Dual energy CT allows for improved characterization of response to antiangiogenic treatment in patients with metastatic renal cell cancer.

OBJECTIVES: To evaluate the potential role of dual energy CT (DECT) to visualize antiangiogenic treatment effects in patients with metastatic renal cell cancer (mRCC) while treated with tyrosine-kinase inhibitors (TKI). METHODS: 26 patients with mRCC underwent baseline and follow-up single-phase abdominal contrast enhanced DECT scans. Scans were performed immediately before and 10 weeks after start of treatment with TKI. Virtual non-enhanced (VNE) and colour coded iodine images were generated. 44 metastases were measured at the two time points. Hounsfield unit (HU) values for VNE and iodine density (ID) as well as iodine content (IC) in mg/ml of tissue were derived. These values were compared to the venous phase DECT density (CTD) of the lesions. Values before and after treatment were compared using a paired Student's t test. RESULTS: Between baseline and follow up, mean CTD and DECT-derived ID both showed a significant reduction (p < 0.005). The relative reduction measured in percent was significantly greater for ID than for CTD (49.8 ± 36,3 % vs. 29.5 ± 20.8 %, p < 0.005). IC was also significantly reduced under antiangiogenic treatment (p < 0.0001). CONCLUSIONS: Dual energy CT-based quantification of iodine content of mRCC metastases allows for significantly more sensitive and reproducible detection of antiangiogenic treatment effects. KEY POINTS: • A sign of tumour response to antiangiogenic treatment is reduced tumour perfusion. • DECT allows visualizing iodine uptake, which serves as a marker for vascularization. • More sensitive detection of antiangiogenic treatment effects in mRCC is possible.

[Rational imaging of metastasized tumor diseases]. / Rationale Bildgebung bei metastasierten Tumorerkrankungen.

Most anticancer medications are effective only in subgroups of patients. Despite considerable improvements in histopathological and molecular pathological diagnostics, tumor response in the individual patient still remains unpredictable. Measuring tumor shrinkage by cross-sectional imaging procedures in patients with metastatic cancer represents the current standard for documenting the effectiveness of anticancer therapy. In addition to the large number of different imaging procedures computed tomography (CT) is certainly the best established and most widely available technique for assessing tumor response. This manuscript reviews the necessity and rationality of imaging procedures for monitoring tumor response in patients with metastatic cancer.

Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib.

BACKGROUND: This phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure. PATIENTS AND METHODS: Patients were randomized 2:1 to nilotinib 400 mg b.i.d. or best supportive care (BSC; BSC without tyrosine kinase inhibitor, BSC+imatinib, or BSC+sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib. RESULTS: Two hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days; P=0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days; P=0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days; P=0.29). Post hoc subset analyses in patients with progression and only one prior regimen each of imatinib and sunitinib revealed a significant difference in median OS of >4 months in favor of nilotinib (405 versus 280 days; P=0.02). Nilotinib was well tolerated. CONCLUSION: In the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS.

Adjuvant therapy in primary GIST: state-of-the-art.

BACKGROUND: The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs. MATERIALS AND METHODS: A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point. RESULTS: Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation. CONCLUSIONS: Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management.

Thermochemotherapy in patients with extremity high-risk soft tissue sarcomas (HR-STS).

PURPOSE: We report data from phase II trials examining the efficacy of multimodality treatment with neoadjuvant chemotherapy, hyperthermia, surgery, radiation and postoperative thermochemotherapy in adult patients with high-risk sarcomas of the extremities. PATIENTS AND METHODS: From 1991 to 2001 47 patients with high risk soft tissue sarcoma of the extremities were prospectively treated in two clinical trials with a treatment plan of four cycles of etoposide, ifosfamide and doxorubicin combined with regional hyperthermia followed by surgery, radiation and adjuvant chemotherapy. RESULTS: Objective response rate assessable in 39 patients was 21% (one complete and seven partial responses). A favourable histological response (>75% tumour necrosis) was observed in 34% of the 35 evaluable patients who had surgical resection. Median overall survival (OS) was 105 months. The five-year probability of local failure-free survival (LFFS), distant disease-free survival (DDFS), event-free survival (EFS) and OS were 48%, 55%, 35% and 57%, respectively. There were no significant differences between responders and non-responders of minimum temperatures (Tmin) and time-averaged temperatures achieved in 50% (T(50)) and 90% (T(90)) at all measured tumour sites. Response to this neoadjuvant regimen predicted for prolonged LFFS (p = 0.0123), but not for OS (p = 0.2). Limb preservation was achieved in 37 patients (79%) and did not result in inferior DDFS (52% versus 50%) or OS (61% versus 50%) at five years (p = 0.8) in comparison to patients who underwent amputation. CONCLUSION: Response to combined modality treatment with RHT and neoadjuvant chemotherapy was predictive for an improved LFFS and led to limb preservation in 79% of patients with extremity sarcomas.

