Dysfunction In Long-term Survivors Research Articles

Systemic Biological Mechanisms of Neurocognitive Dysfunction in Long-Term Survivors of Childhood Hodgkin Lymphoma.

Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system-directed therapy, though little is known about the underlying mechanisms. HL survivors (n = 197) and age-, sex- and race/ethnicity frequency-matched community controls (n = 199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections. HL survivors [mean (SD) current age 36 (8) years, 22 (8) years after diagnosis] demonstrated higher concentrations of interleukin-6 (IL6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared with controls (P's < 0.001). Among survivors, higher concentrations of IL6 were associated with worse visuomotor processing speed (P = 0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (P's < 0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (P's < 0.05). Homocysteine was associated with worse short-term recall (P = 0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, whereas IL6 partially mediated associations between pulmonary conditions and visuomotor processing speed. Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials.

Impaired right ventricular function in long-term survivors of allogeneic haematopoietic stem-cell transplantation

AimsSurvivors of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) are at higher risk of cardiovascular disease. We aimed to describe right ventricular (RV) systolic function and risk factors for RV dysfunction in...

Longitudinal Evaluation of Neuromuscular Dysfunction in Long-term Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Children treated for cancer are at risk for neuromuscular dysfunction, but data are limited regarding prevalence, longitudinal patterns, and long-term impact. Longitudinal surveys from 25,583 childhood cancer survivors ≥5 years from diagnosis and 5,044 siblings from the Childhood Cancer Survivor Study were used to estimate the prevalence and cumulative incidence of neuromuscular dysfunction. Multivariable models adjusted for age, sex, race, and ethnicity estimated prevalence ratios (PR) of neuromuscular dysfunction in survivors compared with siblings, and associations with treatments and late health/socioeconomic outcomes. Prevalence of neuromuscular dysfunction was 14.7% in survivors 5 years postdiagnosis versus 1.5% in siblings [PR, 9.9; 95% confidence interval (CI), 7.9-12.4], and highest in survivors of central nervous system (CNS) tumors (PR, 27.6; 95% CI, 22.1-34.6) and sarcomas (PR, 11.5; 95% CI, 9.1-14.5). Cumulative incidence rose to 24.3% in survivors 20 years postdiagnosis (95% CI, 23.8-24.8). Spinal radiotherapy and increasing cranial radiotherapy dose were associated with increased prevalence of neuromuscular dysfunction. Platinum exposure (vs. none) was associated with neuromuscular dysfunction (PR, 1.8; 95% CI, 1.5-2.1), even after excluding survivors with CNS tumors, cranial/spinal radiotherapy, or amputation. Neuromuscular dysfunction was associated with concurrent or later obesity (PR, 1.1; 95% CI, 1.1-1.2), anxiety (PR, 2.5; 95% CI, 2.2-2.9), depression (PR, 2.1; 95% CI, 1.9-2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90-0.94) and employment (PR, 0.8; 95% CI, 0.8-0.9). Neuromuscular dysfunction is prevalent in childhood cancer survivors, continues to increase posttherapy, and is associated with adverse health and socioeconomic outcomes. Interventions are needed to prevent and treat neuromuscular dysfunction, especially in survivors with platinum and radiation exposure.

Pulmonary Dysfunction after Treatment for Childhood Cancer. Comparing Multiple-Breath Washout with Spirometry.

