Can coracoacromial ligament degeneration be evaluated with preoperative MRI?

BACKGROUND: Subacromial impingement syndrome is one of the most common causes of painful shoulder in the middle-aged and elderly population. Coracoacromial ligament (CAL) degeneration is a well-known indicator for subacromial impingement. PURPOSE: To examine the relationship between CAL thickness on preoperative magnetic resonance imaging (MRI), arthroscopic CAL degeneration and types of rotator cuff tears. MATERIAL AND METHODS: Video records of patients who underwent arthroscopic shoulder surgery between 2015 and 2021 were retrospectively scanned through the hospital information record system. In total, 560 patients were included in this study. Video records of the surgery were used to evaluate the grade of coracoacromial ligament degeneration and the type of cuff tear. Preoperative MRI was used to measure CAL thickness, acromiohumeral distance, critical shoulder angle, acromial index, and acromion angulation. RESULTS: Significant differences were observed between grades of CAL degeneration in terms of CAL thickness (P < 0.001). As CAL degeneration increases, the mean of CAL thickness decreases. According to the results of post-hoc analysis, the mean CAL thickness of normal patients was significantly higher than those of patients with full-thickness tears (P = 0.024) and massive tears (P <0.001). Patients with articular-side, bursal-side, and full-thickness tears had significantly higher CAL thickness averages than patients with massive tears. CONCLUSION: This study showed that the CAL thickness decreases on MRI as arthroscopic CAL degeneration increases. High-grade CAL degeneration and therefore subacromial impingement syndrome can be predicted by looking at the CAL thickness in MRI, which is a non-invasive method.

Effect of plasma nitriding treatment on structural, tribological and electrochemical properties of commercially pure titanium.

In this study, plasma nitriding treatment was applied to commercially pure titanium (Grade 2). Structural properties, electrochemical and tribological behaviours of the nitrided pure titanium specimens were comparatively investigated. Microstructure and morphology of the plasma nitrided specimens were analysed by X-ray diffraction and scanning electron microscopy. Furthermore, corrosion tests were conducted in Ringer's solution, which represents a human body environment, to determine electrochemical properties. Then, tribological and frictional properties were investigated using pin-on-disc tribometer, and a micro-hardness tester was used to measure the hardness of the coatings. The results showed that plasma nitrided specimens exhibited higher surface hardness than the untreated specimens did. In addition, the plasma nitrided specimens at 700 °C presented significantly better performance than the other plasma nitrided specimens (at 500 °C and 600 °C) under dry wear conditions. Moreover, corrosion test results showed that corrosion behaviours of untreated and nitrided samples had similar characteristic.

The Possible Role of Mast Cells and VEGF in Peritumoural Oedema of Secretory Meningioma.

Objective: Secretory meningiomas constitute a relatively rare subtype of meningiomas and present often with massive peritumoural oedema. From our previous report, a high number of mast cells were demonstrable in this subtype of meningiomas. The present study aimed to obtain more information about mast cell derived progangiogenic factors and mediators as well as VEGF receptors in secretory meningioma. Additionally, the correlation of histological factors such as the presence of mast cells and the radiological evidence of surrounding tumour oedema was analysed. Material and Method: Sixteen cases of secretory meningioma were examined. Relevant clinical information was obtained from the patient files. The peritumoural oedema was determined either by CT or MRI scans and graded as mild, moderate and severe. Immunohistochemical studies of histamine, substance P, serotonin, VEGF and VEGF receptors were performed. A double-blind quantitative evaluation of mast cells staining positively for VEGF in a comparison with total mast cells in secretory meningiomas was made by two histopathologists. Results: There was no immunoreactivity against histamine or substance P within the tumour tissue or in mast cells. Fine granules of serotonin were demonstrated within the mast cells and a coarse granular expression of VEGF was found within the mast cells. Our preliminary data demonstrated that tumours with moderate to severe degree of peritumoural oedema usually contained more than 50% of VEGF-staining positive mast cells. Conclusion: Secretory meningiomas are characterized by a significantly increased number of mast cells. VEGF and serotonin might be involved in the pathophysiological process of this vasogenic brain oedema. The preliminary data demonstrated the potential relation between the radiological evidence of increasing oedema and the high numbers of mast cell staining positively for VEGF.

Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer.

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of ≥200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of ≥200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

Comparison of KRAS genotype: therascreen assay vs. LNA-mediated qPCR clamping assay.

BACKGROUND: Kirsten rat sarcoma virus (KRAS) wild-type status determined using a locked nucleic acid (LNA)-mediated quantitative polymerase chain reaction (qPCR) clamping assay (LNA assay) predicted response to therapy in the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study. A companion KRAS diagnostic tool has been developed for routine clinical use (QIAGEN therascreen kit) (QIAGEN Manchester Ltd, Manchester, UK). We wanted to assess the concordance between the validated US Food and Drug Administration (FDA)-approved therascreen assay and the LNA assay in determining the KRAS status of a subset of patients enrolled in the CRYSTAL study. PATIENTS AND METHODS: DNA extracted from paraffin-embedded tumor sections was tested for KRAS status using the therascreen assay. Efficacy data from the CRYSTAL study were assessed to determine if the overall survival (OS) hazard ratio for cetuximab in patients identified as having KRAS wild-type status using the therascreen assay was equivalent to that in patients identified as KRAS wild-type using the LNA assay. This was determined by assessing if the concordance between the therascreen assay and the LNA assay met the minimum threshold (prespecified as 0.8) to achieve a significant difference in the OS hazard ratio in favor of the cetuximab + FOLFIRI (5-fluorouracil, leucovorin [folinic acid], irinotecan) arm in the KRAS wild-type population as identified using the therascreen assay. RESULTS: Of the 148 samples determined to be KRAS wild-type (therascreen assay), 141 (95.3%) samples were also KRAS wild-type (LNA assay) and 7 samples (4.7%) were KRAS mutant (LNA assay). The prespecified primary concordance measure p was 141/148 = 0.953 (95% confidence interval [CI], 0.905-0.981). The concordance was statistically significantly higher than the prespecified threshold of 0.8 for concordance between the therascreen assay and the LNA assay. Consistent with the concordance exceeding the prespecified threshold, the OS hazard ratio (cetuximab + FOLFIRI arm vs. FOLFIRI arm) in the KRAS wild-type population, determined by the therascreen assay, supported a significant benefit for cetuximab (ie, the 95% CI excluded 1) and was comparable to the OS hazard ratio observed in the CRYSTAL study KRAS wild-type population (LNA assay) even after adjustment for potentially confounding baseline variables. CONCLUSION: These results support the utility of the therascreen assay for identifying patients who may benefit from cetuximab therapy for metastatic colorectal cancer.

Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial.

BACKGROUND: Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. METHODS: In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m(2) (on days 1-14) and intravenous cisplatin 80 mg/m(2) (on day 1), with or without weekly cetuximab (400 mg/m(2) initial infusion on day 1 followed by 250 mg/m(2) per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. FINDINGS: Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4.4 months (95% CI 4.2-5.5) compared with 5.6 months (5.1-5.7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1.09, 95% CI 0.92-1.29; p=0.32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3-4 adverse events, including grade 3-4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3-4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3-4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. INTERPRETATION: Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. FUNDING: Merck KGaA.

Reproducibility of immunohistochemical scoring for epidermal growth factor receptor expression in non-small cell lung cancer: round robin test.

CONTEXT: The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non-small cell lung cancer whose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of ≥200 on a scale of 0-300). OBJECTIVE: To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0-3+) and the percentage of cells staining at each intensity. DESIGN: In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non-small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low- (<200) and high- (≥200) EGFR expression groups. RESULTS: After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean κ coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively. CONCLUSIONS: After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of non-small cell lung cancers into clinically relevant high- or low-EGFR expression groups.

Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies.