[Combined functional and morphological imaging of sarcomas: significance for diagnostics and therapy monitoring]. / Kombinierte funktionelle und morphologische Bildgebung bei Sarkomen : Stellenwert für Diagnostik und Therapiemonitoring.

(18)F-fluorodeoxyglucose positron-emission tomography (FDG-PET) and especially hybrid FDG-PET/CT is becoming more and more accepted for the clinical management of adult and pediatric patients with sarcomas. By integrating the CT component the specificity in particular but also the sensitivity of the modality are improved further. With PET/CT a complete staging including the detection of lung metastases is feasible in a single examination. For patients with primary bone and soft tissue sarcomas FDG-PET/CT is utilized for diagnosis, staging and restaging, metabolic tumor grading, guidance of biopsies, detection of tumor recurrence and therapy monitoring. Furthermore, it has been demonstrated that FDG uptake of the tumor prior to treatment and changes of FDG uptake after therapy significantly correlate with histopathologic response and survival of patients. Therefore, PET and PET/CT have a prognostic value. In the future new perspectives of hybrid PET/CT imaging will arise by introducing novel radiotracers and combined functional imaging of tumor metabolism and perfusion. High resolution MRI is essential for local evaluation of the primary tumor and preoperative planning with assessment of possible infiltration of vascular or neural structures. Contrast-enhanced MRI remains a key tool in the diagnosis of recurrent disease, especially in tumors which are not hypermetabolic. Dynamic contrast-enhanced MR sequences can significantly contribute to therapy monitoring. More research is necessary to prospectively compare dynamic contrast-enhanced MRI and FDG-PET/CT for evaluation of local and recurrent diseases.

[18F]-FDG-PET in clinical stage I/II non-seminomatous germ cell tumours: results of the German multicentre trial.

PURPOSE: The aim of this study was to determine the predictive values of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) in primary staging in patients with newly diagnosed non-seminomatous germ cell tumour (NSGCT) clinical stage I/II. PATIENTS AND METHODS: The hypothesis was that FDG-PET would improve the negative predictive value (NPV) from 70% to 90%, thus requiring a total of 169 patients. All scans underwent visual analysis by a reference team of nuclear medicine physicians. Results were validated by histology following retroperitoneal lymph node dissection. RESULTS: Only 72 of the planned 169 patients were included, due to poor accrual. The prevalence of nodal involvement was 26%. Correct nodal staging by FDG-PET was achieved in 83% compared with correct computed tomography (CT) staging in 71%. CT had a sensitivity and specificity of 41% and 95%, respectively. Positive predictive value (PPV) and NPV were 87% and 67%, respectively. FDG-PET had a sensitivity and specificity of 66% and 98%, respectively. PPV was 95%. The primary end point was not reached, with an NPV of 78%. CONCLUSION: FDG-PET as a primary staging tool for NSGCT yielded only slightly better results than CT. Both methods had a high specificity while false-negative findings were more frequent with CT. FDG-PET is mostly useful as a diagnostic tool in case of questionable CT scan.

Cardiac markers (BNP, NT-pro-BNP, Troponin I, Troponin T, in female amateur runners before and up until three days after a marathon.

PURPOSE: Transient cardiac ventricular dysfunction or sudden cardiac deaths have been reported for male athletes participating in marathon racing. Less is known about the myocardial response in females. We examined natriuretic peptides and cardiac troponins in female athletes after a marathon. METHODS: At the 31st real,- Berlin Marathon plasma levels of NT-pro-BNP, BNP, cTnI and cTnT were measured in 15 women (age 35+/-6 years; finishing times between 3:22 h and 5:21 h) at four different time points (before, immediately after, day one and day three). RESULTS: An increase in [NT-pro-BNP] was observed immediately after the marathon (median [NT-pro-BNP] before: 39.6 pg ml(-1), after: 138.6 pg ml(-1), p=0.003) with a further increase on day one. [BNP] did not increase immediately after the marathon but increased on day one (median [BNP] before: 15 pg ml(-1), day one: 27.35 pg ml(-1), p=0.006). On day three, [NT-pro-BNP] and [BNP] returned to initial values. [cTnI] was under the detection limit prior to the marathon in all runners. [cTnT] was under the detection limit before the marathon except in one runner who presented a concentration of 0.03 ng ml(-1). Cardiac troponins (median [cTnl] after: 0.098 ng ml(-1), p=0.028; median [cTnT] after: 0.032 ng ml(-1), p=0.012) increased immediately after the marathon and returned to initial values on day one [cTnT] and three [cTnI]. DISCUSSION: Parameters representing cardiac stress increased in females after a marathon. Different kinetics of natriuretic peptides BNP and NT-pro-BNP post-marathon could be due to their different half-lives and dependence on renal function. The increase of cTnI and cTnT may result from minor myocardial lesions.

