Chronic Adverse Effect Research Articles

Psychometric Properties of the Spanish Version of Breast Cancer and Lymphedema Symptom Experience Index.

Lymphedema is a common late and chronic adverse effect of breast cancer treatment. This study aimed to translate and evaluate the psychometric properties of the BCLE-SEI Spanish version with Spanish-speaking breast cancer patients. 286 patients were recruited (2018 to 2020), from the Hospital Universitario Central de Asturias. Data analysis included descriptive statistics; internal consistency and test-retest reliability; principal component analysis and exploratory factor analysis; average variance extracted; and receiver operating characteristic curves. No semantic modifications to items were needed. The scores of the instrument demonstrated excellent internal consistency (Cronbach´s alpha = .95-.97; McDonald´s omega = .96-.98) and test-retest reliability (r = .78-.87, n = 29). A significant difference was observed between the lymphedema group and non-lymphedema group (p < .001) in terms of total scale, symptom occurrence (p < .001), symptom distress in the physical-functional (p < .001), and psychosocial dimension (p < .001). Principal component analysis for symptom occurrence revealed a unidimensional factor and two factors were identified for symptom distress via exploratory factor analysis, the two of which explained 45.71% and 54.77% of the total sample variance, respectively. This study provided initial evidence to support the psychometric properties of the BCLE-SEI Spanish version.

Leucovorin Rescue After Methotrexate Graft-Versus-Host Disease Prophylaxis Shortens the Duration of Mucositis, Time to Neutrophil Engraftment, and Hospital Length of Stay

Oropharyngeal mucositis (OPM) is common following conditioning for allogeneic hematopoietic cell transplantation (alloHCT) and results in pain, functional status decline, need for nutritional support, infections, and prolonged length of stay (LOS). Methotrexate (MTX) graft-versus-host disease (GVHD) prophylaxis exacerbates OPM and slows hematopoietic engraftment, which may prolong LOS. Previous studies have demonstrated reduced OPM and more rapid engraftment when leucovorin (LCV) is added following MTX GVHD prophylaxis, yet this practice is controversial. The primary objective of this study was to determine if the routine addition of LCV to MTX GVHD prophylaxis impacted the duration of grade 2 to 4 OPM. Secondary objectives included determination of the incidence of grade 2 to 4 and grade 3 to 4 OPM, time to engraftment, ability to receive all four planned MTX doses, use of total parenteral nutrition (TPN), use of patient-controlled analgesia (PCA), LOS, incidence of acute or chronic GVHD, relapse-free survival (RFS), and overall survival (OS). This single-center, retrospective cohort study compared alloHCT outcomes for 46 adult patients who received MTX 15 mg/m2 day +1; MTX 10 mg/m2 days +3, +6, and +11 (15-10-10-10); and LCV following days +3, +6, and +11 MTX compared to historical controls who did not. Patients who received myeloablative conditioning (MAC) and matched related donor (MRD) or matched unrelated donor (MUD) alloHCT were included. The addition of LCV resulted in significant reductions in the duration of grade 2 to 4 OPM (median, 6 days versus 10.5 days; P = .0004), duration of TPN (7 days versus 16 days; P = .001), PCA use (16% versus 39%; P = .0001), time to neutrophil engraftment (median, 18 versus 20 days; P = .008), and LOS (median, 27.5 versus 31 days; P = .017) compared to historical controls. Patients who received routine LCV had similar incidences of grade 2 to 4 acute GVHD (30% versus 28%; relative risk [RR], 1.08; 95% confidence interval [CI], .57 to 2.03; P = 1.0), grade 3 or 4 acute GVHD (2% versus 7%; RR, .33; 95% CI, .04 to 3.09; P = .62) and chronic GVHD (37% versus 30%; RR, 1.21; 95% CI, .67 to 2.16; P = .66) compared to historical controls. Graft failure occurred in 2% of patients in each group. In a multivariable logistic regression analysis, RFS was similar in the LCV group compared to historical controls (HR, .86; 95% CI, .24 to 1.2; P = .13); however, OS was improved in patients who received LCV (HR, .33; 95% CI, .13 to .83; P = .01). In patients undergoing MAC MRD/MUD alloHCT with four planned doses of MTX GVHD prophylaxis (15-10-10-10), LCV was associated with reduced duration of grade 2 to 4 OPM, faster neutrophil engraftment, reduced utilization of TPN and PCA, and shortened LOS compared to historical controls not receiving routine LCV. These benefits were apparent without an increased risk of acute or chronic GVHD or adverse effect on RFS. LCV improved OS; however, it is unclear if this was due to the intervention or an unmeasured confounder. A randomized, prospective trial of LCV prophylaxis in patients receiving MAC alloHCT and MTX 15-10-10-10 GVHD prophylaxis is warranted to confirm our findings.

