Karin S. Kapp

Quality of life and sexual functioning after cervical cancer treatment: a long-term follow-up study.

Objective: The purpose of the study was to investigate the long‐term treatment side effects on the quality of life (QoL) and sexual functioning of cervical cancer survivors undergoing different treatment regimens.

Dosimetry of intracavitary placements for uterine and cervical carcinoma: results of orthogonal film, TLD, and CT-assisted techniques

A total of 720 192Ir high-dose-rate (HDR) applications in 331 patients with gynecological tumors were analyzed to evaluate the dose to normal tissues from brachytherapy. Based on the calculations of bladder base, bladder neck, and rectal doses derived from orthogonal films the planned tumor dose or fractionation was altered in 20.4% of intracavitary placements (ICP) for cervix carcinoma and 9.2% of ICP for treatment of the vaginal vault. In 13.8% of intracervical and 8.1% of intravaginal treatments calculated doses to both the bladder and rectum were greater than or equal to 140% of the initially planned dose fraction. Doses at the bladder base were significantly higher than at the bladder neck (p less than 0.001). In 17.5% of ICP the dose to the bladder base was at least twice as high as to the bladder neck. The ratio of bladder base dose to the bladder neck was 1.5 (+/- 1.19 SD) for intracervical and 1.46 (+/- 1.14 SD) for intravaginal applications. The comparison of calculated doses from orthogonal films with in-vivo readings showed a good correlation of rectal doses with a correlation coefficient factor of 0.9556. CT-assisted dosimetry, however, revealed that the maximum doses to bladder and rectum were generally higher than those obtained from films with ratios of 1-1.7 (average: 1.44) for the bladder neck, 1-5.4 (average: 2.42) for the bladder base, and 1.1-2.7 (average: 1.37) for the rectum. When doses to the specified reference points of bladder neck and rectum from orthogonal film dosimetry were compared with the corresponding points on CT scans, similar values were obtained for both methods with a maximum deviation of +/- 10%. Despite the determination of multiple reference points our study revealed that this information was inadequate to predict doses to the entire rectum and bladder. If conventional methods are used for dosimetry it is recommended that doses to the bladder base should be routinely calculated, since single point measurements at the bladder neck seriously underestimate the dose to the bladder. Also the rectal dose should be determined at several points over the length of the implant due to the wide range of anatomic variations possible.

The elevated preoperative platelet-to-lymphocyte ratio predicts poor prognosis in breast cancer patients

Background:The elevation of the platelet-to-lymphocyte ratio (PLR), an easily applicable blood test based on platelet and lymphocyte counts has been associated with poor prognosis in patients with different types of cancer. The present study was aimed to investigate the prognostic significance of the preoperative PLR in a large cohort of breast cancer patients.Methods:Data from 793 consecutive non-metastatic breast cancer patients, treated between 1999 and 2004, were evaluated retrospectively. The optimal cutoff values for the PLR were calculated using receiver operating curve analysis. Cancer-specific survival (CSS), overall survival (OS) as well as distant metastasis-free survival (DMFS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of PLR, multivariable Cox regression models were applied for all three different end points.Results:Univariable analysis revealed a significant association between the elevated preoperative PLR and CSS (hazard ratio (HR): 2.75, 95% confidence interval (CI): 1.57–4.83, P<0.001) that remained statistically significant in multivariable analysis (HR: 2.03, 95% CI: 1.03–4.02, P=0.042). An increased PLR was also significantly associated with decreased OS in univariable (HR: 2.45, 95% CI: 1.43–4.20, P=0.001) and in multivariable analysis (HR: 1.92, 95% CI: 1.01–3.67, P=0.047). Furthermore, univariable analysis showed a significant impact of increased PLR on DMFS (HR: 2.02, 95% CI: 1.18–3.44, P=0.010). Subgroup analysis revealed significant associations of the elevated PLR on the primary end point CSS for all breast cancer subtypes. This association retained its significance in multivariable analysis in patients with luminal B tumours (HR: 2.538, 95% CI: 1.043–6.177, P=0.040).Conclusions:In this study, we identified the preoperative PLR as an independent prognostic marker for survival in breast cancer patients. Independent validation of our findings is needed.

