Effects of minimally invasive surgery and functional physiotherapy on motor function of children with cerebral palsy: A non-randomised controlled trial.

PURPOSE: This non-randomised controlled trial investigated whether a combined programme of functional physiotherapy and minimally invasive orthopaedic surgery improves the level and degree of capacity and performance of gross motor function in children with spastic cerebral palsy (CP). METHODS: Fifty-two children with spastic CP aged 5-7 years, Gross Motor Function Classification System (GMFCS) levels II-IV, were allocated to two equal groups: experimental group (selective percutaneous myofascial lengthening [SPML] procedure and 9-month functional strengthening physiotherapy programme) and control (standard physiotherapy) groups. At baseline and at the end of the 9-month intervention, the capacity and performance of gross motor function were assessed with the Gross Motor Function Measure (GMFM) D and E subcategories and Functional Mobility Scale (FMS), respectively. The level of gross motor function was measured with the GMFCS. RESULTS: There was a statistically significant difference in the post-intervention improvements in the GMFM D (experimental mean difference = 19.63 ± 10.46; control mean difference = 2.40 ± 4.62) and E (experimental mean difference = 19.33 ± 11.82; control mean difference = 4.20 ± 6.26) between experimental and control group (p < 0.001). There was a significant improvement in the GMFCS level and each FMS distance for the experimental group (p < 0.001), but not for the control group (p > 0.05). CONCLUSION: SPML procedure combined with functional physiotherapy improves gross motor function in children with spastic CP, by raising the degree and level of motor independence.

Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.

Background: Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods: The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results: A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions: HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No: Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

[Tracheal injuries, fistulae from bronchial stump and bronchial anastomoses and recurrent laryngeal nerve paralysis : management of complications in thoracic surgery]. / Tracheaverletzungen, Insuffizienz von Bronchusstumpf/-anastomose und Rekurrensparese : Management der Komplikationen in der Thoraxchirurgie.

BACKGROUND: Complications cannot always be avoided and their treatment is an integral component of a high quality medical treatment. Complications of the central airways are rare but necessitate supportive treatment by an experienced thoracic surgeon. OBJECTIVE: The reader should become acquainted with measures to prevent complications, to recognize and treat complications early and should understand the necessity for an interdisciplinary approach. MATERIAL AND METHODS: A selective literature research was supplemented by personal experiences and complemented with prospectively collected photographs. RESULTS: There are risk constellations for the appearance of all the mentioned complications which the surgeon needs to know in order to be able to take measures for early detection of complications. Iatrogenic tracheal injuries and bronchial stump fistulae are rare (< 5 %) whereas recurrent laryngeal nerve palsy after left-sided pneumonectomy occurs in up to 30 % of cases. DISCUSSION: After the occurrence of complications at the latest, it is very important to include experienced thoracic surgeons and other specialists when necessary to protect the patient from further damage.

HER2 expression and markers of phosphoinositide-3-kinase pathway activation define a favorable subgroup of metastatic pulmonary adenocarcinomas.

OBJECTIVES: Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. MATERIALS AND METHODS: Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH). RESULTS AND CONCLUSION: HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.

Accelerated hyperfractionated radiotherapy within trimodality therapy concepts for stage IIIA/B non-small cell lung cancer: Markedly higher rate of pathologic complete remissions than with conventional fractionation.

BACKGROUND: Radiation dose escalation within definitive radiochemotherapy (RTx/CTx) was not successful for stage III non-small cell lung cancer (NSCLC) using conventional fractionation (CF). Accelerated-hyperfractionation (AHF) counteracts tumour cell repopulation. In this observational study, the effects of neoadjuvant RTx/CTx using AHF or CF were studied by histopathology and using the survival end-point. METHODS: Data from all consecutive lung cancer patients treated with neoadjuvant RTx/CTx and thoracotomy between 08/2000 and 06/2012 were analysed. Patients received induction chemotherapy (cisplatin-doublets) followed by concurrent RTx/CTx using AHF (45 Gy/1.5 Gy bid) or CF-RTx (46 Gy/2 Gy qd). For estimating the AHF versus CF treatment effects, multivariate analysis (MA), propensity score weighting (PS), and instrumental variable analysis (IV) were used. FINDINGS: 239 patients were treated, median age 58 (34-78)years, stage II/IIIA/B: 19/88/132, squamous cell/adenocarcinomas/other: 98/107/34; AHF/CF-RTx 112/127 patients. No significant differences between both groups, in tumour related factors (age, gender, Charlson comorbiditiy score, lactate dehydrogenase (LDH), haemoglobin, stage, histopathology and grading), existed. Crude rates of pathologic complete responses (pCR) in AHF and CF groups were 37% and 24% respectively. The dose fractionation effect on pCR was significant (p ⩽ 0.006, PS and IV analyses). There was a significant dependence of pCR on biologically effective dose. pCR also depended on treatment time (MA, p = 0.04; PS, p = 0.0004). Median treatment time was 22 d or 31 d using AHF or CF (p<0.0001), respectively. Adenocarcinomas had lower pCR rates in comparison to other histologies. Five-year survival of patients with pCR was 65%, independent of the fractionation. INTERPRETATION: This large monoinstitutional analysis demonstrates an increased effect of AHF on pCR of lung cancer which modifies overall survival.