Rationale: Childhood cancer survivors are at risk of long-term pulmonary dysfunction, but we lack sensitive outcome measures to detect early pulmonary damage.Objectives: To assess the ability of nitrogen multiple-breath washout (N2MBW) for detecting pulmonary dysfunction compared with spirometry in long-term survivors of childhood cancer.Methods: We analyzed cross-sectional data from long-term (≥5-yr) survivors of childhood cancer, aged ≤16 years at cancer diagnosis, ≥16 years at study (assessment period 2015-2019). We categorized survivors by risk: high risk for those having had pulmotoxic chemotherapy, chest radiation, thoracic surgery, and/or hematopoietic stem cell transplantation, and standard risk for other cancer therapies. Primary outcomes were the global lung clearance index (LCI) and acinar ventilation inhomogeneity index (SACIN) from N2MBW, and forced expiratory volume in 1 second (FEV1) and functional vital capacity (FVC) from spirometry. We calculated z-scores for N2MBW and spirometry parameters and compared pulmonary dysfunction between risk groups. Pulmonary dysfunction was defined as z-score +1.64 for N2MBW and -1.64 for spirometry.Results: We studied 46 survivors, median age at diagnosis 10 years (interquartile range, 4-14), median age at study 30 years (interquartile range, 25-40). Thirty-seven percent were at high risk and 63% at standard risk for pulmonary dysfunction. LCI and SACIN were higher in the high-risk group compared with the standard-risk group (mean LCI z-scores 2.09, standard deviation [SD] 2.39 vs. 0.95, SD 2.81; mean SACINz-scores 2.45, SD 3.29 vs. 0.65, SD 2.79). FEV1 and FVC were lower in the high-risk compared with the standard-risk group (mean FEV1z-scores -0.94, SD 1.39 vs. -0.10, SD 1.07; mean FVC z-scores -1.14, SD 1.23 vs. 0.15, SD 1.61). Overall, LCI, SACIN, FEV1, and FVC were abnormal in 60%, 53%, 33%, and 33% of high-risk patients compared with 23%, 21%, 0%, and 4% of standard-risk patients.Conclusions: N2MBW identified more cases of pulmonary dysfunction in long-term survivors of childhood cancer than spirometry, even in patients who had cancer therapy not specifically known as being pulmotoxic. N2MBW could be a complementary screening tool for early pulmonary damage after treatment for childhood cancer.Clinical trial registered with www.clinicaltrials.gov (NCT02730767).

Sexual Function in a Nationwide Cohort of 2,260 Survivors of Testicular Cancer after 17 Years of Followup

Evidence on the long-term impact of testicular cancer treatment on sexual function is not clear. Our aim was to estimate the effect of testicular cancer treatment on the risk of sexual dysfunction in long-term survivors of testicular cancer. We performed a cross-sectional study of 2,260 long-term survivors of testicular cancer with a median followup of 17 years (IQR 12-24), including 1,098 who underwent orchiectomy alone (surveillance), 788 treated with bleomycin, etoposide and cisplatin alone or post-chemotherapy retroperitoneal surgery, 300 treated with abdominal radiotherapy and 74 who received more than 1 line of treatment. Sexual function was evaluated by the IIEF-15 (International Index of Erectile Function-15) questionnaire. Results were compared between treatment groups using logistic regression analysis with the results on each of the 5 IIEF-15 dimensions as the outcome and treatment as exposure using surveillance as the referent. The risk of erectile dysfunction was increased in all treatment groups compared to surveillance, including bleomycin, etoposide and cisplatin alone (OR 1.5, 95% CI 1.0-2.1, p <0.05), bleomycin, etoposide and cisplatin with post-chemotherapy surgery (OR 2.1, 95% CI 1.4-3.4, p <0.005), radiotherapy (OR 1.7, 95% CI 1.1-2.5, p <0.05) and more than 1 line of treatment (OR 3.2, 95% CI 1.6-6.3, p <0.005). Orgasmic dysfunction was associated with radiotherapy, bleomycin, etoposide and cisplatin with post-chemotherapy surgery and more than 1 line of treatment. Treatment with bleomycin, etoposide and cisplatin, radiotherapy and more than 1 treatment line increased the risk of erectile dysfunction in long-term survivors of testicular cancer compared to surveillance. Patients should be informed about this as part of the information on treatment related late effects.

Nasogastric Enteral Feeding Is Superior to Percutaneous Gastrostomy in Preventing Late Pharyngeal Dysfunction in Long-Term Survivors of Locoregionally Advanced Head and Neck Squamous Cell Cancer (HNSCC) Treated With Definitive Chemoradiation Therapy (CRT)

Nasogastric Enteral Feeding Is Superior to Percutaneous Gastrostomy in Preventing Late Pharyngeal Dysfunction in Long-Term Survivors of Locoregionally Advanced Head and Neck Squamous Cell Cancer (HNSCC) Treated With Definitive Chemoradiation Therapy (CRT)

Late Pulmonary Dysfunction in Long-Term Survivors after allogeneic Hematopoietic Stem Cell Transplantation with Intensified Conditioning Regimen Including Thiotepa, Cyclophosphamide, and Total Body Irradiation.