Water immersion is associated with an increase in aquaporin-2 excretion in healthy volunteers.

Here, we report the alterations in renal water handling in healthy volunteers during a 6 h thermoneutral water immersion at 34 to 36 degrees C. We found that water immersion is associated with a reversible increase in total urinary AQP2 excretion.

Scintigraphic assessment of pulmonary and whole-body blood flow patterns after surgical intervention in congenital heart disease.

UNLABELLED: Glenn shunt and Fontan procedure, the most widely used surgical procedures in congenital heart anomalies, may be associated with abnormal pulmonary blood flow patterns and the development of pulmonary arteriovenous fistulae. METHODS: This study quantified pulmonary and whole-body blood flow using the microsphere technique by sequential injection of 99mTc microspheres into upper and lower limb veins and performing planar lung imaging in four projections and anterior and posterior whole-body scans in 46 patients with either Glenn shunt or Fontan procedure. The right-to-left shunt volume was estimated by a brain and kidneys-to-lungs ratio and compared with calculations from the whole-body scans. RESULTS: In 31 of 46 patients, the blood from the superior vena cava was drained preferentially into the right lung (75%+/-19%). The inferior venous system was drained equally into both lungs. The right-to-left shunt volume was 24%+/-12% after injection into the superior caval system, 50%+/-18% after injection into the inferior caval system. A subgroup of patients who had undergone a palliative Blalock-Taussig shunt (BTS) before the final surgery showed a perfusion pattern that was not known after pulmonary angiography or contrast echocardiography: 15 of 24 patients with BTS had hypoperfusion of the upper lobe on the side of the BTS after injection into the arm vein and corresponding normal perfusion or hyperperfusion when injected into the foot vein. CONCLUSION: Lung perfusion scintigraphy after tracer application into the superior and inferior caval systems detects more abnormal pulmonary blood flow patterns than contrast echocardiography and is the only procedure able to quantify right-to-left shunt volume individually for the superior and inferior caval systems. Thus, this diagnostic technique should be part of the routine follow-up in children after Glenn shunt or Fontan procedure.

Current trials and new aspects in soft tissue sarcoma of adults.

PURPOSE: For high-risk soft tissue sarcoma (HR-STS) of adults new treatment strategies are needed to improve outcome with regard to local control and overall survival. Therefore, systemic chemotherapy has been integrated either after (adjuvant) or before (neoadjuvant) optimal local treatment by surgery and radiotherapy in HR-STS. METHODS AND RESULTS: The Soft Tissue and Bone Sarcoma Group (STBSG) of the European Organization for Research and Treatment of Cancer (EORTC) is conducting an open randomized trial of adjuvant chemotherapy in high-grade primary or recurrent STS at any site (EORTC 62931). In all cases primary surgery should be curative in intent. All eligible patients are randomized after completion of definitive surgery to receive either radiotherapy alone with no further treatment (observation arm) or five cycles of doxorubicin (70 mg/m(2)) plus ifosfamide (5 g/m(2)) using G-CSF to support dose intensity followed by radiotherapy (chemotherapy arm). This more aggressive chemotherapy regimen within an adjuvant setting might retain sufficient antitumor activity to convert response rates into survival benefit. At present more than 220 patients have been recruited for this trial. To explain the rationale for the EORTC 62931 protocol, reported results of other clinical adjuvant protocols including a meta-analysis are given. In close collaboration with the European Society of Hyperthermic Oncology (ESHO) the STBSG has also initiated a randomized trial of neoadjuvant chemotherapy in primary or recurrent HR-STS as an EORTC Intergroup study. According to the inclusion criteria as defined (tumor size >or=5 cm + grade II or III + deep location + extracompartmental extension) for the EORTC 62961/ESHO RHT-95 Intergroup study, the majority of patients with HR-STS recruited for this pre- and postoperative multimodality treatment protocol cannot be cured by standard procedures. All eligible patients are randomized to receive either four cycles of EIA (etoposide 250 mg/m(2) + ifosfamide 6 g/m(2) + doxorubicin 50 mg/m(2)) within 12 weeks (chemotherapy arm) or the same EIA regimen combined with regional hyperthermia (RHT + chemotherapy arm). The patients then receive optimal local treatment using adequate surgery immediately followed by radiotherapy. Thereafter an additional four cycles of EIA chemotherapy are given with or without RHT according to the initial randomization. At present more than 150 patients have been recruited for this trial. The integration of RHT as a new potent treatment modality if combined with EIA chemotherapy as first-line treatment for well-defined risk groups is based upon encouraging long-term results of phase II studies both in pretreated patients with HR-STS and in those with locally advanced disease. CONCLUSIONS: In summary, significant prognostic variables recognized for patients with STS have been addressed in the design of two open phase III clinical trials on adjuvant and neoadjuvant chemotherapy. The best chance for offering such treatment strategies following evidence-based medicine criteria to eligible patients with HR-STS depends upon early contact with the coordinator of the individual protocol prior to any treatment.