[Glandular papilloma of the right main bronchus. Detection of an exon 2 mutation of the KRAS gene (c.35G>A)]. / Glanduläres Papillom des rechten Hauptbronchus. Nachweis einer Exon-2-Mutation des KRAS-Gens (c.35G>A).

Benign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.

Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study.

BACKGROUND: Adjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement. PATIENTS AND METHODS: Patients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m(2) day (d)1 + 8) and vinorelbine (V: 25 mg/m(2) d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m(2) d1) and pemetrexed (Px: 500 mg/m(2) d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or non-hematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy. RESULTS: One hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P < 0.001), non-hematological toxic effects were comparable (33% and 31%, P = 0.798). Delivery of total mean doses was 90% of planned with CPx, but 66% (cisplatin) and 64% (vinorelbine) with CVb (P < 0.0001). The median number of cycles [treatment time (weeks)] was 4 for CPx (11.2) and 3 for CVb (9.9). Time to withdrawal from therapy differed significantly between arms favoring CPx (P < 0.001). CONCLUSION: Adjuvant chemotherapy with CPx is safe and feasible with less toxicity and superior dose delivery compared with CVb.

ßV-tubulin expression is associated with outcome following taxane-based chemotherapy in non-small cell lung cancer.

BACKGROUND: Tubulin-binding agents (TBAs) are effective in non-small cell lung cancer (NSCLC) treatment. Both ßIII- and ßV-tubulins are expressed by cancer cells and may lead to resistance against TBAs. METHODS: Pre-treatment samples from 65 locally advanced or oligometastatic NSCLC patients, who underwent uniform induction chemotherapy with paclitaxel and platinum followed by radiochemotherapy with vinorelbine and platinum were retrospectively analysed by immunohistochemistry. Protein expression of ßIII- and ßV-tubulin was morphometrically quantified. RESULTS: Median pre-treatment H-score for ßIII-tubulin was 110 (range: 0-290), and 160 for ßV-tubulin (range: 0-290). Low ßIII-tubulin expression was associated with improved overall survival (OS) (P=0.0127, hazard ratio (HR): 0.328). An association between high ßV-tubulin expression and prolonged progression-free survival (PFS, median 19.2 vs 9.4 months in high vs low expressors; P=0.0315, HR: 1.899) was found. Further, high ßV-tubulin expression was associated with objective response (median H-score 172.5 for CR+PR vs 120 for SD+PD patients, P=0.0104) or disease control following induction chemotherapy (170 for CR+PR+SD vs 100 for PD patients, P=0.0081), but not radiochemotherapy. CONCLUSION: Expression of ßV-tubulin was associated with treatment response and PFS following paclitaxel-based chemotherapy of locally advanced and oligometastatic NSCLC patients. Prolonged OS was associated with low levels of ßIII-tubulin. Prospective evaluation of ßIII/ßV-tubulin expression in NSCLC is warranted.

[Lung cancer staging: what is the actual role of mediastinoscopy?]. / Staging des Lungenkarzinoms: Welche Rolle spielt die Mediastinoskopie heute?

Today several methods for invasive mediastinal staging of lung cancer are available. Whereas mediastinoscopy and anterior mediastinotomy had been the gold standard in every situation several years ago, today EBUS-TBNA has been developed as an alternative to mediastinoscopy concerning the status of lymph node positions 2 L / R, 4 L / R and 7. Actually mediastinoscopy is accepted as the gold standard only in special situations such as negative cytology of suspicious lymph nodes after EBUS-TBNA and mediastinal evaluation after neoadjuvant treatment.

Lung segment geometry study: simulation of largest possible tumours that fit into bronchopulmonary segments.

BACKGROUND: Segmental resection in stage I non-small cell lung cancer (NSCLC) has been well described and is considered to have similar survival rates as lobectomy but with increased rates of local tumour recurrence due to inadequate parenchymal margins. In consequence, today segmentectomy is only performed when the tumour is smaller than 2 cm. METHODS: Three-dimensional reconstructions from 11 thin-slice CT scans of bronchopulmonary segments were generated, and virtual spherical tumours were placed over the segments, respecting all segmental borders. As a next step, virtual parenchymal safety margins of 2 cm and 3 cm were subtracted and the size of the remaining tumour calculated. RESULTS: The maximum tumour diameters with a 30-mm parenchymal safety margin ranged from 26.1 mm in right-sided segments 7 + 8 to 59.8 mm in the left apical segments 1-3. CONCLUSIONS: Using a three-dimensional reconstruction of lung CT scans, we demonstrated that segmentectomy or resection of segmental groups should be feasible with adequate margins, even for larger tumours in selected cases.

