TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

[The German cohort of long-term survivors of childhood cancer. A population-based cohort in the German Childhood Cancer Registry]. / Die deutsche Kohorte Langzeitüberlebender nach Krebs im Kindesalter. Eine populationsbezogene Kohorte am Deutschen Kinderkrebsregister.

Due to the considerably improved prognosis of childhood cancer, research regarding the long-term consequences has become highly valuable. The population-based German Childhood Cancer Registry forms the basis of the long-term follow-up of these patients. The cohort comprises over 25,000 patients (with malignant diseases before their 15th birthday) with a current address and who are neither deceased nor lost to follow-up. The current median age is 21 years and 500 individuals are already over 40 years old. All the long-term survivors are contacted every 5 years at the latest and are asked about possible long-term effects. Due to the continued improvement of the prognosis for childhood cancer over the years, such cohorts of long-term survivors have altered in their composition. Corresponding long-term follow-up studies can therefore not easily be compared to one another. This is illustrated by a nested case control study on the possible relationship between the occurrence of second tumors and the therapy undergone for the initial diagnosis. The cohort of long-term survivors in the German Childhood Cancer Registry is highly valuable both for research on long-term effects in Germany as well as for integration into international projects.

Utilization of psychosocial care and oncological follow-up assessments among German long-term survivors of cancer with onset during adolescence.

BACKGROUND: Survivors of pediatric cancer are at increased risk for medical and psychosocial late effects. This study retrospectively investigated the utilization of oncological and psychosocial care by former adolescent cancer patients (≥ 5 years since cancer diagnosis) in Germany. PATIENTS: Based on data of the German Childhood Cancer Registry (N=1 876 survivors of cancer with an age at diagnosis between 15 and 18 years), the study cohort comprised 820 survivors of adolescent cancer (time since diagnosis: M=13.7, SD=6.0, age at follow-up: M=30.4, SD=6.0 years). METHOD: Survivors of adolescent cancer completed standardized questionnaires measuring symptoms of posttraumatic stress, depression and anxiety as well as items on their utilization of medical and psychosocial care. RESULTS: More than a quarter (26.2%) of the survivors was no longer attending regular oncological follow-up assessments. Less than half of the survivors (44.4%) had received psychosocial care, mostly during their in-patient cancer treatment and their post-acute rehabilitation phase. Out of 184 survivors showing clinically relevant symptoms of posttraumatic stress, anxiety and/or depression at time of the study, 12.0% received psychosocial care and 13.6% took psychotropic medication. CONCLUSION: It should be studied further why only a small proportion of the survivors showing clinically relevant symptoms received psychosocial or psychopharmacological treatment. Systematic oncological follow-up assessments should take psychological late effects into greater account.

Strategy for long-term surveillance at the German Childhood Cancer Registry - an update.

BACKGROUND: The objective of this paper is to provide information about the quality (e.g. completeness, response) of long-term surveillance in German paediatric oncology and haematology based on the structures implemented by the German Childhood Cancer Registry (GCCR). METHODS: The GCCR contacts parents or patients to collect and update information on a minimal set of follow-up health status data (e.g. late relapses, subsequent neoplasms, current address) and exchanges this information regularly with the appropriate clinical trials. RESULTS: Between 2006 and 2010, GCCR approached a total of about 20,000 patients (contact at the age of 16 years, inquiry concerning the health status) in the context of long-term surveillance. 11,000 addresses of former patients had to be researched via municipal registrar's offices. The response rates ranged from 56% to 68%, the research in municipal offices provided 93-96% valid addresses. Of 46,115 patients diagnosed between 1980 and 2009, 25,283 are in long-term surveillance in 2010. DISCUSSION: Long-term surveillance requires considerable logistic effort at GCCR and requires that thousands of letters be mailed each year in order to ensure regularly updated information. Long-term surveillance is indispensable for a better understanding of late effects, subsequent neoplasms and quality of life of former childhood cancer patients.

[Hysteroscopic treatment of tubal pregnancy by intratubal injection of methotrexate]. / Hysteroskopische Behandlung von Tubargraviditäten durch die intratubare Injektion von Methotrexat.

The treatment of 3 non-ruptured tubal pregnancies by hysteroscopic intratubal injection of methotrexate was reported. In all 3 cases the beta-hCG serum levels decreased after injection during clinical, serological and sonographical control. In 2 patients the tubes were patent at a later control. In selected cases the intratubal administration of methotrexate via hysteroscopy is an alternative minimal invasive treatment.