[Radiological examination of the thoracic organs for persistent foetal circulation (author's transl)]. / Röntgenuntersuchung der Thoraxorgane bei persistierender fetaler Zirkulation.

The radiological changes seen on chest x-rays of five children with persistent foetal circulation are analysed. There is inconstant cardiac enlargement and a reticulo-nodular appearance of the lungs, indicating interstitial oedema with heart failure. The value of the chest x-ray consists mainly in excluding a pulmonary or a characteristic cardiac abnormality as a cause of dyspnoea; it does not provide direct diagnostic information.

[Pregnancy in patients with congenital heart defect]. / Schwangerschaft bei Patientinnen mit angeborenem Herzfehler.

A process of adaptation of the cardiovascular system occurs during pregnancy, entailing physiologic changes. In women with congenital heart disease these changes lay a great burden on the cardiovascular system. Therefore there is an increased risk for mother and fetus, depending on the form of congenital heart disease, preceding operations and the grade of maternal hypoxemia. Overall, the maternal mortality is low, but in certain forms of congenital heart disease the mortality rate can rise to 50%. Infective endocarditis and anticoagulation therapy represent further problems for mother and fetus. It is the duty of the cardiologist, general practitioner and obstetrician to counsel the patient before conception on potential complications and risks of pregnancy, expected physical deterioration of the mother, as well as possible malformations of the child, including the recurrence risk of congenital heart disease. If pregnancy is contraindicated because of the severity of the heart disease, the patient has to be advised about reliable contraceptive methods tailored to her individual needs and their risks, including possible endocarditis, bleeding under anticoagulation therapy, thrombosis, toxic shock syndrome etc.

[Hemodynamic studies of nifedipine (Adalat) in pulmonary hypertension in childhood]. / Hämodynamische Untersuchungen von Nifedipin (Adalat) bei pulmonaler Hypertension im Kindesalter.

Under long-term oral treatment with nifedipine (N) 2 of 3 patients (2 children with VSD and Eisenmenger, 1 patient with Truncus I after corrective surgery) showed a remarkable improvement in exercise tolerance and reduction in the total pulmonary resistance. Therefore a single-dose testing with N was performed in 9 patients aged 2 to 20 years with primary pulmonary hypertension (n = 2), secondary pulmonary hypertension because of congenital heart disease with intracardiac shunts (n = 6) and after correction of Truncus Type I (n = 1). Before and after the injection of 0.5 mcg/kg of N into the main pulmonary artery, pulmonary artery pressure, cardiac output and systolic blood pressure were measured at 1 minute intervals during right heart catheterization. The maximal reaction occurred 3 to 4 minutes after the injection. The total pulmonary vascular resistance decreased significantly from 2684.2 +/- 1829.2 to 1300.2 +/- 1117.0 dyn.sec.cm-5.m2 (p less than 0.025), the cardiac index increased significantly from 3.1 +/- 1.65 to 5.73 +/- 1.95 l/min.m2 (p less than 0.01) concomitantly with a mild reduction in the mean pulmonary artery pressure. No significant change in heart rate and systolic blood pressure was seen; no side effects were observed. 4 of the 5 patients with the highest pulmonary vascular resistance showed the best positive reactions. Therefore these 9 patients may benefit from a long-term oral treatment with nifedipine.

[Immunosuppressive treatment of chronic myocarditis]. / Immunsuppressive Behandlung der chronischen Myocarditis.