Prognostic factors in patients with carcinoma of the uterine cervix treated with external beam irradiation and IR-192 high-dose-rate brachytherapy

PURPOSE Prognostic factors in cancer of the cervix for patients treated with external beam irradiation (EBR) and low-dose-rate (LDR) brachytherapy have been characterized. However, despite the increasing use of high-dose-rate (HDR) intracavitary placements (ICP), few studies with adequate follow-up have analyzed prognostic factors. This study investigates pretreatment and treatment factors for their correlation with treatment outcome after EBR and HDR-ICP. METHODS AND MATERIALS Between September 1985 and December 1994, 181 patients with carcinoma of the cervix FIGO stages IB-IV received EBR and HDR brachytherapy. Hemoglobin (Hb) levels were maintained above a level of 11 g/dl during the treatment by transfusion. Patient age ranged from 34 to 84 years (median: 66). The median follow-up time for patients at risk is 69 months (range: 23-140). Pretreatment and treatment parameters analyzed to determine their prognostic value included age, FIGO stage, tumor size, tumor type and grade, pretreatment Hb level, number of HDR-ICP, total dose from HDR-ICP, overall dose to point A, and overall treatment time. Also evaluated was the prognostic value of enlarged lymph nodes noted on pretreatment CAT scan of the abdomen and pelvis. Endpoints studied in uni- and multivariate analyses were disease-specific survival (DSS), freedom from disease (FFD), pelvic control (PC), and probability of distant metastases (DM). RESULTS At 5 years the DSS, FFD, and PC rates for all patients were 60%, 58%, and 67%, respectively. The 5-year FFD by stage was: IB: 94%; II: 63%; IIIB: 43%; and IV: 0%. The PC rates were 94%, 66%, 59%, and 0%, respectively. In univariate analysis the prognostic factors identified for FFD were FIGO stage, tumor size, initial Hb level, and enlarged pelvic and/or paraaortic nodes (all: p < 0.0001). Age was inversely correlated with outcome (p = 0.0081). The 5-year FFD rates for tumors (< 3, > or = 3 < 6, > or = 6 cm) were 97%, 65%, and 24%; patients with initial Hb levels < or = 11g/dl had a FFD of 26% versus 69% for patients with levels > 11g/dl; and those with pelvic and/or paraaortal nodes > or = 1 cm had a survival of 32% versus 68% in patients with negative readings. The same factors were also prognostically significant for DSS, PC, and DM. Patients with persistent disease or pelvic failures had a significantly higher incidence of DM than patients in whom pelvic disease was controlled (p < 0.0001).Histological and treatment parameters including overall treatment time were not of prognostic significance for any of the endpoints studied. In multivariate analysis tumor size was the most powerful parameter for DSS, FFD, PC (p < 0.0001) and DM (p = 0.0001), followed by low initial Hb level (DSS: p = 0.0004, FFD: p = 0.0009, PC: p = 0.0012, DM: p = 0.0265), and enlarged pelvic and/or paraaortic nodes which were predictive for DSS (p = 0.0210) and DM (p = 0.0011). CONCLUSION This study confirms that prognostic factors for patients treated with HDR brachytherapy are similar to those reported in previous series that employed LDR brachytherapy. The significance of tumor size, pretreatment Hb level, and enlarged pelvic and/or paraaortic lymph nodes on CAT scan over FIGO stage of disease were demonstrated. Future prospective trials should be undertaken to confirm the validity of these factors and to elucidate their therapeutic implications.

Carcinoma of the cervix: analysis of complications after primary external beam radiation and Ir-192 HDR brachytherapy.