Background: Late pulmonary dysfunction is a clinical problem influencing on quality-of-life (QOL) in long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). In this study we retrospectively assessed pulmonary function test (PFT) in patients surviving 5 years or more after HSCT with intensified conditioning regimen and identified pre-and post-transplant risk factors.Methods: Sixty-five long-term survivors transplanted between May 1994 and March 2003 (minimum 5 years follow-up after HSCT) were included in this analysis. There were 36 males and 29 females. Median age was 39 years, with a range of 16 to 53 years. All patients were transplanted because of hematologic malignancies (20 patients with AML, 16 with ALL, 9 with MDS, and 20 with CML). The pre-transplant conditioning regimen consisted of thiotepa (200 mg/m2 for 2 days), cyclophosphamide (2,000–2,250 mg/m2 for 2 days), and total body irradiation (12.5 Gy in five fractions). The prophylaxis of graft-versus-host disease (GVHD) consisted of short-term methotrexate and cyclosporine or tacrolimus. Bone marrow (BM) from related donor or unrelated donor, and peripheral blood stem cell (PBSC) from related donor were transplanted in 33 patients, 22, and 10, respectively. PFT was performed pre-conditioning and then post-transplant at 3 months, 1 year, and thereafter annually. Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV1/FVC ratio were used to measure ventilatory capacity. Vital capacity (VC) and total lung capacity (TLC) were used to measure lung volumes. Diffusion capacity for carbon monoxide (DLCO) was determined by using a carbon monoxide single-breath technique with correction for hemoglobin concentration.Results: Seven (11%) patients showed abnormalities in PFT after HSCT. Temporary abnormality (restrictive pattern) within 1 year was detected in 2 patients. Five patients developed late-onset and continuous abnormality (restrictive pattern in 2 patients, obstructive in 2, and mixed in 2) with a cumulative incidence of 8%. These were clinically diagnosed as having bronchiolitis obliterans in 3 patient and interstitial pneumonia in 1. DLCO was significantly lower after transplantation of PBSC than after BM (P=0.02 at 3 year and P=0.00 3 at 5 year). More than 40 years old, female, high risk of disease status, and abnormal PFT pre-transplant were related with a decline of PFT within 1 year after HSCT, but there were no association with PFT abnormality at 3 or 5 years. The cumulative incidence of late PFT abnormality in patients with CML was significantly higher than that in those with other than CML (P=0.01).Other factors including age, sex, smoking, disease status, and donor sources were not significant for developing late pulmonary dysfunction. Extensive chronic GVHD was associated with late PFT abnormality with statistical significance (P=0.002 for VC and P=0.01 for FEV1). Three of 7 patients receiving immunosuppressant at 5 years after HSCT had pulmonary complication.Conclusions: The results showed relatively a low incidence of PFT abnormality in long-term survivors who received HSCT with intensified conditioning regimen. However, late pulmonary dysfunction lowers QOL in survivors despite long-term remission of leukemia Longer follow-up should be needed to determine whether more patients with chronic GVHD will develop PFT abnormality.

Clostridium perfringens Enterotoxin as a Novel-Targeted Therapeutic for Brain Metastasis

Brain metastasis is the most commonly occurring intracranial tumor whose incidence seems to be increasing. With standard therapy, the average survival time of patients is approximately 8 months, and treatment often leads to neurologic dysfunction in long-term survivors, emphasizing the need for novel therapeutics. Clostridium perfringens enterotoxin (CPE) has recently been shown to rapidly and specifically destroy cancer cells expressing CPE receptors claudin-3 and claudin-4. Unfortunately, the utility of CPE is precluded by systemic toxicity because its receptors are expressed in numerous organs. Here, we provide the first preclinical evidence that CPE may be uniquely suited to the local treatment of brain metastasis. By immunohistochemical analysis, claudin-3 and claudin-4 were expressed frequently in metastases from breast (15 of 18), lung (15 of 20), and colon (12 of 14) carcinoma, and infrequently in metastases from renal cell carcinoma (2 of 16) and melanoma (2 of 16). In contrast, expression of claudin-3 and claudin-4 was absent in adjacent normal brain tissue. Further examination of the central nervous system (CNS) revealed low or undetectable levels of claudin-3 and claudin-4 in all regions tested by Western and immunohistochemical analysis. Treatment of breast cancer cell lines (MCF-7, MDA-MB-468, NT2.5-luc) and normal human astrocytes with CPE in vitro resulted in rapid and dose-dependent cytolysis exclusively in breast cancer cells, correlating with claudin-3 and claudin-4 expression. Moreover, intracranial CPE treatment significantly inhibited tumor growth and increased survival in two murine models of breast cancer brain metastasis, without any apparent local or systemic toxicity. These data suggest that CPE therapy may have efficacy against a wide variety of brain metastases without CNS toxicity.