Cytoprotective effects of CI-959 in the rat gastric mucosa: modulation of leukocyte adhesion.

BACKGROUND & AIMS: CI-959 is an anti-inflammatory agent that inhibits neutrophil adhesion, respiratory burst, and mast cell histamine release in vitro. In view of the emerging role of neutrophils in gastric erosive damage, the goals of this study were to assess the gastric cytoprotective effects of CI-959 and identify the mechanism responsible for this action. METHODS: Cytoprotective effects in the rat nonsteroidal anti-inflammatory drug and ethanol erosion models were assessed using image analysis. The in vivo effects of CI-959 on gastric acid secretion, arachidonic acid metabolism, and intracellular sulfhydryl and leukocyte adhesion were also examined. RESULTS: CI-959 protected prophylactically against the erosive damage induced by aspirin, indomethacin, and ethanol with 50% effective doses (ED50s) of 0.05, 1.0, and 0.07 mg/kg administered orally, respectively. When administered after indomethacin or ethanol, CI-959 had no effect on the healing of erosive damage. CI-959 did not alter gastric acid secretion, arachidonic acid metabolism, or intracellular sulfhydryl levels. In vivo, CI-959 blocked leukocyte adhesion in intravital microscopy studies using indomethacin (ED50, < 5 mg/kg orally) or platelet-activating factor (50% inhibiting concentration, approximately 10 mumol/L) as the adhesion stimulus. CONCLUSIONS: The most likely mechanism responsible for the cytoprotective effects of CI-595 is its inhibitory effects on leukocyte trafficking and/or adhesion.

The vascular-interstitial pH gradient during and after hemorrhagic shock.

The interstitial fluid space (IFS) response to hemorrhagic shock (HS)-induced metabolic acidosis is reported. Prenodal skin lymph was used as a mirror of IFS changes. Twenty-three conditioned dogs had a reservoir HS insult followed by resuscitation with shed blood, crystalloid solution containing a total of 6.5 milliequivalents of sodium per kilogram of body weight and 250 milliliters of autologous banked blood. Prenodal skin lymph pH, oxygen tension (pO2), carbon dioxide tension (pCO2), bicarbonate level (HCO3) and flow rate measured before shock, during HS and in postresuscitation in 17 dogs in group 1 were compared with simultaneous samples of central venous blood. Peripheral venous values were not measured in dogs in group 1 to preclude any effects that local dissection might have on prenodal skin lymph. Six dogs in group 2 underwent the same HS and resuscitation model; the sequential changes in central mixed venous pH and lymphatic pH were compared with peripheral venous pH. HS caused metabolic acidosis; in group 1, the mixed venous pH decreased to 7.16 and in group 2, the peripheral venous pH decreased to 7.03. In contrast, the prenodal skin lymph pH in both groups was maintained at PS levels (7.51). Mixed venous pO2 decreased sharply with HS, whereas skin lymph pO2 was maintained. Maintained prenodal skin lymph pH and pO2 during HS-induced metabolic acidosis implies that the IFS undergoes stoichiometric changes. This facilitates the preferential adherence of highly charged proteins, like albumin, to the matrix to maintain cellular homeostasis.

Triiodothyronine (T3) improves cardiovascular function during hemorrhagic shock.

Prior work showed that an intact thyroid axis augments survival from hemorrhagic shock (HS); this study assesses the effects of specific thyroid-related hormones on cardiovascular (CV) function during HS. Following thyroidectomy, 32 conditioned male dogs were subjected to HS to a mean arterial pressure (MAP) of 60 mm Hg for 90 min then to 40 mm Hg for 30 min. Postshock (PS), the dogs received thyroid-releasing hormone (TRH; 2 mg/kg), thyroid-stimulating hormone [control (TSH; 10 IU)], T3 (12 micrograms/kg), or T4 (40 micrograms/kg). Thirty minutes following treatment (PTX), they were resuscitated with shed blood and 50 ml/kg saline. CV and hormonal parameters were measured PS, PTX, postresuscitation (PR), and on day 2 (D2). There were no PS differences in CV parameters between groups. Following treatment, T3 significantly increased MAP (59.0 +/- 13 vs, 39.9 +/- 2.2 mm Hg) and cardiac output (CO; 0.92 +/- 0.1 vs. 0.80 +/- 0.1 liter/min; P < 0.05 by ANOVA). TRH treatment significantly improved PTX MAP (62.7 +/- 10 vs. 40.8 +/- 2.1; P < 0.05 by ANOVA). TSH and T4 did not significantly change PTX MAP or CO. There were no significant CV differences in the four groups following resuscitation or on D2. In conclusion, T3 improves MAP and CO during hemorrhagic shock. TRH transiently improved PTX blood pressure. Further study of the mechanism of this beneficial response afforded by T3 administration is warranted.