A systematic review on the skin whitening products and their ingredients for safety, health risk, and the halal status.

Skin-whitening products are in the high trend of demand for skin beautifying and lightening. Sources of ingredients for cosmetics could be natural, semi-synthetic, and synthetic that may affect the halal status of a product. The lack of scientific evidence on the safety and risks of such ingredients is a major concern to many consumers. This review paper aimed to shed light on the skin-whitening ingredients and their issues related to safety, health risk, and halal status. Based on the reviews scientific publications published from January 2015 to July 2020 using Web of Science and Scopus engines. Based on the review, most of the common ingredients in the skin-whitening products are originated from plants, animals, microbes, and heavy metals. Health risk of the ingredients was evaluated based on the usage, chronic or acute adverse effect, frequency of incidence, and the hazardous chemical contents of a halal cosmetics. The halal status of the ingredients was investigated based on the sources of origin, safety evaluation, and associated health risk of the ingredients. This review shows that ingredients play a vital role in the halal status decision-making of a cosmetic product. Therefore, the categories of Halal-Safe, Haram-Prohibited, and Critical-Need further evaluation were suggested to integrate the sources of ingredients with safety.

Referral Patterns And Barriers To Physical Rehabilitation For Children And Adolescents With Cancer Across Canada

Two thirds of children who have been diagnosed with cancer will develop at least one chronic or long-term adverse effect of cancer treatment, many of which are amenable to physical rehabilitation (PR). PR may help reduce the burden of cancer side effects; however, research suggests few childhood cancer survivors access PR services. PURPOSE: To explore PR referral patterns and barriers to service provision for children and adolescents with cancer across Canada. METHODS: A cross-sectional web-based survey in English and French languages was conducted. Participants identified were Canadian healthcare professionals (HCPs) who provide and/or refer children and adolescents with cancer to PR services. The survey gathered data on numbers of childhood cancers either seen or referred to PR, reasons that prompted referral to PR, and existing barriers and facilitators to PR programs. RESULTS: A total of 54 responses were received including physical therapists (n= 27), nurse and nurse practitioners (n= 10), pediatric oncologists and oncology residents (n= 9), occupational therapists (n= 6), a speech-language pathologist (n= 1), and an exercise professional (n= 1). Data indicate that approximately 25% of children with cancer are being referred to PR, suggesting less than optimal referral rates. While 70% of HCPs report referring children and adolescents to PR services; the primary reason for referral is when the child presents with, or is at risk of functional disability. Chemotherapy-induced peripheral neuropathy (CIPN) was the second most common reason for referral to PR services (63%), and was identified by survey respondents as a rehabilitation research priority. The existence of a multidisciplinary team (52%), as well as the availability of PR space and equipment (33%) were the most commonly reported facilitators by the oncology medical team; while barriers to service provision included a lack of staffing (24%) and specialized PR services (17%). CONCLUSIONS: The survey results demonstrate that gaps in the health system such as limited resources and specialized services exist, that impact the implementation of PR programs. Results from this survey have informed the design of upcoming research investigating the feasibility and effects of an early PR program in children at risk of developing CIPN. No funding was received.

The Chronic Adverse Effect of Chloroquine on Kidney in Rats through an Autophagy Dependent and Independent Pathways