High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation

To determine the prevalence and identify variables associated with renal dysfunction in long-term survivors of pediatric liver transplantation. Data from 117 patients who survived>or=3 years after liver transplantation were analyzed. Demographic and clinical information was obtained from chart review and from a clinical care database. The dependent variable was renal function as determined by measured glomerular filtration rate (mGFR). Univariate and multivariate analyses were performed to identify independent variables associated with renal dysfunction (mGFR<70 mL/min per 1.73 m2). The average time since liver transplant was 7.6+/-3.4 years (range, 3 to 14.6 years). When the last available mGFR for all patients was analyzed, renal dysfunction was present in 32%. In the univariate analysis, mGFR at 1 year after transplant, cyclosporine immunosuppression, and time since transplant were significant; the second two were strongly collinear. Using multiple logistic regression modeling excluding time since transplant, cyclosporine and mGFR at 1 year after transplant were strongly associated with renal dysfunction. Renal dysfunction is a common complication in children who survive liver transplantation. Our observations are of critical importance because children may live long enough to move from a stage of renal insufficiency characterized by asymptomatic decreased GFR to symptomatic end-stage renal disease.

Diagnosing Growth Hormone Deficiency After Aneurysmal Subarachnoid Hemorrhage

To the Editor: We read with interest the article by Dimopoulou1 on hypopituitarism after aneurysmal subarachnoid hemorrhage (SAH). Although this topic deserves the attention of the neurological community treating these patients, especially those readers who, from the scope of the journal cannot be expected to be familiar with diagnostic criteria for endocrine disorders, deserve to be assured about the soundness of the proposed definitions of neuroendocrine dysfunction and the conclusions derived thereof. In the case of the authors’ definition of growth hormone deficiency (GHD) in SAH patients, this should be questioned for several reasons. The authors assume inadequate growth hormone secretion indicative of GHD in their patients if IGF-I levels are <2 standard deviations for the appropriate age range, quoting an article by Aimaretti et al.2 However, insulin-like growth factor (IGF)-I levels do not only reflect growth hormone (GH) secretory status but also are influenced by several other factors. Therefore, low IGF-I levels can only be considered a parameter of impaired GH secretion if malnutrition, liver failure, poorly controlled diabetes mellitus, and uremia are ruled out.3 It is well-known that the IGF-I levels observed in hypopituitary patients and the normal range of IGF-I levels progressively overlap with advancing age of the patients. Along these …

High prevalence of endocrine dysfunction in long-term survivors after allogeneic bone marrow transplantation for hematologic diseases.

The progressively increasing number of long-term survivors after allogeneic bone marrow transplantation (allo-BMT) led researchers to focus on the early and late complications of this procedure. Endocrine dysfunction occurred mostly in patients who had undergone total body irradiation (TBI) as part of pretransplantation treatment. The extent to which chemotherapy and immune system derangement affect endocrine function in allo-BMT recipients is still unclear. Forty consecutive patients (21 women, 19 men) with hematologic diseases surviving 12 or more months after allo-BMT from HLA-identical siblings were studied. Patients' age at transplantation ranged from 13 to 45 years and their post-BMT follow-up lasted 12-62 months. The conditioning regimen BUCY2 was employed. Graft versus host disease (GVHD) was observed in the acute form in 13 patients and in the chronic form in 26. The function of hypothalamic-pituitary-gonad, thyroid, somatotrophic, and adrenal axes was assessed. The most common endocrine dysfunction was ovarian insufficiency (95% of women), followed by an increase in follicle-stimulating hormone in 47% of men, indicating spermatogenesis damage. Hormone replacement therapy was contraindicated in three women because of chronic liver GVHD and it was ineffective partially in four others because of reduced intestinal or cutaneous absorption. Thyroid dysfunction occurred in 47.5% of patients and included low T3 syndrome, chronic thyroiditis, and transient subclinical hyperthyroidism and subclinical hypothyroidism. Adrenal function was abnormal in 10%, mostly related to the prolonged corticosteroid treatment. IGF-I was lower than age-reference values in 27% of all patients and in 38% of those with chronic GVHD. Thyroid, adrenal, and IGF-I impairments were more frequent in patients with chronic GVHD than in patients without this disease (P = 0.048). A high prevalence of endocrine dysfunction was detected in a cohort of allo-BMT recipients not treated by TBI. Although gonadal failure was likely related to intensive myeloablative treatments, thyroid, adrenal, and IGF-I impairments were late events, suggesting that immunosuppressive treatment and immune system derangement may play a role in the development of endocrine dysfunction after allografting.

