Effects of high-intensity exercise training on physical fitness, quality of life and treatment outcomes after oesophagectomy for cancer of the gastro-oesophageal junction: PRESET pilot study.

BACKGROUND: Treatment for cancer of the gastro-oesophageal junction (GOJ) can result in considerable and persistent impairment of physical fitness and health-related quality of life (HRQoL). This controlled follow-up study investigated the feasibility and safety of postoperative exercise training. METHODS: Patients with stage I-III GOJ cancer were allocated to 12 weeks of postoperative concurrent aerobic and resistance training (exercise group) or usual care (control group). Changes in cardiorespiratory fitness, muscle strength and HRQoL were evaluated. Adherence to adjuvant chemotherapy, hospitalizations and 1-year overall survival were recorded to assess safety. RESULTS: Some 49 patients were studied. The exercise group attended a mean of 69 per cent of all prescribed sessions. After exercise, muscle strength and cardiorespiratory fitness were increased and returned to pretreatment levels. At 1-year follow-up, the exercise group had improved HRQoL (+13·5 points, 95 per cent c.i. 2·2 to 24·9), with no change in the control group (+3·7 points, -5·9 to 13·4), but there was no difference between the groups at this time point (+9·8 points, -5·1 to 24·8). Exercise was safe, with no differences in patients receiving adjuvant chemotherapy (14 of 16 versus 16 of 19; relative risk (RR) 1·04, 95 per cent c.i. 0·74 to 1·44), relative dose intensity of adjuvant chemotherapy (mean 57 versus 63 per cent; P = 0·479), hospitalization (7 of 19 versus 6 of 23; RR 1·41, 0·57 to 3·49) or 1-year overall survival (80 versus 79 per cent; P = 0·839) for exercise and usual care respectively. CONCLUSION: Exercise in the postoperative period is safe and may have the potential to improve physical fitness in patients with GOJ cancer. No differences in prognostic endpoints or HRQoL were observed. Registration number: NCT02722785 ( https://www.clinicaltrials.gov).

ANTECEDENTES: El tratamiento del cáncer de la unión gastroesofágica (gastroesophageal junction, GEJ) puede determinar un deterioro considerable y persistente de la condición física y de la calidad relacionada con la salud (health-related quality of life, HRQoL). El objetivo de este estudio controlado de seguimiento fue investigar la factibilidad y seguridad del entrenamiento físico postoperatorio. MÉTODOS: Pacientes con cáncer de GEJ en estadio I-III fueron asignados a 12 semanas de entrenamiento postoperatorio simultáneo aeróbico y de resistencia o a cuidados médicos habituales. Se evaluaron los cambios en el estado cardiorrespiratoria, fuerza muscular y HRQoL. Se recogieron datos de la adherencia a la quimioterapia adyuvante, hospitalizaciones y supervivencia global a 1 año para evaluar la seguridad. RESULTADOS: Se estudiaron un total de 49 pacientes. El grupo con ejercicio asistió al 69% de todas las sesiones planificadas. Después del ejercicio, la fuerza muscular y el estado cardiorrespiratorio aumentaron y volvieron a los niveles previos al tratamiento. Si bien al año de seguimiento, el grupo con ejercicio presentó una mejoría de la HRQoL (+13,5 puntos (i.c. del 95% 2,2 a 24,9)), sin cambios en el grupo con atención médica habitual (+3,7 puntos (i.c. del 95% −5,9 a 13,4)), no hubo diferencias entre los grupos en ese momento (+9,8 puntos (i.c. del 95% −5,1 a 24,8)). El ejercicio fue seguro, sin diferencias entre el ejercicio o la atención médica habitual en pacientes que recibían quimioterapia adyuvante 87,5% versus 84,2% (RR 1,04 (i.c. del 95% 0,74 a 1,44)), intensidad relativa de la dosis de quimioterapia adyuvante 56,8% versus 63,3% (P = 0,479), hospitalizaciones 36,8% versus 26,1% (RR 1,41 (i.c. del 95% 0,57 a 3,49)) o supervivencia global a 1 año 80,0% versus 79,3% (P = 0,839). CONCLUSIÓN: El ejercicio en el periodo postoperatorio es seguro y puede tener potencial para mejorar la condición física en pacientes con cáncer de GEJ. No se observaron diferencias en los resultados pronósticos o en la HRQoL.