Background: Chloroquine (CQ), a classic autophagy inhibitor, is used clinically for malaria prophylaxis and pulmonary hypertension treatment. The adverse effects of CQ on morphological and functional changes in the kidney were investigated in the current study due to CQ accumulation in the kidney. Methods: Twelve male Sprague-Dawley rats were randomly divided into 2 groups for 4 weeks: group 1, control (n = 6); and group 2, CQ administration group (50 mg^–1·kg per day ip; n = 6). Serum aldosterone and vasopressin were measured by radioimmunoassay. Immunofluorescence was used to colocalize Tunel with aquaporin 1, aquaporin 2 (AQP2), and Tamm-Horsfall protein. Expression of AQP2 and mineralocorticoid (MR) was detected by western blot and immunohistochemistry. Results: In the present study, 4 weeks of CQ administration were shown to induce severe kidney injury, including glomerular sclerosis and tubular cells apoptosis, especially distal tubular cells. Decreased expression of LC3II/I and p-AKT was demonstrated in CQ-treated rats. Glomerular and proximal tubule injury were associated with impaired autophagy flux, and distal tubule injury may be associated with downregulated cyclic adenosine monophosphate (cAMP)/PKA/AKT signaling. Both MR and AQP2, which are mainly located in the distal tubule and collecting duct, were significantly reduced in CQ-treated rats, thus leading to increased exosomal secretion of AQP2 in urine. Additionally, chronic CQ administration increased aldosterone and vasopressin levels in serum, but lowered the blood pressure, glomerular filtration rate, and urine concentration. Conclusions: CQ administration damages glomerular, proximal tubule autophagy, and severe distal tubular cells apoptosis by inhibiting cAMP/PKA/AKT signaling.

Adverse effects of yoga: a national cross-sectional survey

BackgroundWhile yoga is increasingly used for health purposes, its safety has been questioned. The aim of this cross-sectional survey was to analyze yoga-associated adverse effects and their correlates.MethodsA cross-sectional anonymous national online survey among German yoga practitioners (n = 1702; 88.9% female; 47.2 ± 10.8 years) was conducted from January to June 2016. Participants were queried regarding their yoga practice, i.e. yoga styles used, length and intensity of yoga practice, practice patterns, and whether they had experienced acute or chronic adverse effects of their yoga practice. Independent predictors of acute or chronic adverse effects were identified using multiple logistic regression analyses.ResultsAshtanga yoga (15.7%), traditional Hatha yoga (14.2%), and Sivananda yoga (22.4%) were the most commonly used yoga styles. 364 (21.4%) yoga users reported 702 acute adverse effects, occurring after a mean of 7.6 ± 8.0 years of yoga practice. The most commonly reported yoga practices that were associated with acute adverse effects were hand-, shoulder- and head stands (29.4%). Using Viniyoga was associated with a decreased risk of acute adverse effects; practicing only by self-study without supervision was associated with higher risk. One hundred seventy-three participants (10.2%) reported 239 chronic adverse effects. The risk of chronic adverse effects was higher in participants with chronic illnesses and those practicing only by self-study without supervision. Most reported adverse effects concerned the musculoskeletal system. 76.9% of acute cases, and 51.6% of chronic cases reached full recovery. On average 0.60 injuries (95% confidence interval = 0.51–0.71) per 1000 h of practice were reported, with Power yoga users reporting the highest rate (1.50 injuries per 1000 h; 95% confidence interval = 0.98–3.15).ConclusionsOne in five adult yoga users reported at least one acute adverse effect in their yoga practice, and one in ten reported at least one chronic adverse effect, mainly musculoskeletal effects. Adverse effects were associated with hand-, shoulder- and head stands; and with yoga self-study without supervision. More than three quarters of of cases reached full recovery. Based on the overall injury rate per 1000 practice hours, yoga appears to be as safe or safer when compared to other exercise types.

Identifying and Treating Opioid Side Effects: The Development of Methylnaltrexone.

Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient. To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation. Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998. Clinical research center of a university hospital. Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation. Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups. The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study. Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.

Can Therapeutic-Range Chronic Phenytoin Administration Cause Cerebellar Ataxia?

Phenytoin (PHT) is a first line antiepileptic drug (AED) used to treat many epilepsy syndromes. As with other AEDs, there are various adverse effects associated with PHT. For this brief review, we searched for evidence of cerebellar ataxia as a chronic adverse effect of therapeutic-range PHT treatment. Many previous studies appeared related to this issue, but many of those studies were designed to resolve questions related to the persistent residual effects of toxic-range PHT therapy, or they were inconclusive due to an absence of critical information such as PHT serum concentration, cerebellar symptoms/signs, and other factors contributing to cerebellar degeneration. Nevertheless, there were a few reports suggesting that cerebellar ataxia may be a chronic adverse effect of therapeutic-range PHT therapy and that a possible pathomechanism for that effect is folate deficiency. Moreover, there is the possibility that there may be patient-specific susceptibility factors affecting ataxia. Further studies are needed to elucidate the incidence, risk factors, and pathomechanism of cerebellar ataxia as a chronic adverse effect of therapeutic-range PHT treatment.