BACKGROUND: The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) and KRAS wild-type metastatic colorectal cancer (mCRC). In advanced non-small-cell lung cancer (NSCLC), high EGFR expression was identified as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy. We investigated whether tumour EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL study patients. METHODS: Prospectively collected tumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score (scale 1-300) for patients in the EXTREME and CRYSTAL studies. For each study, the association between tumour immunohistochemistry score and cetuximab benefit was investigated. The EXTREME and CRYSTAL studies are registered with Clinical Trials.gov, numbers NCT00122460 and NCT00154102, respectively. FINDINGS: Tumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients from the ITT population of the CRYSTAL study with EGFR-expressing, KRAS wild-type disease. The distribution of immunohistochemistry scores was similar between the treatment arms of each study, but differed between studies. A clinically relevant benefit for progression-free and overall survival associated with the addition of cetuximab to chemotherapy was seen across the full score range in EXTREME study patients. Similarly, CRYSTAL study patients derived a clinical benefit across the full score range, with no meaningful association between EGFR expression level and benefit. INTERPRETATION: The addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent/metastatic SCCHN and KRAS wild-type mCRC regardless of tumour EGFR expression level, indicating that in contrast to findings in NSCLC, EGFR expression level is not a clinically useful predictive biomarker in these settings.

Guideline on the requirements of external quality assessment programs in molecular pathology.

Molecular pathology is an integral part of daily diagnostic pathology and used for classification of tumors, for prediction of prognosis and response to therapy, and to support treatment decisions. For these reasons, analyses in molecular pathology must be highly reliable and hence external quality assessment (EQA) programs are called for. Several EQA programs exist to which laboratories can subscribe, but they vary in scope, number of subscribers, and execution. The guideline presented in this paper has been developed with the purpose to harmonize EQA in molecular pathology. It presents recommendations on how an EQA program should be organized, provides criteria for a reference laboratory, proposes requirements for EQA test samples, and defines the number of samples needed for an EQA program. Furthermore, a system for scoring of the results is proposed as well as measures to be taken for poorly performing laboratories. Proposals are made regarding the content requirements of an EQA report and how its results should be communicated. Finally, the need for an EQA database and a participant manual are elaborated. It is the intention of this guideline to improve EQA for molecular pathology in order to provide more reliable molecular analyses as well as optimal information regarding patient selection for treatment.

Does contrast-enhanced cervical ultrasonography improve preoperative localization results in patients with sporadic primary hyperparathyroidism?

OBJECTIVE: Pre-operative localization studies are inevitable in patients with primary hyperparathyroidism (pHPT), who are eligible for focused or minimally invasive parathyroidectomy (MIP). High-resolution ultrasonography (US) in combination with planar (99m)Tc-Sestamibi-scintigraphy (MIBI) and additional single-photon emission computed tomography (SPECT) are the standard procedures to localize enlarged parathyroid glands. Our aim was to evaluate the practicability and significance of contrast-enhanced ultrasonography (CEUS) in patients with pHPT. MATERIALS AND METHODS: All investigations were performed at the University Hospital Marburg. Totally, 25 patients with biochemical proven pHPT underwent preoperative US, MIBI/SPECT, and CEUS. For CEUS, a suspension of phospholipid-stabilized sulfur-hexafluoride (SF6) microbubbles in combination with a special 12 MHz linear US probe was used. All patients were investigated by two sonographers, who did not get to view the findings noted by the other. Finally, surgery was performed and histopathological results were obtained from 24 patients. RESULTS: In 17 (68%) patients, US and MIBI/SPECT already raised suspicion of parathyroid lesions and all suspected lesions were reassessed by CEUS. However, no additional information was obtained using CEUS. Especially in eight patients with negative or inconsistent US and MIBI/SPECT results, CEUS did not provide additional information regarding the site of the suspected parathyroid adenoma. Overall, no side effects were observed using CEUS. Surgical cure was achieved in all patients. CONCLUSION: In this limited cohort of patients, no additional information could be obtained using the costly CEUS compared to results of US and MIBI/SPECT.

Association of KRAS G13D tumor mutations with outcome in patients with metastatic colorectal cancer treated with first-line chemotherapy with or without cetuximab.

PURPOSE: We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D-mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment. METHODS: Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed. RESULTS: Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D-mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies. CONCLUSION: The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D-mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.

Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials.

BACKGROUND: The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies. METHODS: Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests. RESULTS: In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p<0.001) and ORR (odds ratio 2.16; p<0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours. CONCLUSION: Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study.

BACKGROUND: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. METHODS: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). INTERPRETATION: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. FUNDING: Merck KGaA.

Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study.

BACKGROUND: Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting. METHODS: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). INTERPRETATION: The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed. FUNDING: Merck KGaA.

Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.

PURPOSE: The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. RESULTS: The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. CONCLUSION: The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.

Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study.

PURPOSE: This study assessed biomarkers for cetuximab efficacy in tissue samples collected during a phase I dose-escalation study exploring every second week administration of cetuximab as first-line therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Sixty-two patients received cetuximab monotherapy for 6 weeks, followed by cetuximab plus infusional fluorouracil, leucovorin, and irinotecan until disease progression. Patients in the control arm received cetuximab as a 400 mg/m(2) initial dose then 250 mg/m(2) per week; patients in the dose-escalation arms received 400 to 700 mg/m(2) every second week. Tumor and skin biopsies were taken for immunohistochemical and microarray expression analyses (tumor only) at baseline and week 4. Plasma was collected for proteomic analysis at baseline and week 4. KRAS tumor mutation status was assessed. RESULTS: In subsets of paired skin samples from 35 patients, cetuximab treatment was associated with substantial downregulation of phospho(p)-EGFR, p-MAPK and proliferation and substantial upregulation of p27(Kip1) and p-STAT3 levels. No marked difference in these effects was noted for different schedules of administration and dose levels. In the cetuximab monotherapy phase, responses were seen only in patients whose tumors were wild-type for KRAS (eight of 29 v zero of 19 for KRAS mutant tumors; P = .015). Progression-free survival was longer for patients with KRAS wild-type compared with KRAS mutant tumors (log-rank P = .048). Genomics/proteomics analyses (42 and 45 patients, respectively) identified candidate biomarkers associated with response. CONCLUSION: Biomarker analysis supported the functional equivalence of weekly and every second week administration of cetuximab and provided further confirmation that patients with KRAS wild-type mCRC were those most likely to benefit from cetuximab treatment.

Cilengitide induces cellular detachment and apoptosis in endothelial and glioma cells mediated by inhibition of FAK/src/AKT pathway.

BACKGROUND: The antiangiogenic agent cilengitide disrupts integrin binding to the extracellular matrix leading to apoptosis of activated endothelial cells. Integrins are also widely expressed in malignant glioma and integrin inhibitors may directly target tumor cells in this disease. Aim of the current study was to investigate effects of cilengitide on endothelial and glioma cells on molecular and cellular levels. RESULTS: Cilengitide caused dose-dependent detachment of endothelial cells from cell culture dishes. Proliferation of endothelial cells was significantly inhibited while the proportion of apoptotic cells was increased. Incubation of integrin-expressing glioma cells with cilengitide caused rounding and detachment after 24 hours as observed with endothelial cells. Cilengitide inhibited proliferation and induced apoptosis in glioma cells with methylated MGMT promotor when given alone or in combination with temozolomide. In endothelial as well as glioma cells cilengitide inhibited phosphorylation of FAK, Src and Akt. Assembly of cytoskeleton and tight junctions was heavily disturbed in both cell types. CONCLUSION: Cilengitide inhibits integrin-dependent signaling, causes disassembly of cytoskeleton, cellular detachment and induction of apoptosis in endothelial and glioma cells thereby explaining the profound activity of integrin inhibitors in gliomas. The combination of cilengitide with temozolomide exerted additive effects in glioma cells as observed clinically.

Surgical treatment of tertiary hyperparathyroidism: the choice of procedure matters!

BACKGROUND: Parathyroid surgery (PTX) in patients with tertiary hyperparathyroidism (tHPT) may endanger the long-term survival of transplanted renal grafts. The mechanism by which graft function deteriorates is unknown. We reviewed our experience in regard to the operative procedures and postoperative outcome. METHODS: Sixty-nine patients were operated on for tHPT between 1987 and 2006 at our institution. Serum (s) calcium, s-creatinine, and levels of intact parathyroid hormone (PTH) were measured before and after PTX. The Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (GFR). RESULTS: The entire patient group developed a deterioration of kidney graft function after PTX. Nineteen of 69 patients developed a decrease in GFR of more than 20% during the hospital stay, persisting for more than one year after PTX. Ten of them had to restart dialysis during the first year after PTX. Mean preoperative s-creatinine was 4.4 +/- 0.6 mg/dl in these patients. When divided according to the surgical procedure performed, only the subgroup who underwent total parathyroidectomy showed a significant worsening of graft function when compared to subtotal or reoperative PTX. CONCLUSIONS: PTX is an efficient way to treat tHPT but represents a risk for impairing graft function, especially for patients that already demonstrate poor kidney function at the time of surgery. In the aim to prevent transient hypoparathyroidism, which may provoke reduced graft perfusion, as one possible cause of kidney graft deterioration associated with PTX, one should consider subtotal instead of total parathyroidectomy.