Quantifying Anterior Chest Wall Deformity in Adolescent Idiopathic Scoliosis: Correlation With Other Deformity Measures and Effects of Anterior Thoracoscopic Scoliosis Surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: This study investigated how anterior chest wall deformity is affected by thoracoscopic anterior scoliosis fusion (TASF) surgery in adolescent idiopathic scoliosis patients. We aimed to determine correlations pre- and postoperatively with other clinical and radiological scoliosis measures. BACKGROUND DATA: Scoliosis surgery aims to halt progression of the deformity, and to reduce its severity. Currently, deformity correction is clinically measured in terms of Cobb angle and rib hump (RH); however, a significant cosmetic concern for patients is anterior chest wall deformity. METHODS: Pre- and postoperative CT scans of 28 female, Lenke type 1 patients with a mean preoperative Cobb angle of 50.2° ± 7.1° were retrieved from the Research Group's surgical database. Using ImageJ, 3D reconstructions of the thorax were created. Two observers measured the anterior chest wall deformity as a chest wall angle (CWA) and posterior deformity as a posterior apical deformity angle (PDA). We investigated pre- to postoperative changes in CWA, PDA, RH, and Cobb angle as well as their interrelationship. RESULTS: All deformity parameters (Cobb angle, RH, CWA, and PDA) showed statistically significant improvement post TASF. Correlation was found between RH and Cobb angle pre- and postoperatively, Cobb angle and CWA preoperatively and between postoperative change in Cobb angle and CWA. No relationship was found between CWA and RH or PDA. CONCLUSIONS: Anterior chest wall deformity is independent from the posterior chest wall measures RH and PDA, indicating that the anterior chest wall deformity is not reflected in the posterior rib cage. The correlation between Cobb angle and CWA indicates that the deformity in the spine and the deformity in the ribs are related, and shows that the anterior chest wall deformity is improved post thoracoscopic anterior scoliosis fusion surgery as the lateral deviation of the spine is corrected. LEVEL OF EVIDENCE: Level III.

A platform for phenotypic discovery of therapeutic antibodies and targets applied on Chronic Lymphocytic Leukemia.

Development of antibody drugs against novel targets and pathways offers great opportunities to improve current cancer treatment. We here describe a phenotypic discovery platform enabling efficient identification of therapeutic antibody-target combinations. The platform utilizes primary patient cells throughout the discovery process and includes methods for differential phage display cell panning, high-throughput cell-based specificity screening, phenotypic in vitro screening, target deconvolution, and confirmatory in vivo screening. In this study the platform was applied on cancer cells from patients with Chronic Lymphocytic Leukemia resulting in discovery of antibodies with improved cytotoxicity in vitro compared to the standard of care, the CD20-specific monoclonal antibody rituximab. Isolated antibodies were found to target six different receptors on Chronic Lymphocytic Leukemia cells; CD21, CD23, CD32, CD72, CD200, and HLA-DR of which CD32, CD200, and HLA-DR appeared as the most potent targets for antibody-based cytotoxicity treatment. Enhanced antibody efficacy was confirmed in vivo using a patient-derived xenograft model.

Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro.

Inappropriate signalling through the EGFR and ErbB2/HER2 members of the epidermal growth factor family of receptor tyrosine kinases is well recognised as being causally linked to a variety of cancers. Consequently, monoclonal antibodies specific for these receptors have become increasingly important components of effective treatment strategies for cancer. Increasing evidence suggests that ErbB3 plays a critical role in cancer progression and resistance to therapy. We hypothesised that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific single-chain Fv (bs-scFv) antibody would promote increased targeting selectivity over antibodies specific for a single tumour-associated antigen (TAA). In addition, we hypothesised that targeting this important heterodimer could induce a therapeutic effect. Here, we describe the construction and evaluation of the A5-linker-ML3.9 bs-scFv (ALM), an anti-ErbB3/ErbB2 bs-scFv. The A5-linker-ML3.9 bs-scFv exhibits selective targeting of tumour cells in vitro and in vivo that co-express the two target antigens over tumour cells that express only one target antigen or normal cells that express low levels of both antigens. The A5-linker-ML3.9 bs-scFv also exhibits significantly greater in vivo targeting of ErbB2'+'/ErbB3'+' tumours than derivative molecules that contain only one functional arm targeting ErbB2 or ErbB3. Binding of ALM to ErbB2'+'/ErbB3'+' cells mediates inhibition of tumour cell growth in vitro by effectively targeting the therapeutic anti-ErbB3 A5 scFv. This suggests both that ALM could provide the basis for an effective therapeutic agent and that engineered antibodies selected to co-target critical functional pairs of TAAs can enhance the targeting specificity and efficacy of antibody-based cancer therapeutics.