[Tracheoesophageal fistula]. / Tracheoösophageale Fistel.

Congenital deformities, various forms of trauma, foreign bodies, granulomatous infection and tumors are the most common causes of tracheoesophageal fistulas. This is a rare but life-threatening complication with mortality rates up to 60% due to chronic aspiration and innominate artery arrosion and bleeding. Bronchoscopy should be done promptly if a fistula is suspected, followed by esophagoscopy. Radiologic examinations are only helpful for operational planning. Surgical treatment is mandatory for benign fistulas with excellent short-term and long-term results. However, for malignant fistulas the survival time is often only weeks to months and are best treated by palliative stenting, which offers a short-term improvement in the quality of life.

[Role of mediastinoscopy and repeat mediastinoscopy today]. / Heutige Rolle der Mediastinoskopie und der Remediastinoskopie.

For patients with lung cancer preoperative evaluation of the mediastinal lymph nodes is important to estimate local operability and/or to consider the necessity of neoadjuvant treatment. Cervical mediastinoscopy is generally accepted as a safe and highly accurate procedure in the staging of lung cancer. Nodes accessible to CM are the levels of the superior (level 2R and 2L) and inferior (level 4R and 4L) paratracheal and subcarinal (level 7) nodal stations. Additionally extended CM and left parasternal mediastinotomy allow the exploration of the aortopulmonary window (level 5) and anterior mediastinal nodes (level 6). In locally advanced lung cancer repeat mediastinoscopy was used after induction chemotherapy or chemoradiation to reexplore the upper mediastinum in order to select patients with a higher probability to undergo complete resection. Operative mortality of both investigations is less than 0.5%; the preoperative complication rate is very low (less than 4%). Because of the higher sensitivity, specificity, and accuracy, mediastinoscopy and repeat mediastinoscopy are superior to new methods like FDG-PET, FDG-PET/CT, EBUS-FNA, and EUS-FNA.

[Pulmonary resection. Postoperative consequences]. / Lungenresektionen. Postoperative Folgezustände.

The physician involved in internal medicine and general practice is confronted with a series of challenges in patients with pulmonary resection. In the early post-operative phase, optimal analgesia and physiotherapy are the primary factors for achieving the best possible function after loss of pulmonary tissue and for the determination of complications. Post thoracotomy syndrome requires interdisciplinary therapy. In the later course, it is necessary to take into consideration effects on pulmonary circulation, on the musculoskeletal system and on the digestive tract as well as sleep disturbances due to diaphragm dysfunction. Corresponding symptoms should be considered and actively sought, for example using echocardiography for assessment of cor pulmonale or outpatient sleep monitoring for detection of sleep-disordered breathing. Thus, aftercare includes much more than the search for a relapse or formation of metastases in cases of the most common cause of pulmonary resection, bronchial cancer.

Induction chemotherapy, concurrent chemoradiation and surgery for Pancoast tumour.

The traditional treatment of Pancoast tumour with local approaches (surgery, radiotherapy or a combination of both) leads to a poor outcome due to the high rate of incomplete resection and the lack of systemic control. The aim of the present prospective feasibility study was to determine whether a trimodality approach improves local control and survival. Patients with stage IIB-IIIB Pancoast tumour received induction chemotherapy (three courses of split-dose cisplatin and etoposide or paclitaxel) followed by concurrent chemoradiotherapy (a course of cisplatin/etoposide combined with 45 Gy hyperfractionated accelerated radiotherapy). After restaging, eligible patients underwent surgery 4-6 weeks post-radiation. A total of 31 consecutive patients with T3 (81%) or T4 (19%) Pancoast tumour were enrolled in the study. Induction chemoradiotherapy was completed in all patients without treatment-related deaths. Grade 3-4 toxicity was observed in 32% of cases. In total, 29 (94%) patients were eligible for surgery. Complete resection was achieved in 94% of patients. The post-operative mortality rate was 6.4% and major complications arose in 20.6% of the patients. The median survival was 54 months with 2- and 5-yr survival rates of 74 and 46%, respectively. In conclusion, this intensive multimodality treatment of Pancoast tumour is feasible and improves local resectability rates and long-term survival as compared with historical series.

Solitary pulmonary nodule with growth and contrast enhancement at CT: inflammatory pseudotumour as an unusual benign cause.