BACKGROUND AND PURPOSE There is still a concern that the use of HDR brachytherapy might result in an increase of late tissue damage. This restrospective study evaluates the incidence and severity of late complications in patients with carcinoma of the cervix who underwent combined external beam radiation (EBR) and Ir-192 HDR brachytherapy and attempts to identify pretreatment and treatment parameters correlating with late complications. MATERIAL AND METHODS Between 1985 and 1992, 161 patients with carcinoma of the cervix (FIGO stages IB-IVB) received EBR to the pelvis (ave, max. dose 48.8 Gy) followed by 1-6 Ir-192 HDR placements (median 2). Doses to point A ranged from 8.5 to 38.7 Gy (median 17 Gy). Parameters examined included age, diabetes, obesity, history of inflammatory bowel disease or diverticulitis, prior surgery, hemoglobin level, FIGO stage, EBR dose, technique and daily dose fraction, number of HDR treatments and total dose to point A, maximum doses to bladder and rectum delivered by brachytherapy and cumulative dose to point A. Median follow-up for all patients was 37 months. Complications were rated using an in-house scoring system and according to the French-Italian Glossary (FIG). RESULTS Actuarial 5-year survival was 93%, 57%, 46%, and 0% for stages IB, II, IIIB, and IV, respectively. Of 161 patients, 11% developed moderate and 3.7% severe sequelae (FIG: 2.5%, 3.7%). Since some patients experienced more than one complication, the overall incidence was 13.6% and 4.9% (FIG: 3.1%, 4.9%) with respective 5-year actuarial rates of 14% and 5% for moderate, and 2% and 8% for severe bowel and genitourinary tract complications (FIG: 3.5%, 0, and 2%, 8%). All severe bowel complications occurred within 1.5 years whereas urinary tract sequelae continued to develop throughout the follow-up period. FIGO stage was associated with a significant increase in late sequelae (P = 0.015). Analysis of the remaining pretreatment and treatment parameters failed to reveal any statistically significant correlation with moderate or severe sequelae. CONCLUSION In our series using HDR brachytherapy, complication and survival rates were comparable with other series employing either LDR or HDR procedures. Of all parameters analysed, stage of disease was the only parameter significantly correlated with complications in univariate and multivariate analysis.

Evaluation of the effect of routine packed red blood cell transfusion in anemic cervix cancer patients treated with radical radiotherapy

PURPOSE It is well established that anemia predicts diminished radiocurability in cervix cancer. However, the therapeutic benefit of measures to correct the anemia remains controversial. The objective of this study was to determine the impact of routine transfusion in patients with hemoglobin level (hb-l) < or =11 g/dl. METHODS AND MATERIALS Since 1985, it has been departmental policy to attempt to correct hb-l < or =11 g/dl before and/or during radiotherapy by red blood cell transfusion (RBCT) in patients undergoing radical radiotherapy for primary cervix cancer. To assess the benefit of RBCT, the charts of 204 patients (FIGO: IB-IV) treated until 1997 were reviewed. Parameters analyzed for their impact on disease-specific survival (DSS), pelvic control (PC), and metastases-free survival (MFS) included pretreatment hb-l, treatment hb-l, stage, tumor size, and lymph node status. To determine any differences in outcome according to type of anemia, a separate analysis was performed, grouping patients by cause of anemia (tumor vs. other medical illness related). RESULTS Each of the parameters tested was significantly correlated with the end points studied in univariate analysis. Patients whose hb-l were corrected (18.5%) had an outcome that did not differ significantly from that of nontransfused patients, whereas DSS, PC, and MFS (all: p < 0.001) were significantly decreased in nonresponders to RBCT. Subgroup analysis showed no impact of hb-l in patients with other medical illness-related anemia (n = 12). In multivariate analysis treatment, but not pretreatment, hb-l remained predictive for DSS, PC, and MFS. Persistent anemia was associated with a significantly increased risk of death (relative risk: 2.1) and pelvic failure (relative risk: 2.4) compared with nontransfused patients. If only patients with tumor anemia were considered, the respective risks increased (2.7; 3.6). None of the patients with other causes of anemia recurred, whether or not their hb-l was maintained. Assessment of the therapeutic gain in patients who responded to RBCT showed improved PC (p = 0.02) and a trend toward increased DSS (p = 0.06), but no effect on MFS after adjustment for tumor size and lymph node status. CONCLUSION Treatment hb-l, in addition to tumor size and lymph node status, independently predicted outcome. Although our final multivariate analysis showed a therapeutic benefit for patients whose hb-l was corrected, the response to RBCT was disappointing. Results of our subgroup analysis suggest that the cause of anemia in patients with cervical cancer warrants in-depth investigation.