Planning for intracavitary anti-EGFR radionuclide therapy of gliomas. Literature review and data on EGFR expression.

Targeting with radionuclide labelled substances that bind specifically to the epidermal growth factor receptor, EGFR, is considered for intracavitary therapy of EGFR-positive glioblastoma multiforme, GBM. Relevant literature is reviewed and examples of EGFR expression in GBM are given. The therapeutical efforts made so far using intracavitary anti-tenascin radionuclide therapy of GBM have given limited effects, probably due to low radiation doses to the migrating glioma cells in the brain. Low radiation doses might be due to limited penetration of the targeting agents or heterogeneity in the expression of the target structure. In this article we focus on the possibilities to target EGFR on the tumour cells instead of an extracellular matrix component. There seems to be a lack of knowledge on the degree of intratumoral variation of EGFR expression in GBM, although the expression seemed rather homogeneous over large areas in most of the examples (n=16) presented from our laboratory. The observed homogeneity was surprising considering the genomic instability and heterogeneity that generally characterises highly malignant tumours. However, overexpression of EGFR is, at least in primary GBMs, one of the steps in the development of malignancy, and tumour cells that lose or downregulate EGFR will probably be outgrown in an expanding tumour cell population. Thus, loss of EGFR expression might not be the critical factor for successful intracavitary radionuclide therapy. Instead, it is likely that the penetration properties of the targeting agents are critical, and detailed studies on this are urgent.

Successful simultaneous kidney-pancreas transplantation from extreme donors.

UNLABELLED: The purpose of this study was to retrospectively review our experience with "extreme" pancreas donors compared to conventional (CONV) donors. METHODS: "Extreme" (EX) pancreas donors were defined as deceased donors (DDs) age >50 years, <8 years, donation after cardiac death (DCD), and targeted for organ discard. RESULTS: From January 2002 through January 2005, we performed 40 simultaneous kidney-pancreas transplants (SKPT) with Thymoglobulin induction, including 9 (22.5%) from EX and 31 from CONV DDs. Mean DD age was higher in EX DD (41.2 years EX vs 26.0 CONV, P < .05), but mean recipient age and cold ischemia times did not differ between groups. With a mean follow-up of 16.8 months in the EX DD group, patient and kidney graft survival rates are both 100%, and the pancreas graft survival rate is 89%. With a mean follow-up of 21.7 months in the CONV DD group, patient and kidney graft survival rates are both 93.5% and the pancreas graft survival rate is 77.4%. All patients with surviving grafts exhibited good initial (1 case of delayed kidney graft function in a CONV DD) and stable long-term kidney and pancreas graft function. Mean length of initial hospital stay and the incidences of acute rejection, readmissions, operative complications, and infections were similar between groups. CONCLUSIONS: The results of this study suggest that the limits of donor acceptability continue to evolve as excellent outcomes can be achieved in SKPTs from selected EX DDs.

Experience with alternate-day thymoglobulin induction in pancreas transplantation with portal-enteric drainage.