Peri-operative quality of life assessment in endoscopically treated patients with pineal region tumours.

BACKGROUND: Therapeutic modalities for pineal region tumours are still matter of debate. Endoscopic treatment is a minimally invasive approach. The aim of this study was to assess the quality of life of patients with pineal region tumours who underwent endoscopic procedures. MATERIALS AND METHODS: Eight patients (male:3, female 5) were included in this study. Post-operative evaluation of surgical outcome in terms of quality of life (QoL) was performed using the Quality of Life Questionnaire (QLQ-C30). The patient's outcome scores were compared with normative outcome values of the German population. Pre-operative and post-operative global QoL and symptoms such as headache, visual disturbance, gait disturbance, cognitive function and unconsciousness were documented. Descriptive and explorative statistics were performed. RESULTS: There were no significant differences between the normal German population and the endoscopically treated patients in different health domains and measures of QLQ-C30 (physical functioning 87.5%, emotional functioning 50%, cognitive functioning 50%, social functioning 62.5%; percentage represents regular functioning). Improved quality of life could be demonstrated in short-term (3-12 months, n = 3) and long-term (21-29 months, n = 5) follow-up. Global QoL improved significantly (p < 0.001; t-test) post-operatively. The following changes between pre-operative and post-operative clinical symptoms were found (headache 87.5%/62.5%, visual disturbance 50%/25%, gait disturbance 87.5%/25%, cognitive functioning 75%/37.5%, unconsciousness 25%/-). CONCLUSION: Endoscopic treatment of patients with pineal region tumours produces improved post-operative quality of life in all health domains. Therefore, the endoscopic approach should be considered as an alternative treatment in patients with newly diagnosed pineal tumours and/or related hydrocephalus.

Present status of known and possible outcomes in neurosurgery: a survey of outcome assessment.

OBJECTIVES: In the area of health care research, quality of life (QoL) is considered as a diagnostic tool for problem-oriented care of postoperative cancer patients. The aim of this study was to assess the attitude of neurosurgeons towards the different outcome measurements. MATERIALS AND METHODS: This prospective study was conducted between the 15(th) and 18th of June 2005 during the third world conference of the International Study Group on Neuroendoscopy (ISGNE) in Marburg, Germany. Copies of the questionnaire that was generated for this purpose were distributed to the participants from all over the world. Respondents were asked to return the completed questionnaire to the registration/information desk. The acquired data from the questionnaires were transferred to Excel spreadsheet. Only data from completely filled out questionnaires were included in the descriptive and explorative analysis. RESULTS: Forty of the 150 questionnaires that were distributed were complete without missing values and mistakes. Data from these 40 questionnaires were used for analysis. Sixty eight percent (27:40) of the neurosurgeons considered mortality as the first or the second rank of outcome measurement, whereas morbidity was also found to be the other important outcome measurement (the first or the second rank of outcome measurement) in 45% (18:40) of the neurosurgeons. Improved QoL was considered as the third or the fourth priority of outcome measurement in 53% (22:40) of the respondents. Although from these data, it may be difficult to infer that there is a real transfer of QoL concept from the scientific theory and the measurement level into clinical application. However, this may reflect a change in attitude of the surgeon. CONCLUSION: Besides disseminating new QoL concepts through publication and information technology, an implementation of this contemporary concept would provide a postoperative neurosurgical patient an optimal and rapid therapy according to the disclosed problems in the somatic, psychological, and social domains. Therefore, a QoL profile that can be used in each group of neurosurgical patient should be created.