Prevalence and predictors of sexual dysfunction in long-term survivors of marrow transplantation.

To describe the prevalence of sexual difficulties in men and women after marrow transplantation (MT), and to define medical, demographic, sexual, and psychologic predictors of sexual dysfunction 3 years after MT. Four hundred seven adult MT patients were assessed pretransplantation. Survivors repeated measures of psychologic and sexual functioning at 1 and 3 years posttransplantation. Data were analyzed from 102 event-free 3-year survivors who defined themselves as sexually active. Men and women did not differ in sexual satisfaction pretransplantation. At 1 and 3 years posttransplantation, women reported significantly more sexual dysfunction than men. Eighty percent of women and 29% of men reported at least one sexual problem by 3 years after MT. No pretransplantation variables were significant predictors of 3-year sexual satisfaction for women. For men, pretransplantation variables of older age, poorer psychologic function, not being married, and lower sexual satisfaction predicted sexual dissatisfaction at 3 years (R2=.28; P < .001). Women who were more dissatisfied 3 years after MT did not receive hormone replacement therapy (HRT) at 1 -year posttransplantation and were less satisfied at 1 year, but not pretransplantation (R2=.35; P < .001). Sexual problems are significant in the lives of MT survivors, particularly for women. Although HRT before 1 year posttransplantation improves sexual function, it does not ensure sexual quality of life. Intervention for women is needed to apply hormonal, mechanical, and behavioral methods to prevent sexual difficulties as early after transplantation as possible.

Role of non-transferrin bound iron in iron overload and liver dysfunction in long term survivors of acute leukaemia and bone marrow transplantation.

To determine whether nontransferrin bound iron is present in the serum of long term survivors of acute leukaemia and bone marrow transplantation who have liver dysfunction as indicated by consistently raised serum aspartate aminotransferase (AST) activities. Thirty eight patients, who were at least three years from the end of treatment, were studied. Serum samples were analysed for hepatitis C, hepatitis B, AST, ferritin, and non-transferrin bound iron. A bleomycin based assay was used to detect non-transferrin bound iron. Patient and blood bank records were examined to determine the number of units of transfused blood received by each patient. Ten patients had consistently raised serum AST activities. Of these, two had evidence of hepatitis C infection, one had chronic hepatitis B infection and one had chronic graft versus host disease affecting the liver. None of these four patients had detectable non-transferrin bound iron. The remaining six patients had no obvious reason for raised AST activities, but four had non-transferrin bound iron detectable in their serum as compared with only two out of 28 patients with normal AST activities. Patients with abnormal AST activities had higher serum ferritin concentrations than those with normal AST, though serum ferritin was raised in 21 of 28 patients without liver dysfunction. Non-transferrin bound iron may be found in this group of patients, suggesting that iron overload is the cause of the observed liver dysfunction. Non-transferrin bound iron may also be a more specific indicator of iron overload than the serum ferritin concentrations.

Radiation treatment planning for malignant astrocytomas

Treatment planning for malignant astrocytomas has been an area of controversy for the past 30 years. Several key studies have supported widely divergent treatment philosophies. Before the availability of computerized tomography (CT) scanning, whole brain irradiation (WBRT) was necessary to ensure adequate tumor coverage, due to limitations of less-sophisticated imaging studies. Following the introduction of high-quality CT scanning and magnetic resonance imaging (MRI), there was a shift to the use of more-limited radiation fields to treat only the contrast-enhancing tumor plus a margin. Additional impetus for use of smaller treatment fields came from studies implicating WBRT in cerebral dysfunction in long-term survivors.‘~* Recently, the appeal of limited field irradiation has been tempered by biopsy and autopsy studies that suggest wider migration of malignant cells than previously believed?” There have thus emerged two schools of thought. One is that patients should receive limited field irradiation, with the hope of avoiding mental deterioration in the few long-term survivors. The opposite argument is that patients should receive WBRT in order to treat all potential sites of tumor infiltration in all patients. While both points of view have merit, they must be reconciled with the fact that many patients will die of their disease within 1 year of diagnosis, regardless of the radiation fields used. The bulk of retrospective data available do not show a survival advantage to large versus small field irradiation (for review, see reference 5). The first study to systematically analyze radiation planning for high-grade astrocytomas was published by Concannon et al” in 1960. Partial brain irradiation (PBRT) fields were compared with tumor volumes identified at autopsy in 2 1 patients who died shortly after starting treatment. The fields were designed