The purpose of this study was to retrospectively review outcomes in patients undergoing pancreas transplantation (PTX) with a novel induction protocol of alternate-day thymoglobulin (rATG) in combination with tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. From January 2002 through January 2005, we performed 55 PTXs in 53 patients. The first dose of rATG (1.5 mg/kg) was given intraoperatively, and subsequent doses were given on alternate days until therapeutic TAC levels (>8 ng/mL) were achieved. All patients underwent PTX with enteric drainage, including 51 with portal and 4 with systemic venous drainage. Patients received a minimum of 2 and maximum of 6 doses of rATG induction (median 3 doses). The patient group had a mean age of 42.8 years and included 40 simultaneous kidney-PTX, 11 sequential PTX after kidney, and 4 PTX-alone transplant recipients. Patient, kidney, and pancreas graft survival rates are 96%, 96%, and 84%, respectively, with a mean follow-up of 21 months. The incidence of acute rejection was 18%; there were no graft losses due to isolated acute rejection. The incidence of infection was 60%, but there were no cases of polyomavirus or Epstein-Barr virus infection and only 6 cases (11%) of cytomegalovirus infection. The composite endpoint of no rejection, graft loss, or mortality was attained by 71% of patients. At present, 94% of surviving patients are both dialysis and insulin-free, including 5 successful PTX retransplants. These findings suggest that PTX with portal-enteric drainage and alternate day rATG induction may result in excellent intermediate-term outcomes.

Multivariate analysis of the influence of donor and recipient cytomegalovirus sero-pairing on outcomes in simultaneous kidney-pancreas transplantation: the South-Eastern Organ Procurement Foundation Experience.

The purpose of this study was to determine if donor (D) and recipient (R) CMV sero-pairing at the time of simultaneous kidney-pancreas transplantation (SKPT) subsequently influenced outcomes in a large cohort of patients with long-term follow-up. Between January 1, 1997 and December 31, 1999 complete data were available on 723 primary SKPTs performed at South-Eastern Organ Procurement Foundation member institutions. For purposes of this study, four groups were defined: D+/R-, n = 203 (28%); D+/R+, n = 206 (28%); D-/R+, n = 156 (22%); and D-/R-, n = 158 (22%). Patient and graft survival rates for the study groups were computed by Kaplan-Meier estimates and tests of equality of survival curves were performed utilizing both the log-rank and Wilcoxon test statistics. A multivariate analysis was performed using a Cox proportional hazards model and logistic regression. A total of 56% of Ds were CMV+ and 50% of Rs were CMV-. D serostatus was not, but R serostatus was, a significant independent risk factor for patient and kidney, but not pancreas, graft survival rates in the uncensored analysis. When examining the CMV D/R groups in both univariate and multivariate fashion, CMV sero-pairing was not an independent risk factor for death, graft loss, or rejection. However, when considering CMV sero-pairing as a binary variable (D-/R- versus all other D/R groups), 6-year patient, kidney, and pancreas graft survival rates were significantly higher in the D-/R- group (P < .05). In conclusion, CMV seronegativity is present in half of diabetic patients at the time of SKPT, and protective CMV seronegative matching confers a long-term survival advantage.

Pilot study of rapid steroid elimination with alemtuzumab induction therapy in kidney and pancreas transplantation.

This study evaluates our initial experience using alemtuzumab induction with rapid corticosteroid elimination in kidney (KTX) and pancreas transplant (PTX) patients. Data were collected retrospectively for all patients who received single-dose alemtuzumab (30 mg IV intraoperatively) with steroid pretreatment and a control group who received alternate day rabbit antithymocyte globulin (rATG) induction with a steroid-based regimen. Patients in both groups received tacrolimus (TAC) and mycophenolate mofetil (MMF). There were 16 patients in each group, including 9 deceased donor KTXs, 5 living donor KTXs, 1 simultaneous K-PTX, and 1 sequential PTX after KTX. Demographic, immunologic, and transplant characteristics were similar between groups. Nine patients (56%) in the alemtuzumab group compared to five (25%) in the control group developed neutropenia requiring MMF or valganciclovir dose reduction (or both). Absolute lymphocyte counts at 3 months were 340 +/- 200/mm3 and 890 +/- 544/ mm3 in the alemtuzumab and control groups, respectively (P = .001). There were two biopsy-proven acute rejection episodes (12.5%) in each group, and no difference in the incidence of infection. Creatinine clearance at 6 months was 58 mL/min in each group. Patient and kidney graft survival rates were both 94% in the alemtuzumab group (one death from cardiac arrest), compared with 100% patient and kidney graft survival rates in the control group (P = NS), with a mean follow-up of 9 and 11 months, respectively. The results of this pilot study suggest that similar short-term outcomes can be achieved using a rapid steroid elimination protocol with alemtuzumab induction therapy compared to rATG with steroids in patients receiving TAC and MMF maintenance therapy.