Colloid oncotic pressure and body water dynamics in septic and injured patients.

Colloid oncotic pressure (COP) and fluid shifts were studied in 43 septic (SS) patients and 33 injured (HS) patients (ISS = 48.2). During maximal postresuscitation fluid retention, plasma volume (PV/RISA), red cell volume (RBC/51Cr), inulin space (ECF), and COP were measured. Interstitial space (IFS), PV/IFS ratio, and correlation coefficients (r) were calculated. A subgroup of 22 SS patients and 22 HS patients of equal study weight were also compared. Septic patients had greater IFS expansion (17.6 L vs. 11.5 L) than HS patients who, by inference, had more intracellular expansion. Expansion of IFS in SS patients correlated (r = -0.76, p less than 0.02) with reduced plasma COP; this was not seen in HS patients (r = -0.09, p less than 0.35). In contrast, plasma COP correlated (r = 0.72, p less than 0.001) with PV/RISA in HS patients but not in SS patients (r = 0.09, p greater than 0.35). We conclude: (1) SS patients with greater IFS expansion that correlates with reduced plasma COP likely have increased capillary permeability; and (2) HS patients with less IFS expansion that does not correlate with reduced plasma COP likely have maintained capillary permeability with altered IFS matrix configuration causing reduced protein exclusion.

Effect of hemostatic agents in canine gastric serosal blood vessels.

The efficacy of various sclerotherapeutic agents in the control of acute bleeding, via subserosal injection, was assessed in 10 dogs. Blood flow rate (BFR) from severed gastric serosal vessels (diameter, 1.6 to 2.2 mm) was measured for 3 min (ml/min) for a control group and the agent used. The agents tested were 5 ml of normal saline (NS), 5 ml of 3% hypertonic saline (HS), 5 ml of 1:10,000 epinephrine in NS, 5 ml of 1:10,000 epinephrine/HS, 5 ml of 1:20,000 epinephrine/HS, 2 ml of old thrombin "cocktail" (thrombin, cephapirin + 1% tetradecyl), and 2 ml of fresh thrombin cocktail (total seven). One agent was tested per dog; there were one to two dogs in each subgroup. All of the agents showed significant reduction in BFR (except old thrombin) when compared with BFR of control vessels. The reduction ranged from 30% to more than 75% after 1:10 epinephrine/HS. Complete hemostasis was achieved in up to 47% of vessels using 1:20 epinephrine/HS. Overall, the epinephrine solutions achieved the best results. No systemic effects were observed with the use of any of the agents. Histological studies showed that epinephrine caused mild tissue damage, whereas the cocktail caused significant tissue necrosis. This serosal vessel model permits comparison of the effectiveness of each agent; however, clinical extrapolation to mucosal vessels in a patient and the long-term histological changes are not known.

The effects of chemotherapy on murine wound healing and orocutaneous fistula closure.

The effects of cisplatin and 5-fluorouracil on wound breaking strength and the rate of closure of an orocutaneous fistula were studied in 80 male rodents. Treatment rats received a total of 4.6 mg/kg cisplatin and 62 mg/kg 5-fluorouracil in six doses/12 days; control rats received 0.9 per cent saline. After treatment, 30 treatment and 30 control rats received a dorsal skin incision which was closed primarily. Wound breaking strength were tested at one, three and five weeks in ten rats from each group. An 8-mm orocutaneous fistula was made in the remaining ten treatment and ten control rats; the rate of closure was noted weekly. Cisplatin and 5-fluorouracil did not significantly impair wound breaking strength at one, three, or five weeks. The rate of closure of the orocutaneous fistula was not effected by cisplatin/5-fluorouracil. The chemotherapy caused severe facial cellulitis and death in four orocutaneous fistula rats. Combined chemotherapy with cisplatin and 5-fluorouracil should not interfere with planned surgical care of head and neck tumors. Concomitant antibiotic coverage, however, is advocated.

Efficacy of liver wound healing by secondary intent.