Odontoiatric perspectives and osteonecrosis of the jaw as a possible adverse effect of bisphosphonates therapy in fibrous dysplasia and McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is characterized by the triad of polyostotic bone fibrous dysplasia (PFD), endocrine disorders, and café-au-lait skin pigmentation. Ninety percent of MAS patients have fibrous dysplasia (FD) craniofacial lesions. Osteonecrosis of the jaw (ONJ) has been described as an adverse side effect of bisphosphonate therapy. The aim of the study was to investigate evidence of clinical and/or radiological signs of ONJ in FD/MAS pediatric patients due to bisphosphonate therapy and describe odontoiatric tools in this population. Thirteen FD/MAS patients were enrolled. All patients during pediatric age have been treated with pamidronate infusions. They underwent complete oral clinical examination. Ortopantomography and/or CT were evaluated in all cases. No patient developed ONJ. None of them showed radiological signs different from jaw FD. In spite of the low number of patients enrolled, results confirm that, in this population, ONJ can be ruled out as a chronic adverse side effect of bisphosphonate therapy.

Hydroxycinnamic acid amide derivatives of polyamines reverse spermine-induced CNS excitation

The aim of this study was to examine the acute effect of a range of novel hydroxycinnamic acid derivatives of spermine on the development of spermine-induced CNS excitation and convulsions in female Laca mice, and to assess the chronic adverse behavioural effect profile of these compounds over a 5day period. Four of the six novel polyamine analogues dose-dependently inhibited body tremor and tonic convulsions caused by spermine, when administered centrally (icv) or peripherally (ip). BU43b was the most potent analogue tested, but BU31b, 33b, and 36b were also effective (p<0.01, Mann–Whitney U test). A similar profile of effectiveness was seen with peripheral and central administration, indicating that the analogues may cross the blood brain barrier. More chronic investigation of the adverse effects of the compounds administered alone over 5days of observation indicated that the drugs were well tolerated, only causing reduced locomotor activity on the first day of the study and mild changes in behaviours linked to CNS and ANS function. It is likely that NMDA receptor NR2B subunit inhibition is involved in the anticonvulsant effect of these novel analogues, but other mechanisms may also be involved. These novel polyamine derivatives warrant further investigation of their therapeutic potential in treating epilepsy and CNS disorders where excitotoxicity is implicated.

&amp;lt;i&amp;gt;Acacia etbaica&amp;lt;/i&amp;gt; as a Potential Low-Cost Adsorbent for Removal of Organochlorine Pesticides from Water

The presence of pesticides in the environment is of great concern due to their persistent nature and chronic adverse effect on human health and the environment. Water bodies are subject to pollution by organochlorine pesticides, especially in developing countries, where water pollution is a key sustainability challenge. Hence, activated carbon is considered a universal adsorbent for the removal of organochlorine pollutants from water. Activated carbon from Acatia etbaica was prepared using traditional kilns with low investment costs. Pesticides such as aldrin, dieldrin and DDT were selected for adsorption because of their common usage in agricultural and malaria control activities and may occur in high concentrations in surface waters that are used as drinking water sources. The effect of the adsorbent dose and initial concentration were investigated. To describe the equilibrium isotherms the experimental data were analyzed by the Langmuir and Freundlich isotherm models. The Freundlich model gave the best correlation with the experimental data. Activated carbon prepared from Acacia etbaica was found to be an effective and low-cost alternative for the removal of organochlorine pesticides from aqueous solutions. The preparation method allows the use of this material by local communities for effective remediation of pollution by pesticides.

Early thermal quantitative sensory testing to measure acute oxaliplatin neurotoxicity and predict chronic neuropathy in gastrointestinal malignancies.