A UV resonance Raman (UVRR) spectroscopic study on the extractable compounds of Scots pine (Pinus sylvestris) wood. Part I: lipophilic compounds.

The wood resin in Scots pine (Pinus sylvestris) stemwood and branch wood were studied using UV resonance Raman (UVRR) spectroscopy. UVRR spectra of the sapwood and heartwood hexane extracts, solid wood samples and model compounds (six resin acids, three fatty acids, a fatty acid ester, sitosterol and sitosterol acetate) were collected using excitation wavelengths of 229, 244 and 257 nm. In addition, visible Raman spectra of the fatty and resin acids were recorded. Resin compositions of heartwood and sapwood hexane extracts were determined using gas chromatography. Raman signals of both conjugated and isolated double bonds of all the model compounds were resonance enhanced by UV excitation. The oleophilic structures showed strong bands in the region of 1660-1630 cm(-1). Distinct structures were enhanced depending on the excitation wavelength. The UVRR spectra of the hexane extracts showed characteristic bands for resin and fatty acids. It was possible to identify certain resin acids from the spectra. UV Raman spectra collected from the solid wood samples containing wood resin showed a band at approximately 1650 cm(-1) due to unsaturated resin components. The Raman signals from extractives in the resin rich branch wood sample gave even more strongly enhanced signals than the aromatic lignin.

Glutathione transferase alpha as a marker for tubular damage after trichloroethylene exposure.

To investigate possible persistent nephrotoxic effects of trichloroethylene (TRI), a retrospective study was carried out on 39 workers exposed to high levels of TRI from 1956 to 1975. Total protein levels in urine, as well as serum and urine creatinine and serum urea were unchanged in comparison with the control. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) was applied to differentiate between tubular and/or glomerular dysfunction. Urinary excretion of alpha-1-microglobulin and glutathione transferase (GST) alpha, as markers of proximal tubular damage, were correlated with the SDS-PAGE patterns of urinary proteins both in the TRI exposed and the control group. GST alpha was found in elevated concentrations in the urine of the TRI-exposed workers. No increase of urinary GST alpha was observed in the control group, even when alpha-1-microglobulin was elevated as a result of non-toxic damage. Both in the control and exposed groups, GST pi, a marker of distal tubular damage, was in the normal range. The results show that chronic exposure to high doses of TRI causes persistent changes to the proximal tubular system of the kidney and that GST alpha excretion into the urine is a marker well suited for quantitation of the extent of renal damage.

Pathological excretion patterns of urinary proteins in renal cell cancer patients exposed to trichloroethylene.

A study was carried out to investigate urinary protein excretion patterns by means of SDS-polyacrylamide-gel-electrophoresis (SDS-PAGE) in renal cell cancer patients who had previously been exposed to high levels of trichloroethylene. Thirty-eight out of 41 (93%) renal cell cancer patients investigated had former extensive trichloroethylene exposure, but only 23 out of 50 (46%) renal cell cancer patients without a history of occupational exposure to trichloroethylene revealed urinary protein patterns indicative of toxic effects on the tubular system. One hundred controls without histories of overt renal disease and not occupationally exposed to trichloroethylene were examined in the same way; only 11 (11%) of them displayed protein excretion patterns indicative of damage to the renal tubule. These results are supported by alpha 1-microglobulin excretion data. The following conclusions are drawn: (1) Substantially more cases of tubular damage are found amongst renal cell carcinoma patients having been exposed to substantial levels of trichloroethylene over many years as compared with renal cell carcinoma patients not exposed to trichloroethylene. (2) The results support the view that chronic tubular damage is a precondition for the nephrocarcinogenic effect of trichloroethylene. (3) The findings indicate that urine protein patterns, on the basis of the SDS-PAGE methodology, represent a 'biological effect parameter' for the medical surveillance of persons occupationally exposed to trichloroethylene.