Small (< or =10 mm) pulmonary nodules are frequently detected at modern chest CT. As most of these nodules are benign, non-invasive classification is required--usually based on assessment of growth and perfusion. Absence of growth and no evidence of perfusion, as demonstrated by lack of enhancement at contrast-enhanced CT or MRI, strongly suggest a benign nodule. On the other hand, growth with a doubling of the nodule's volume between 20 days and 400 days or enhancement suggest a malignant nature of the lesion. We present an example of a nodule with strong contrast enhancement and a doubling time of approximately 260 days, which histologically represented a benign inflammatory pseudotumour.

Repeat mediastinoscopy as a restaging procedure.

BACKGROUND: Repeat cervical mediastinoscopy is a diagnostic surgical procedure for preoperative nodal staging in patients with insufficient first mediastinoscopy, with recurrent or second primary lung neoplasms, and following induction chemotherapy or chemo-/radiotherapy for locally advanced lung cancer. The aim of this study was to critically analyse indications, technical characteristics, intra- and postoperative complications, also to define selection criteria for patients with a higher probability of successful complete resection. MATERIAL AND METHODS: 279 patients with lung cancer (66 female and 213 male patients, mean age 58 years, range 28 to 78 years) underwent repeat mediastinoscopy from 1968 to 2004, 12 because of inadequate first procedure (group A), 67 because of recurrent lung cancer (group B) 35 because of second primary lung cancer (group C), and 165 following induction chemo-/radiotherapy for IIIa and IIIb disease (group D). The interval between first and second procedure was 17 days (range, 12 - 38) in group A, 14 months (range, 5 - 29) in group B, 27 months (range, 19 - 124) in group C, and 132 days (range, 113 - 145) in group D. RESULTS: No intra- or postoperative deaths were observed, 7 patients developed minor complications. N2 or N3 disease was found in 3/12 patients of group A (25 %), in 17/67 patients of group B (25.4 %) and in 6/35 patients of group C (17.1 %). Of the 116 patients with N2, and 49 with N3 disease before induction treatment (group D), repeat mediastinoscopy showed 126 N0, 20 N2 and 14 N3 status. Because of the presence of inseparable adhesions repeat mediastinoscopy was not possible in 5 cases. Five-year survival for patients with persistent N2 in repeat mediastinoscopy was despite surgery only 5 %. CONCLUSION: Repeat mediastinoscopy is a safe explorative procedure for the restaging of patients with primary locally advanced, recurrent or second primary lung cancer. In patients after induction treatment it is, however, less sensitive than the primary mediastinoscopy because of adhesions and fibrotic tissue. Patients with persistent N2 or N3 disease in repeat mediastinoscopy have a poor survival so that the indication for surgery has to be taken into consideration very carefully.

[Operative and interventional therapy of lung metastases]. / Lungenmetastasen--Welche Chancen hat lhr Patient jetzt noch?

Almost every third patient succumbing to a malignant disease has metastases in the lungs. However, these are often asymptomatic and are detected fortuitously during a routine examination. Today, the surgical removal of lung metastases is associated with a risk of less than 1%, but only one-third of the patients meet the criteria for such a procedure. The long-term outcome after resection of lung metastases depends in particular on the nature of the primary tumor, the number of metastases, the duration of the period between the occurrence of the primary and development of metastases, and the completeness of the resection. In the case of inoperable metastases, interventional measures may suffice to achieve local tumor control. For the treatment of lung metastases, radiofrequency ablation in particular is currently being investigated.

High-dose chemotherapy with autologous stem cell transplantation in patients with oligometastatic breast cancer.

The purpose of this prospective trial was to study a combined-modality treatment including local consolidation by surgery or radiotherapy and high-dose chemotherapy (HDC) followed by peripheral-blood stem-cell (PBSC) transplantation. In all, 48 patients with oligometastatic breast cancer amenable to local treatment after induction chemotherapy with epirubicin and cyclophosphamide or paclitaxel and cisplatin, depending on prior adjuvant chemotherapy, were enrolled. The median follow-up was 41 months (range, 7-85 months). PBSC were collected in 47 patients, and 40 received one or two courses of HDC. Local therapy was given in 37 patients. No treatment-related deaths occurred. Of 47 evaluable patients, 36 (75% of intention-to-treat population) had no evidence of disease or complete remission after completion of therapy. Six patients (12.5%) had partial response, two patients (4%) no change, and three patients (6%) progressive disease. The median time to progression and overall survival was 17.5 (95% confidence interval (CI), 14-21 months) and 42.2 months (95% CI, 33-52 months), respectively, and 27% of patients were progression free after 5 years. In conclusion, patients with oligometastatic breast cancer can be treated safely with this combined modality protocol with promising relapse-free survivals.