425 Background: Acute oxaliplatin neurotoxicity has been shown to be predictive of chronic oxaliplatin neuropathy. A recent study by Attal et al showed that tQST (thermal quantitative sensory testing) at cycle 4 provides a noninvasive method for predicting chronic neuropathy. A high risk population defined as those experiencing pain with a ≥ 20 degree cold stimulus had an OR of 39 for developing a severe chronic neuropathy at 1 year. Our study was designed to test the utility of tQST at earlier time points for predicting chronic neuropathy. Methods: Gastrointestinal cancer patients receiving FOLFOX were evaluated over a 1 year period for the development of acute and chronic oxaliplatin neurotoxicity: before starting FOLFOX, 1 hour into oxaliplatin infusion, before cycles 2, 4 and 12, and 1 year after start of treatment. Patients underwent a series of QSTs to measure thermal and mechanical sensitivities, fine motor skills, vibration detection, validated questionnaires, and presence of hyperalgesia. Results: Preliminary analysis of 13 patients using cycle 4 data as a surrogate for chronic neuropathy shows that cold pain (the temperature at which subjects report pain) prior to starting FOLFOX and at cycle 2 is predictive of cold pain at cycle 4, rs = 0.67 (p=.01) and 0.49 (p=0.09), respectively. There is a significant difference in cold pain across all time points between high and low risk populations(p=0.02 at baseline, p=0.04 during cycle 1, p=0.08 at cycle 2, and p=0.03 at cycle 4). Correlation between cycles 1 and 4 is seen for changes in cold sensitivity from baseline, rs = 0.52 (p=0.07). Conclusions: Baseline tQST correlates to cycle 4 measurements and may be an early predictor of patients at the highest risk for chronic neuropathy. These preliminary data indicate an inherent, pre-existing sensitivity to oxaliplatin induced chronic neuropathy for high risk patients which can be detected with tQST. Early identification of these patients can allow for preventive measures to decrease the incidence of this debilitating chronic adverse effect of oxaliplatin. A larger biomarker validation study is planned using tQST to stratify patients into high and low risk.

Richtwerte für 2-Furaldehyd in der Innenraumluft. Mitteilung der Ad-hoc-Arbeitsgruppe ­Innenraumrichtwerte der Innenraumluft­hygiene-Kommission des Umweltbundesamtes und der Obersten Landesgesundheitsbehörden

The German Working Group on Indoor Guidelines of the Federal Environment Agency and the States' Health Authorities is issuing indoor air guide values to protect public health. For health evaluation of 2-furaldehyde in air valid human studies are missing. In a subacute inhalation study well documented and assessed as reliable respiratory epithelial lesions such as squamous metaplasia and atypical hyperplasia were observed. The Working Group assessed a lowest observed adverse effect level of 20 mg 2-furaldehyde/m³ for the endpoint irritation following subacute exposure and extrapolated to a chronic lowest adverse effect level of 1 mg 2-furaldehyde/m³. By applying a factor of 5 for interindividual variability of irritation and a modifying factor of 2 regarding data gaps especially for children a health hazard guide value (RW II) of 0.1 mg 2-furaldehyde/m³ is obtained. A health precaution guide value of 0.01 mg 2-furaldehyde/m³ is recommended.

Amphotericin B: side effects and toxicity

Amphotericin B (AmB) is a crucial agent in the management of serious systemic fungal infections. In spite of its proven track record, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. The mechanism of action of AmB is based on the binding of the AmB molecule to the fungal cell membrane ergosterol, producing an aggregate that creates a transmembrane channel, allowing the cytoplasmic contents to leak out, leading to cell death. Most of the efforts at improving AmB have been focused on the preparation of AmB with a lipid conjugate. AmB administration is limited by infusion-related toxicity, an effect postulated to result from proinflammatory cytokine production. The principal acute toxicity of AmB deoxycholate includes nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia. Its principal chronic adverse effect is nephrotoxicity. AmB probably produces renal injury by a variety of mechanisms. Risk factors for AmB nephrotoxicity include male gender, higher average daily dose of AmB (≥35 mg/day), diuretic use, body weight ≥90 kg, concomitant use of nephrotoxic drugs, and abnormal baseline renal function. Clinical manifestations of AmB nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic academia, and polyuria due to nephrogenic diabetes insipidus. Human studies show convincingly that sodium loading in excess of the usual dietary intake notably reduces the incidence and severity of AmB-induced nephrotoxicity.

