Martin Totsch

Mediastinal Lymph Node Clearance After Docetaxel-Cisplatin Neoadjuvant Chemotherapy Is Prognostic of Survival in Patients With Stage IIIA pN2 Non–Small-Cell Lung Cancer: A Multicenter Phase II Trial

PURPOSE A multicenter, phase II trial investigated the efficacy and toxicity of neoadjuvant docetaxel-cisplatin in locally advanced non-small-cell lung cancer (NSCLC) and examined prognostic factors for patients not benefiting from surgery. PATIENTS AND METHODS Ninety patients with previously untreated, potentially operable stage IIIA (mediastinoscopically pN2) NSCLC received three cycles of docetaxel 85 mg/m2 day 1 plus cisplatin 40 mg/m2 days 1 and 2, with subsequent surgical resection. RESULTS Administered dose-intensities were docetaxel 85 mg/m2/3 weeks (range, 53 to 96) and cisplatin 95 mg/m2/3 weeks (range, 0 to 104). The 265 cycles were well tolerated, and the overall response rate was 66% (95% confidence interval [CI], 55% to 75%). Seventy-five patients underwent tumor resection with positive resection margin and involvement of the uppermost mediastinal lymph node in 16% and 35% of patients, respectively (perioperative mortality, 3%; morbidity, 17%). Pathologic complete response occurred in 19% of patients with tumor resection. In patients with tumor resection, downstaging to N0-1 at surgery was prognostic and significantly prolonged event-free survival (EFS) and overall survival (OS; P =.0001). At median follow-up of 32 months, the median EFS and OS were 14.8 months (range, 2.4 to 53.4) and 33 months (range, 2.4 to 53.4), respectively. Local relapse occurred in 27% of patients with tumor resection, with distant metastases in 37%. Multivariate analyses identified mediastinal clearance (hazard ratio, 0.22; P =.0003) and complete resection (hazard ratio, 0.26; P =.0006) as strongly prognostic for increased survival. CONCLUSION Neoadjuvant docetaxel-cisplatin is effective and tolerable in stage IIIA pN2 NSCLC. Resection is recommended only for patients with mediastinal downstaging after chemotherapy.

Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-Year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel–cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m−2 (day 1) plus cisplatin 40 or 50 mg m−2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel–cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Matrix metalloproteinase-7 as a marker of metastasis and predictor of poor survival in bladder cancer

Matrix metalloproteinases (MMPs) play an important role in tumor progression and metastasis. Here, we investigated the prognostic relevance of MMP‐7 in urinary bladder cancer. MMP‐7 gene expression was measured in tissue samples of 101 patients using quantitative real‐time PCR. Circulating MMP‐7 serum levels of 98 individuals (79 patients and 19 controls) were analyzed by enzyme‐linked immunosorbent assay. The results were compared with the clinical follow‐up data, performing Kaplan–Meier log‐rank test as well as univariate and multivariate Cox analysis. In representative cases, immunohistochemical analysis for MMP‐7 was performed. We detected significantly elevated MMP‐7 levels both in tissue and serum samples of patients with metastatic disease (P = 0.001 and P = 0.002). Multivariate analysis revealed that high MMP‐7 tissue expression and serum concentration are stage‐ and grade‐independent predictors of both metastasis‐free (hazard ratio [HR] = 3.80, 95% confidence interval [CI], 1.29–11.23, P = 0.016, and HR = 2.53, 95% CI, 1.01–6.37, P = 0.048) and disease‐specific survival (HR = 1.89, 95% CI, 1.00–3.55, P = 0.050 and HR = 1.95, 95% CI, 1.03–3.71, P = 0.041). Based on these findings, we conclude that MMP‐7 is a promising marker to detect present and to predict future metastasis. Serum MMP‐7 analysis provides information about the risk of metastasis before surgery which could help to optimize therapeutic procedures. Furthermore, high MMP‐7 tissue and/or serum levels could identify patients most likely to benefit from early adjuvant chemotherapy.