6 children aged 9 months to 13 8/12 years developed reduced physical capacity, failure to thrive, dyspnoea on effort and heart failure after viral infection. Bed rest and anticongestive therapy did not reduce the severe heart failure. Immunosuppressive therapy with prednisolone 2 mg/kg/d and azathioprine 2 mg/kg/d was added on the assumption of chronic myocarditis (n = 4) or endocardial fibrosis (n = 2). 3 of the 6 children showed a considerable improvement in heart size, ECG and systolic heart function. Interruption of immunosuppressive therapy due to side effects in one child led to cardiac deterioration, which was reversed by renewed prednisolone therapy. Two patients died of progressive congestive heart failure. Heart transplantation was successfully performed in the now 14 year-old girl who was suffering from terminal dilated cardiomyopathy. Since there is no specific test for selecting patients who are likely to benefit from immunosuppressive therapy we feel this regimen would be justified in hopeless cases of congestive cardiomyopathy who have not responded to conventional therapy with anti-congestive drugs.

[Doppler echocardiographic evaluation of pressure in the pulmonary artery in children with congenital heart defects]. / Dopplerechokardiographische Beurteilung des Drucks in der Arteria pulmonalis bei Kindern mit angeborenen Herzfehlern.

In children with congenital heart disease serial noninvasive assessment of the pulmonary vascular bed is desirable in order to determine the appropriate timing of cardiac catheterization and corrective surgery. To assess the value of pulmonary Doppler echocardiography for the estimation of pulmonary arterial pressure we correlated the rightsided systolic time intervals (preejection period, acceleration period, ejection period) derived from pulmonary artery Doppler traces with catheterization data (systolic, mean and diastolic pulmonary arterial pressure, total and vascular pulmonary resistances). 62 children aged from 1 month to 15 years suffering from congenital heart disease (n = 52), from rheumatic heart disease (n = 4), from cardiomyopathy (n = 5) or from primary pulmonary hypertension (n = 1) were investigated. The major finding was a highly significant correlation between the acceleration period and the systolic pulmonary arterial pressure (r = 0.79; p less than or equal to 0.0001). However the acceleration period could not be used for prediction of pulmonary arterial pressure in children with poor myocardial contractility.

[Value of myocardial scintigraphy of coronary anomaly in the differential diagnosis of pediatric cardiomegaly]. / Wertigkeit der Myokardszintigraphie bei Koronaranomalie in der Differentialdiagnose der kindlichen Kardiomegalie.

The differentiation between anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) and other causes of cardiomegaly and thereby the decision to operate, as opposed to undertaking conservative therapy is often extremely difficult in clinical practice. Electrocardiographically, signs of myocardial infarction can be missed in ALCAPA, other forms of dilative cardiomyopathy (DCMP) often showing similar clinical features. Up to now aortography alone can make a clear-cut distinction between these two entities. In order to determine the diagnostic value of thallium-201 myocardial scintigraphy in ALCAPA, we investigated 18 children, 7 of them with angiographically or autoptically established ALCAPA and 11 patients with DCMP. The coronary artery anomaly was diagnosed on the basis of the typical myocardial perfusion defects in only 3 of the relevant 7 patients. In 9 of the 11 patients with DCMP ALCAPA was excluded by the homogeneous perfusion pattern or small focal reduction in thallium-201 activity in the left ventricular muscle mass. In view of the overall disappointing results of this method in achieving a specific diagnosis in ALCAPA, all patients with DCMP with or without suspected fibroelastosis should undergo invasive diagnosis with aortography.

[L-carnitine therapy and myocardial function in children treated with chronic hemodialysis]. / L-Carnitintherapie und Myokardfunktion bei chronisch hämodialysierten Kindern.

Six out of 14 chronically hemodialysed children with significantly decreased serum carnitine levels were substituted with L-carnitine (15-30 mg/kg/day-Biocarn) up to normal and above normal carnitine levels. None of these patients were digitalised. During the time of investigation plasma carnitine levels were investigated monthly and, simultaneously, three echocardiographic parameters in M-mode were quantitatively und qualitatively determined: shortening fraction (SF-%), ratio of left ventricular pre-ejection/ejection time (LVPT/LVET) and velocity of circumferential fibre shortening (Vcf). Carnitine substitution produced measurable changes in echocardiographic parameters, and a significant quantitative improvement in left ventricular function and performance: after 6 months of carnitine substitution a 24% improvement was seen, after 18 months a 44% mean improvement. No side effects of carnitine were observed; the compatibility was good. Beside these positive effects all patients reported decreased dialysis-associated spasms and polyneuropathic symptoms and increased somatic ability.