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.

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.

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.

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.

Role of Roux-en-Y feeding jejunostomy for patients with acute head injury.

The total care of a patient with severe head injury is challenging and may extend for weeks, months, or even years. A major challenge of this care includes nutritional support: swallowing is impaired, aspiration accompanies gastric tube feeding, parenteral nutrition is limited to short term in hospital care, and needle jejunostomy or transabdominal jejunostomy are prone to inadvertent removal. The role of Roux-en-Y feeding jejunostomy was evaluated in 13 patients with acute head injury. Procedure related complications include prolapse of the ostomy (1 patient) and stoma-ischemia requiring revision (1 patient). The effect of ostomy tube feedings on gastric acid secretions was studied in five patients, and no significant change was noted when saline feeding was compared to blenderized diet feeding. Blenderized diet feedings were advanced gradually, and antidiarrheals were added as needed once gastrointestinal function returned. In conclusion, Roux-en-Y feeding jejunostomy provides an attractive, safe method for long-term enteral nutrition in the head injury patient. Easy replacement of the feeding tube facilitates nursing care, and the threat of acid-induced stress gastric bleeding is not enhanced.

The effect of steroids for shock on the immune response to tetanus toxoid.

The effect of corticosteroids on the immune response after severe injury and hemorrhagic shock was studied in 88 patients, who received an average of 13 blood transfusions for injury and hemorrhagic shock, which caused the systolic blood pressure to be below 80 torr for an average of 29 minutes. The immune response to tetanus toxoid was tested in the postoperative period. Besides the administration of blood, crystalloid solution, and plasma for coagulation factor deficiency, 42 patients also received methyl-prednisolone 1 g during additional resuscitation followed by an average of 15 mg/kg given daily for the next 2 days. The total dose of methylprednisolone averaged 3.9 g. The two groups of patients were similar for resuscitation needs and for insult. The immune response to tetanus toxoid was not significantly different between the two groups of patients. These data show that a short-term bolus of massive steroids does not appear to alter, significantly, the immune mechanism following severe hemorrhagic shock.

Calcium homeostasis after parathyroidectomy in normal and shocked states.

The natural history of parathyroidectomy was studied for 75 weeks in two dogs. After parathyroidectomy, the dogs required intravenous and intramuscular calcium supplementation for 1 week. Despite calcium supplementation, in 2 weeks the ionized calcium (Ca++) level fell from 4.67 mg/dl to 2.39 mg/dl. The Ca++ level rose to 4.25 mg/dl by 7 weeks after which the intramuscular calcium supplement was gradually weaned so that no calcium was given after 20 weeks. The Ca++ level stabilized at 3.15 to 3.25 mg/dl after 20 weeks. Postoperative parathormone (PTH) levels remained low. The response to hemorrhagic shock in these two calcium-independent dogs was compared with that seen in two calcium-dependent dogs 4 weeks after parathyroidectomy and to that seen in two euparathyroid dogs. Shock caused a sharp decrease in Ca++ in all animals that had parathyroid ectomy. Prostaglandin E2 (PGE2) was elevated preoperatively in these dogs and fell markedly during shock. Ca++ remained normal and PGE2 increased slightly after shock in the euparathyroid dogs. Cardiac output rose with resuscitation in the euparathyroid dogs but remained constant in the calcium-dependent dogs and increased slightly in the calcium independent parathyroidectomized animals. PTH levels were low in the parathyroidectomy groups and did not react to shock. PTH increased markedly after resuscitation in the euparathyroid dogs, suggesting its role as an acute-phase hormone. All levels returned to baseline levels within 3 days after shock. Adaptation to hypocalcemia occurs in parathyroidectomized dogs and involves PGE2 as well as other factors. Hemorrhagic shock exceeds this compensatory response which in euparathyroid dogs involves active PTH release in response to hypocalcemia.

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.

[Effect of maternal constitutional factors and weight increase in pregnancy on the neonatal measurements of weight and length]. / Uber den Einfluss mütterlicher konstitutioneller Faktoren und der Gewichtszunahme während der Schwangerschaft auf die Neugeborenenmasse Gewicht und Länge.

The significance of maternal constitutional factors and of maternal body weight increase during pregnancy for the condition of the newborn was investigated in 9,578 pregnancies. Statistical calculations were made by means of two-dimensional contingency table analyses. The body size of the mother, her relative weight at the beginning of pregnancy and the increase of body weight during pregnancy were correlated positively with the measures of the newborn. The weight of newborn has been mostly influenced by the maternal body size. It seems to be necessary to include the maternal constitution in the clinical valuation of the newborn status. The use of regional correction tables enables a more exact identification of hypotrophic newborns.

[Metastases in the hypophysis]. / Metastasen in der Hyypophyse.

Among 1521 malignant extracranial tumours, 64 metastases (4.2%) were found in the pituitary. The most frequent occurrence was found for carcinomas of the breast (21.4%) and for bronchial malignomas (5.9%). A statistically significant difference with regard to the location in the anterior and the posterior lobe was not found in our own patients. A remarkable fact is the high degree of affection of the pituitary gland in case of malignant melanomas.

[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.

[Methods of chorion sampling for prenatal diagnosis in the 1st trimester of pregnancy. Report of experiences]. / Methoden der Choriongewinnung zur pränatalen Diagnostik im 1. Trimenon der Schwangerschaft. Erfahrungsbericht.

Report on first experiences in chorionic villi sampling in the first trimester of 131 pregnancies. Chorion biopsy was performed just before termination of pregnancy in the 9th-11th week of gestation. Of 3 tested biopsy methods we found the biopsy with a flexible forceps under guidance of real-time ultrasound to be the best.

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.

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.

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.

Studies on the kinetics and distribution of dihydralazine in pregnancy.

Plasma kinetics of dihydralazine (50 mg p.o.) was studied in 11 women in late pregnancy. The distribution pattern between maternal and umbilical plasma was investigated in 12 patients who received 75-100 mg dihydralazine per day. In one patient amniotic fluid concentration and in another breast milk levels could be evaluated twice. Plasma concentrations of dihydralazine were very low. Continuous plasma level curves could be estimated in only four of the examined patients. In every case dihydralazine concentrations were higher in umbilical blood than in maternal plasma. Concentrations found in breast milk were clinically negligible.

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.