Association between single nucleotide polymorphisms in the gene for XRCC1 and radiation-induced late toxicity in prostate cancer patients

BACKGROUND AND PURPOSE Polymorphisms in genes responsible for DNA damage signaling and repair might modulate DNA repair capacity and, therefore, affect cell and tissue response to radiation and influence individual radiosensitivity. The purpose of the present prospective investigation was to evaluate the association of single nucleotide polymorphisms in XRCC1 with radiation-induced late side effects in prostate cancer patients treated with radiotherapy. MATERIAL AND METHODS To analyze the role of XRCC1 polymorphisms for late toxicity 603 participants from the Austrian PROCAGENE study treated with three-dimensional conformal radiotherapy were included in the present investigation. Three non-synonymous candidate polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene (Arg194Trp; Arg280His; Arg399Gln) were selected and determined by 5´-nuclease (TaqMan) assays. RESULTS Within a median follow-up time of 35 months, 91 patients (15.7%) developed high-grade late toxicities (defined as late bladder and/or rectal toxicity RTOG≥2). In a Kaplan-Meier analysis, carriers of the XRCC1 Arg280His polymorphism were at decreased risk of high-grade late toxicity (p=0.022), in multivariate analysis including clinical and dosimetric parameters as potential confounders the XRCC1 Arg280His polymorphism remained a significant predictor for high-grade late toxicity (HR=0.221, 95% CI 0.051-0.956; p=0.043). No significant associations were found for the remaining polymorphisms. CONCLUSIONS We conclude that the XRCC1 Arg280His polymorphism may be protective against the development of high-grade late toxicity after radiotherapy in prostate cancer patients.

Long-term follow-up of patients with pituitary macroadenomas after postoperative radiation therapy: analysis of tumor control and functional outcome.

Purpose:Evaluation of long-term tumor control, normalization of hormonal hypersecretion, including incidence and time course of pituitary dysfunction following postoperative radiotherapy of pituitary macroadenomas.Patients and Methods:In a retrospective study, the data of 87 patients with pituitary macroadenomas (61 non-secreting adenomas, 26 secreting adenomas) treated between 1984 and 1994 were analyzed. All patients underwent surgery and received postoperative external-beam radiotherapy with a mean dose of 50.4 Gy (range 46–54 Gy).Results:After a follow-up of 15 years the local tumor control rate achieved was 93.0% for non-secreting adenomas and 100% for secreting adenomas, respectively. Normalization of endocrine hypersecretion was noted in 24 of 26 patients (92%). Detailed endocrinological follow-up data were analyzed by an experienced endocrinologist in 77 patients. After a median follow-up of 10.54 years (mean 10.22; range 1.39–20.75 years), in 75 of 77 patients (97%) a hypopituitarism was observed (partial hypopituitarism, n = 28 [36%], panhypopituitarism, n = 47 [61%]), and 68 out of 77 patients (88%) showed evidence of radiotherapy-induced pituitary disorders. The somatotropic function was most commonly affected, followed by gonadal, thyroid and adrenal function. The gonadal axis showed to be the first to be disturbed. 67 patients (87%) required a hormone replacement therapy.Conclusion:Radiotherapy after pituitary surgery is highly effective in reducing hormonal hypersecretion and preventing recurrences of pituitary adenomas. However, pituitary insufficiencies are commonly observed after radiotherapy requiring a close follow-up to ensure timely diagnosis of pituitary dysfunction and an early inception of hormone replacement therapy.Ziel:Ziel der retrospektiven Analyse war die Evaluation der lokalen Tumorkontrolle sowie der hormonellen Normalisierung nach konventioneller postoperativer Strahlentherapie in der Langzeitbeobachtung. Zusätzlich wurden die Inzidenz und der zeitliche Verlauf von Hypophyseninsuffizienzen untersucht.Patienten und Methodik:Zwischen April 1984 and November 1994 wurden 87 Patienten mit Makroadenomen der Hypophyse (nicht-sezernierende Adenome: n = 61, sezernierende Adenome: n = 26) einer postoperativen Strahlentherapie unterzogen. Die Bestrahlung erfolgte mit einer medianen Dosis von 50,4 Gy (Spannweite 46–54 Gy).Ergebnisse:Nach 15 Jahren betrug die lokale Kontrolle bei nicht-sezernierenden Adenomen 93% und bei sezernierenden Adenomen 100%. Eine Normalisierung der hormonellen Hypersekretion konnte bei 24 von 26 Patienten (92%) erreicht werden. Detaillierte Informationen über die hypophysäre Funktion lagen bei 77 Patienten vor. Nach median 10,54 Jahren wurde bei 75 von 77 Patienten (97%) eine Funktionsstörung des Hypophysenvorderlappens diagnostiziert (partieller Hypopituitarismus: n = 28 [36%], Panhypopituitarismus: n = 47 [61%]). Bei 68 von 77 Patienten (88%) zeigte sich eine radiotherapiebedingte Störung hormoneller Funktionen. Die somatotrope Achse war am häufigsten betroffen, gefolgt von der gonadotropen, der thyreotropen und der adrenokortikotropen Achse. In der Analyse des zeitlichen Verlaufs zeigte die gonadotrope Achse als Erste eine funktionelle Störung. 67 Patienten (87%) entwickelten eine substitutionspflichtige Hypophysenvorderlappeninsuffizienz.Schlussfolgerung:Mit der konventionellen postoperativen Strahlentherapie konnte eine ausgezeichnete lokale Kontrolle in der Langzeitbeobachtung erreicht werden. Die Rate an Hypophyseninsuffizienzen erfordert jedoch in einem hohen Prozentsatz eine Hormonersatztherapie und macht lebenslange endokrinologische Kontrollen notwendig.