Organophosphorus pesticide residues in milled rice ( Oryza sativa ) on the Chinese market and dietary risk assessment

The present study investigates the occurrence of acetylcholinesterase (AChE)-inhibiting organophosphorus (OP) pesticide residues in milled rice samples obtained form local markets in China during the period 2004–2006 and estimates their cumulative exposure. Concentrations of OP pesticides were determined by gas chromatography with flame photometric detection (GC–FPD). The results showed that 9.3% of the samples contained detectable residues of at least one of the seven target OP pesticides (chlorpyrifos, dichlorvos, omethoate, methamidophos, parathion-methyl, parathion and triazophos) mainly used for agriculture in China, with concentrations ranging 0.011–1.756 mg kg−1. Rice consumption data was obtained from an individual food consumption survey. Relative potency factors (RPFs) for each pesticide were calculated with methamidophos as the index compound (IC), using 1- or 2-year chronic non-observed adverse effect levels (NOAEL) for AChE inhibition, mostly in rat brain, obtained from international evaluations of pesticides. Exposure to AChE-inhibiting pesticides for the population above 7 years old at P99.9 represented 52–94.5% of the acceptable daily intake (ADI) expressed as methamidophos. Estimated exposure for children aged 2–4 and 4–7 years at P99.9 were 119 and 104.3% of the ADI level, respectively. This study suggests that a yearly monitoring program for OP pesticide residues and strict implementation of the national safety standard for milled rice is necessary.

Physical activity and lymphedema (the PAL trial): Assessing the safety of progressive strength training in breast cancer survivors

Lymphedema is a chronic and progressive long-term adverse effect of breast cancer treatment commonly defined by swelling of the affected arm. Current clinical guidelines indicate that women with and at risk for lymphedema should protect the affected arm from overuse. In clinical practice, this often translates into risk aversive guidance to avoid using the arm. This could lead to a disuse pattern that may increase the likelihood of injury from common activities of daily living. Further, such guidance poses an additional barrier to staying physically active, potentially translating to weight gain, which has been shown to be associated with worse clinical course for women with lymphedema. We hypothesize that a program of slowly progressive strength training with no upper limit on the amount of weight that may be lifted would gradually increase the physiologic capacity of the arm so that common activities represent a decreasing percentage of maximal capacity. Theoretically, this increased capacity should decrease the risk that daily activities put stress on the lymphatic system of the affected side. The Physical Activity and Lymphedema (PAL) Trial is a recently completed randomized controlled exercise intervention trial that recruited 295 breast cancer survivors (141 with lymphedema at study entry, 154 at risk for lymphedema at study entry). The purpose of this report is to provide detail regarding the study design, statistical design, and protocol of the PAL trial.

819. Molecular Follow-Up of Patients Treated with Allogeneic Hematopoietic Stem Cell Transplantation and Donor Lymphocytes Transduced with a Retroviral Vector Expressing HSV-TK and ÄLNGFR

Donor lymphocyte infusion (DLI) plays a crucial role in promoting immune reconstitution and anti-tumor activity in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). The efficacy of DLI is, however, limited by the occurrence of graft-versus-host disease (GvHD). We showed that the infusion of lymphocytes transduced by a retroviral vector expressing a suicide gene (HSV-TK) and a surface marker (|[Delta]|LNGFR) allows to control GvHD in 100% of the cases, while preserving anti-tumor and antiviral activities in 65% and 83% of the patients. Expansion (up to 40% of circulating cells) and long-term persistence (>10 years) of transduced cells was observed in >40 patients treated with HSV-TK+ DLI in the context of HLA-identical and haplo-identical HSCT. No acute or chronic adverse or toxic effect due to the gene transfer procedure was observed in these patients, who were treated with a total of >1011 cells generated by >60 independent transductions. Analysis of gene expression profiles showed that <1% of the 16,000 genes contained in an Affimetrix HG-U133A Gene chip|[reg]| were differentially expressed in |[Delta]|LNGFR+ (transduced) vs. |[Delta]|LNGFR- (untransduced) T-cells ex vivo, suggesting the substantial biological identity of T-cell populations generated by HSCT and those administered as DLI. Administration of NGF to |[Delta]|LNGFR+ T cells in culture caused no significant variation in their gene expression profile. Vector integration sites were analyzed by sequencing the vector-genome junctions amplified by LM-PCR from DNA of |[Delta]|LNGFR+ lymphocytes obtained up to 10 years after treatment from 4 different patients. Over 85% of proviral integrations occurred within transcription units, with a preference for first introns (27%) and regions upstream of transcription start sites (24%). Over 75% of intragenic integrations occurred in genes active in T cells at the time of transduction. Interestingly, distribution of integration sites and transcriptional orientation of integrated proviruses showed different patterns in T cells obtained ex vivo from transplanted patients compared to cultured T cells. Persistence of T-cell clones carrying specific vector integrations was followed in individual patients by quantitative PCR analysis of PBL-derived genomic DNA at different times after infusion. The effect of vector integration on the expression of hit genes was analyzed by microfluidic real-time PCR in RNA extracted from individual T-cell clones harboring proviral integrations in the first intron or <10 kb upstream of the transcription start site of one or more genes. This analysis indicated that only a minority of the selected, potentially |[ldquo]|dangerous|[rdquo]| integration events led to detectable perturbation of gene expression.