Determination of urinary thymidine glycol using affinity chromatography, HPLC and post-column reaction detection: a biomarker of oxidative DNA damage upon kidney transplantation.

Reactive oxygen species are generated during ischaemia-reperfusion of tissue. Oxidation of thymidine by hydroxyl radicals (HO) leads to the formation of 5,6-dihydroxy-5,6-dihydrothymidine (thymidine glycol). Thymidine glycol is excreted in urine and can be used as biomarker of oxidative DNA damage. Time dependent changes in urinary excretion rates of thymidine glycol were determined in six patients after kidney transplantation and in six healthy controls. A new analytical method was developed involving affinity chromatography and subsequent reverse-phase high-performance liquid chromatography (RP-HPLC) with a post-column chemical reaction detector and endpoint fluorescence detection. The detection limit of this fluorimetric assay was 1.6 ng thymidine glycol per ml urine, which corresponds to about half of the physiological excretion level in healthy control persons. After kidney transplantation the urinary excretion rate of thymidine glycol increased gradually reaching a maximum around 48 h. The excretion rate remained elevated until the end of the observation period of 10 days. Severe proteinuria with an excretion rate of up to 7.2 g of total protein per mmol creatinine was also observed immediately after transplantation and declined within the first 24 h of allograft function (0.35+/-0.26 g/mmol creatinine). The protein excretion pattern, based on separation of urinary proteins on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), as well as excretion of individual biomarker proteins, indicated nonselective glomerular and tubular damage. The increased excretion of thymidine glycol after kidney transplantation may be explained by ischaemia-reperfusion induced oxidative DNA damage of the transplanted kidney.

The anterior vaginal wall as an organ for the transmission of active forces to the urethra and the clitoris.

Attention is drawn to the fact that the anterior vaginal wall is not a simple mucous membrane but an active organ, with a hammock-like effect on the urethra. It also functions during intercourse to transmit the effect of penile introduction into the vagina to the clitoris, by stretching the two ligaments that insert around its base.

ELISA procedures for the quantitation of glutathione transferases in the urine.

The proximal portion of the human kidney tubular system contains the alpha form, while the distal portion contains the pi form of glutathione transferase. These cytoplasmic proteins are released into the urine under pathological conditions, and an ELISA procedure has been developed for their quantitation. Optimal conditions with respect to concentrations of antibody and antigen and incubation times were determined. The procedure developed can detect as little as 0.5 ng enzyme per ml urine, even in the presence of high concentrations of other proteins. No cross reaction between these two isoenzymes or with a number of other proteins in the urine was observed. Antibodies interacted with these antigens in urine samples in the same manner as they interacted with the purified proteins. Storage of samples without loss of antigen required the presence of low concentrations of detergent, such as Tween 20, which both stabilized the enzymes and prevented their adsorption to the walls of the plastic tubes. The results indicate that increased urinary levels of these two enzyme proteins, as determined by the ELISA procedure, are useful markers for tubular damage.

Glutathione transferases in the urine: sensitive methods for detection of kidney damage induced by nephrotoxic agents in humans.

With the aid of immunohistochemical methods the localization of the various isoenzymes of glutathione S-transferase was investigated. The alpha isoenzyme was present solely in the proximal tubular cells of the human kidney, while the pi form was restricted to the distal convoluted tubules, the thin loop of Henle, and the collecting ducts. Damage to the epithelial cell membranes results in the increased excretion of these enzymes with the urine. The alpha and pi isoenzymes have been isolated in a highly purified form and used for the production of polyclonal antisera. Subsequently, radioimmunological and ELISA techniques were developed for quantitation of these proteins in the urine; the methods exhibited a high specificity and were sufficiently sensitive to determine nanogram quantities or less. Disease affecting tubular function, cyclosporine A treatment, administration of nephrotoxic antibiotics, and exposure to cadmium all resulted in characteristic changes in the pattern of the glutathione transferase isoenzymes present in urine. Such effects were seen also in patients who had previously been exposed to nephrotoxic agents, but in whom conventional tests for kidney function were apparently normal. Thus, it appears that radioimmunologic or immunochemical quantitation of alpha and pi forms of the enzyme can be used as sensitive and relatively simple markers for the early detection of toxic effects with respect to the renal tubuli.