Nonoperative treatment of liver injury raises questions about liver wound healing (LWH) when the edges are not approximated by primary intent. The efficacy of LWH was studied in 18 dogs and 18 pigs with a total of 108 standard 6-cm injuries. The 36 injuries in six dogs and six pigs were compressed for hemostasis and then allowed to heal by second intent. LWH in these animals was compared to 36 liver wounds in six dogs and six pigs following primary closure (hepatorrhaphy) and 36 liver wounds after omental buttress plus hepatorrhaphy in six dogs and six pigs. Average wound breaking strength (WBS) of liver wounds was studied at 3 weeks (54 wounds) and 6 weeks (54 wounds) with a Chatillon tensiometer and microscopic analysis. The WBS of liver wounds was also compared to normal uninjured liver WBS. The porcine WBS at 3 weeks after healing by second intent (0.31 kg/cm2) was similar to the WBS at 3 weeks after healing by hepatorrhaphy (0.30 kg/cm2) and omental buttress (0.25 kg/cm2). Porcine WBS at 6 weeks after healing by second intent was significantly greater than WBS at 6 weeks after hepatorrhaphy or omental buttress. The canine WBS at 3 weeks after healing by second intent exceeded WBS at 3 weeks after hepatorrhaphy or omental buttress. Canine WBS at 6 weeks after healing by second intent exceeded WBS at 6 weeks after omental buttress and was similar to WBS at 6 weeks after hepatorrhaphy. WBS in all groups paralleled the extent of fibrosis seen on microscopic analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of Hespan on serum and lymphatic albumin, globulin, and coagulant protein.

The effects of hydroxyethyl starch (Hespan) resuscitation on serum and lymphatic proteins following hemorrhagic shock were studied in 34 splenectomized dogs. Following shock, five randomly assigned treatment groups received the shed blood plus 50 mL/kg of salt solution (RL) or RL with varying concentrations (0.22-1.5 gm/kg) of Hespan. Each dog received 50 ml/kg/d of the test solution for three days after shock. Prothrombin time, partial thromboplastin time, thrombin time, total serum protein, albumin, globulin, and coagulant protein activity of fibrinogen, prothrombin, and factor VIII were measured before shock, at the end of shock, following resuscitation, and on day 3; thoracic duct lymph values were obtained on day 3. Hespan-supplemented resuscitation lowered all serum proteins including albumin, globulin and coagulant proteins; concomitantly, the lymph protein rose after Hespan resuscitation. This decrease in serum proteins and rise in lymph proteins parallels similar results after albumin resuscitation in man and animals and suggests that Hespan induces an oncotically controlled extravascular protein relocation. Further studies on the significance of these findings need to be conducted.

[Diagnostic chorionic biopsies in the first trimester. Report of experiences over a 2 year period]. / Diagnostische Chorionbiopsien im ersten Trimester. Erfahrungsbericht aus einem Zweijahreszeitraum.

We report about 58 ultrasonographically guided transcervical chorionic villus biopsies from January 1985 to November 1987. Maternal age greater than 35 years (n = 28), followed by trisomy 21 or 18 (n = 10) were the mean indications. Biochemically evaluation of storage diseases (n = 6) and genomically DNA-analysis because of phenylketonuria (n = 2) were combined in each case with cytogenetic diagnosis. In the other cases certain indications were the reasons for biopsy. In 52 of 58 cases we were successful in biopsies and diagnoses. In the other 6 biopsy specimen we didn't found chorionic villi. 3 abortions we observed up to day 3 after operation (n = 3) and after 6 weeks (n = 1). Pathological findings were 1 trisomy 16, 1,47,XYY-karyotype and 1 embryo with phenylketonuria. Another reason for termination of pregnancy was male karyotype in a Morbus Duchenne-risk and 1 risk for Rett-syndrome. Meanwhile 30 healthy babies were born.

Relocation of nonalbumin proteins after albumin resuscitation.

Prior work showed that albumin (5% A) resuscitation lowered serum globulins and coagulation protein activity levels compared to balanced electrolyte solution (BES) resuscitation. In this experiment, the effect of 1.25% A in BES (A-BES) on serum and lymphatic levels of nonalbumin proteins was studied in 20 splenectomized dogs subjected to reservoir shock and then treated with (a) BES or A-BES, (b) shed blood, and (c) autogenous bank blood. Serum levels of albumin, globulin, and coagulation protein activity were measured preshock, postshock, and daily for 3 days; skin lymph levels were measured on Day 3. Compared to BES, A-BES resuscitation significantly decreased serum globulins and coagulation protein activity of fibrinogen, Factor VIII, and antithrombin III. In contrast, skin lymph globulins and coagulation protein activity levels increased significantly with A-BES compared to BES resuscitation. These data suggest that the serum protein changes seen with albumin-supplemented resuscitation result from extravascular relocation of nonalbumin proteins, possibly, due to an oncotic homeostatic factor.