Molecular Follow-Up of Patients Treated with HSV-TK/ΔLNGFR Engineered Donor Lymphocytes after Allogeneic Stem Cell Transplantation.

Donor lymphocyte infusions (DLI) play a crucial role in promoting immune reconstitution and anti-tumor activity in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). The efficacy of DLI is, however, limited by the occurrence of graft-versus-host disease (GvHD). In three different clinical trials, we showed that the infusion of lymphocytes transduced by a retroviral vector expressing a suicide gene (HSV-TK) and a surface marker (ΔLNGFR) allows to control GvHD in 100% of cases, while preserving anti-tumor and antiviral activities. In >40 patients treated with TK-cells in the context of HLA identical and haplo-identical HSCT, we observed consistent expansion (up to 40% of circulating cells) and long-term persistence (>10 years) of transduced cells. No acute or chronic adverse or toxic effect due to the gene transfer procedure was observed in these patients, who were treated with a total of >1011 cells generated by >60 independent transductions. Analysis of vector integration sites was preformed by LM-PCR on lymphocytes obtained up to 10 years after treatment from 4 patients, and selected for ΔLNGFR expression. 60% of the sequences met our validity criteria and were unambiguously mapped onto the human genome by Ensembl BLAST analysis. Transduced T-cells were highly polyclonal, with vector integrations occurring preferentially within genes (52%), and particularly within the first intron (25%). Quantitative PCR analysis of selected integrations was performed to follow the dynamics of individual T-cell clones during time. Microchip analysis of the gene expression profile showed that <200 out of >22,000 genes (0.9%) were differentially expressed in ΔLNGFR+ vs. ΔLNGFR- T-cells from two different patients, suggesting that no significant perturbation was induced by retroviral transduction or HSV-TK/ΔLNGFR expression in human lymphocyte populations. Interestingly, these data also show the substantial biological identity of T-cell population generated by HSCT and those administered as DLI. Finally, the influence of proviral integration on the expression of targeted genes was studied in individual T-cell clones transduced in vitro or obtained ex vivo from treated patients by quantitative gene expression analysis.

Pentoxifylline and vitamin E combination improves superficial radiation-induced fibrosis

Pentoxifylline and vitamin E combination improves superficial radiation-induced fibrosis

Interactive effect of cytochrome P450 17α-hydroxylase and dopamine D3 receptor gene polymorphisms on abnormal involuntary movements in chronic schizophrenia

Background: Tardive dyskinesia is a chronic adverse effect of anti psychotic drugs, where association with a polymorphic site in the dopamine D3 receptor gene has been previously reported. Cytochrome P 450 17α-hydroxylase activity has been implicated with modulation of central dopamine release as well as neuroprotection. We investigated the association of a T →C variation in the cytochrome P 450 17α-hydroxylase gene with tardive dyskinesia in patients with chronic schizophrenia. Methods: Cytochrome P 450 17 allele and genotype frequencies were compared between matched schizophrenia patients with ( n = 55) or without tardive dyskinesia ( n = 58). Interactive effects of cytochrome P 450 17α-hydroxylase with the dopamine D3 Ser9Gly polymorphism on abnormal involuntary movements were examined. Results: There was no difference in cytochrome P 450 17α-hydroxylase genotype distribution between patients with and without tardive dyskinesia; however, patients carrying the cytochrome P 450 17α-hydroxylase A2-A2 genotype and the dopamine D3gly allele had the highest orofacial ( p < .04), distal ( p < .05), and incapacitation ( p < .04) scores on the Abnormal Involuntary Movements Scale. Conclusions: Schizophrenia patients who carry the dopamine D3gly allele and the cytochrome P 450 17α-hydroxylase A2-A2 genotype may be more likely to develop abnormal orofoacial and distal involuntary movements and to be incapacitated by these movements when chronically exposed to classical antipsychotic drugs.