Co-stimulation of cultured peripheral blood mononuclear cells from intrinsic asthmatics with exogenous recombinant IL-6 produce high levels of IL-4-dependent IgE.

Asthma is an inflammatory airway disorder, traditionally subdivided into extrinsic, immunoglobulin E (IgE)-mediated, and intrinsic asthma of unknown aetiology. IgE synthesis requires contact between T- and B-cells and a signal provided by interleukin (IL)-4, which can be modulated by IL-6. The objective of this study was to evaluate the effects of IL-4 and IL-6 on total IgE synthesis by peripheral blood mononuclear cells from intrinsic and extrinsic asthmatics. Peripheral blood mononuclear cells from intrinsic and extrinsic asthmatic patients and from healthy subjects were cultured and stimulated with pokeweed mitogen, recombinant IL-4 and IL-6. The IgE level in serum and supernatants was measured by an enzyme-linked immunoassay. Serum IgE was significantly lower in intrinsic asthma than in extrinsic asthma, but significantly higher than in control subjects. IgE production by cultured mononuclear cells from extrinsic asthmatics was not modified after exogenous IL-4 and IL-6 addition. However, intrinsic asthmatics showed enhancement of IgE synthesis in response to IL-4 stimulation, reaching a threefold increase of the spontaneous IgE values, when simultaneous recombinant IL-4 plus IL-6 stimulus was used. Our results indicate that exogenous recombinant interleukin-6 can significantly upregulate the interleukin-4-dependent immunoglobulin E synthesis in intrinsic asthma. This suggests that immunoglobulin E could also play a role in the pathogenesis of intrinsic asthma, in which an interleukin-6 threshold would be critical.

Cytokine serum profiles in allergic and non-allergic asthma. Increased production of IL-10 by non-allergic asthmatic patients.

Studies were undertaken to determine whether differences in serum cytokine balances could be involved in the pathogenesis of allergic and in non-allergic asthma. At this propose, interferon-gamma, tumor necrosis factor-alpha, interleukin-2, interleukin-4, interleukin-6, and interleukin-10 were measured by enzimoimmunoassay. The analysis was performed on 24 allergic and 24 non-allergic asthmatic patients and 16 healthy subjects. IFN-gamma and TNF-alpha, included into the type 1 cytokines, appeared significantly increased in the allergic with respect to the non-allergic asthmatic patients (p = 0.01) and (p < 0.001) respectively, while IL-10, which belongs to the type 2 cytokines, was significantly increased in the non-allergic asthmatic (p < 0.001). The IL-6 analysis did not show any significant difference in either of the study group. The most interesting finding was the high serum IL-10 values detected in intrinsic asthmatic patients, which in turn, suggests that this cytokine could participate in the regulation of different immunological features that occurs in non-allergic asthma, and maybe it could indicate a higher stimulated state of cells in this type of asthma. The data presented in this report show a different cytokine profile in serum from allergic and non-allergic asthmatic patients and denote a stronger prevalence of type 2 cytokines in intrinsic asthma.