Wide Tangential Fields Including the Internal Mammary Lymph Nodes in Patients with Left-Sided Breast Cancer

Purpose:To evaluate the impact of wide-tangent fields including the internal mammary chain during deep inspiration breath-hold (DIBH) radiotherapy in patients with left-sided breast cancer on cardiac exposure.Patients and Methods:Eleven patients with left-sided breast cancer were irradiated postoperatively and underwent CT scans during free breathing and DIBH. For scientific interest only, treatment plans were calculated consisting of wide tangents including the ipsilateral mammary lymph nodes using both, the free breathing and respiratory-controlled CT scan. The resulting dose-volume histograms were compared for irradiated volumes and doses to organs at risk.Results:The mean patient age was 51 years (range: 37–65 years). Radiotherapy using wide tangents with DIBH as compared to free breathing led to a significantly lower cardiac exposure. Mean irradiated heart volumes (≥ 20 Gy) were 14 cm3 (range: 0–51.3 cm3) versus 35 cm3 (range: 2.1–78.7 cm3; p = 0.01). For eight patients, DIBH reduced irradiated relative lung volume, while in three patients, the lung volume slightly increased.Conclusion:Radiation exposure of organs at risk can significantly be reduced for breast cancer patients using the DIBH technique. If radiotherapy of the internal mammary lymph nodes is considered necessary, DIBH may be the preferable technique.Ziel:Untersuchung des Stellenwerts einer atemgesteuerten (DIBH) Strahlenbehandlung bei Verwendung flacher tangentialer Felder und Einschluss der Lymphknoten entlang der A. mammaria interna bei Patientinnen mit linksseitigem Mammakarzinom im Hinblick auf die Herzbelastung.Patienten und Methodik:Bei elf Patientinnen mit linksseitigem Mammakarzinom wurde postoperativ eine lokale Strahlenbehandlung durchgeführt. Für diese CT-Studie wurden unter Bedingungen der Normalatmung und in tiefer Inspiration (Abbildung 1) ein Planungs-CT durchgeführt und jeweils ein optimierter Bestrahlungsplan mit zwei flachen tangentialen Bestrahlungsfeldern unter Berücksichtigung der ipsilateralen Lymphknoten entlang der A. mammaria interna erstellt. Die Dosis-Volumen-Histogramme für die Risikoorgane wurden zwischen beiden Atmungstechniken verglichen.Ergebnisse:Der Mittelwert des Alters lag bei 51 Jahren (Range: 37–65 Jahre). Die Bestrahlung mit flachen Tangenten und DIBH erbrachte im Vergleich zur Normalatmung eine signifikant geringere Herzbelastung. Die mittlere Herzbelastung (≥ 20 Gy) ergab 14 cm3 (Range: 0–51,3 cm3) im Vergleich zu 35 cm3 (Range: 2,1–78,7 cm3; p = 0,01; Tabelle 1). Bei acht Patientinnen reduzierte die atemgetriggerte Bestrahlung auch das bestrahlte Lungenvolumen (%), wobei es bei drei Patientinnen geringfügig anstieg (Tabelle 2).Schlussfolgerung:Die atemgetriggerte Bestrahlung in tiefer Inspiration reduziert signifikant die Strahlenbelastung an Risikoorganen. Bei Indikation des Einschlusses der Lymphknoten entlang der A. mammaria interna kann die Bestrahlung in DIBH von Vorteil sein.

Long-Term Follow-up of Patients with Pituitary Macroadenomas after Postoperative Radiation Therapy

Purpose:Evaluation of long-term tumor control, normalization of hormonal hypersecretion, including incidence and time course of pituitary dysfunction following postoperative radiotherapy of pituitary macroadenomas.Patients and Methods:In a retrospective study, the data of 87 patients with pituitary macroadenomas (61 non-secreting adenomas, 26 secreting adenomas) treated between 1984 and 1994 were analyzed. All patients underwent surgery and received postoperative external-beam radiotherapy with a mean dose of 50.4 Gy (range 46–54 Gy).Results:After a follow-up of 15 years the local tumor control rate achieved was 93.0% for non-secreting adenomas and 100% for secreting adenomas, respectively. Normalization of endocrine hypersecretion was noted in 24 of 26 patients (92%). Detailed endocrinological follow-up data were analyzed by an experienced endocrinologist in 77 patients. After a median follow-up of 10.54 years (mean 10.22; range 1.39–20.75 years), in 75 of 77 patients (97%) a hypopituitarism was observed (partial hypopituitarism, n = 28 [36%], panhypopituitarism, n = 47 [61%]), and 68 out of 77 patients (88%) showed evidence of radiotherapy-induced pituitary disorders. The somatotropic function was most commonly affected, followed by gonadal, thyroid and adrenal function. The gonadal axis showed to be the first to be disturbed. 67 patients (87%) required a hormone replacement therapy.Conclusion:Radiotherapy after pituitary surgery is highly effective in reducing hormonal hypersecretion and preventing recurrences of pituitary adenomas. However, pituitary insufficiencies are commonly observed after radiotherapy requiring a close follow-up to ensure timely diagnosis of pituitary dysfunction and an early inception of hormone replacement therapy.Ziel:Ziel der retrospektiven Analyse war die Evaluation der lokalen Tumorkontrolle sowie der hormonellen Normalisierung nach konventioneller postoperativer Strahlentherapie in der Langzeitbeobachtung. Zusätzlich wurden die Inzidenz und der zeitliche Verlauf von Hypophyseninsuffizienzen untersucht.Patienten und Methodik:Zwischen April 1984 and November 1994 wurden 87 Patienten mit Makroadenomen der Hypophyse (nicht-sezernierende Adenome: n = 61, sezernierende Adenome: n = 26) einer postoperativen Strahlentherapie unterzogen. Die Bestrahlung erfolgte mit einer medianen Dosis von 50,4 Gy (Spannweite 46–54 Gy).Ergebnisse:Nach 15 Jahren betrug die lokale Kontrolle bei nicht-sezernierenden Adenomen 93% und bei sezernierenden Adenomen 100%. Eine Normalisierung der hormonellen Hypersekretion konnte bei 24 von 26 Patienten (92%) erreicht werden. Detaillierte Informationen über die hypophysäre Funktion lagen bei 77 Patienten vor. Nach median 10,54 Jahren wurde bei 75 von 77 Patienten (97%) eine Funktionsstörung des Hypophysenvorderlappens diagnostiziert (partieller Hypopituitarismus: n = 28 [36%], Panhypopituitarismus: n = 47 [61%]). Bei 68 von 77 Patienten (88%) zeigte sich eine radiotherapiebedingte Störung hormoneller Funktionen. Die somatotrope Achse war am häufigsten betroffen, gefolgt von der gonadotropen, der thyreotropen und der adrenokortikotropen Achse. In der Analyse des zeitlichen Verlaufs zeigte die gonadotrope Achse als Erste eine funktionelle Störung. 67 Patienten (87%) entwickelten eine substitutionspflichtige Hypophysenvorderlappeninsuffizienz.Schlussfolgerung:Mit der konventionellen postoperativen Strahlentherapie konnte eine ausgezeichnete lokale Kontrolle in der Langzeitbeobachtung erreicht werden. Die Rate an Hypophyseninsuffizienzen erfordert jedoch in einem hohen Prozentsatz eine Hormonersatztherapie und macht lebenslange endokrinologische Kontrollen notwendig.