Primary Invasive Aspergillosis of the Digestive Tract: Report of Two Cases and Review of the Literature

Background:Disseminated aspergillosis is thought to occur as a result of vascular invasion from the lungs with subsequent bloodstream dissemination, and portals of entry other than sinuses and/or the respiratory tract remain speculative.Methods:We report two cases of primary aspergillosis in the digestive tract and present a detailed review of eight of the 23 previously-published cases for which detailed data are available.Results and Conclusion:These ten cases presented with symptoms suggestive of typhlitis, with further peritonitis requiring laparotomy and small bowel segmental resection. All cases were characterized by the absence of pulmonary disease at the time of histologically-confirmed gastrointestinal involvement with vascular invasion by branched Aspergillus hyphae. These cases suggest that the digestive tract may represent a portal of entry for Aspergillus species in immunocompromised patients.

Expression of galectin-3 in normal and malignant thyroid tissue by quantitative PCR and immunohistochemistry

Galectin-3 has been extensively studied as an immunohistochemical marker of thyroid malignancy, and a high diagnostic accuracy has been reported even for difficult pathological diagnoses, such as minimal invasive follicular carcinoma. We consequently hypothesized that the quantitative analysis of galectin-3 mRNA rather than the more observer-dependent immunohistological determination might enhance the diagnostic workup of ambiguous thyroid lesions. In the present study, we set out to validate this approach by analyzing concomitantly the expression and production of galectin-3 in benign and malignant thyroid tumors by means of quantitative PCR and immunohistochemistry. Twenty-eight benign and 31 malignant thyroid samples were quantified by real-time PCR for the mRNA levels of galectin-3 and thyroglobulin. Galectin-3 protein expression was examined by immunohistochemistry in 13 benign and 14 malignant thyroid samples. There was a significant increase in galectin-3 at both the mRNA (12/20) and protein levels in papillary cancer (8/8), although the mRNA values overlapped partly with benign lesions. Surprisingly, only a focal and discrete galectin-3 immunoreactivity was seen in follicular cancer (1/5); no augmentation of the mRNA was found. The expression of the thyroid-specific gene thyroglobulin was highly variable in benign and malignant thyroid tissue. These results suggest that the quantitative measurement of galactin-3 mRNA is unlikely to be clinically useful and underscore the need for searching for novel markers for thyroid malignancies.

Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing's syndrome

Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushings syndrome is a rare disease. Recent evidence suggests that these tumors form part of a continuous spectrum ranging from well-differentiated carcinomas to small cell carcinomas. We report two new cases and review the 23 cases reported in the literature since 1972. The different diagnostic modalities are discussed, and an algorithm for the diagnosis of ectopic secretion of adrenocorticotropin (ACTH) is presented. In the future, the advent of radiologic and nuclear imaging as well as more accurate workup should help to diagnose these tumors at an earlier stage and improve the long-term outcome.

CD4+CD25+ T-cell populations expressing CD134 and GITR are associated with disease activity in patients with Wegener's granulomatosis

BACKGROUND An increased CD4(+) CD25(+) T-cell population is observed in Wegeners granulomatosis (WG). This T-cell population is not well characterized yet and their contribution to the disease pathogenesis remains obscure. METHODS Thirty patients with WG and 18 healthy controls (HC) were included in this study. The disease activity and extension were measured by the Birmingham Vasculitis Activity Score (BVAS) and the Disease Extent Index (DEI). Lymphocytes from peripheral blood were analysed by FACS for the expression of CD4, CD25, CD134 and GITR. Cytokine expression in these subsets was assessed too. Nasal, lung and renal tissues from WG patients were immunohistochemically stained for CD3 and CD134. RESULTS The percentage of CD134(+) as well as GITR(+) expressing CD4(+)CD25(+) lymphocytes was increased in patients as compared to HC (37 +/- 12% versus 27 +/- 8%, P = 0.005; 18 +/- 9% versus 11 +/- 6%, P = 0.003). The expression of CD134 and GITR showed a significant correlation with disease activity (r = 0.5, P = 0.009; r = 0.55, P = 0.001). Most of these displayed the phenotype of effector memory T-cells (94 +/- 4% and 91 +/- 6%). CD134 T-cells were found in tissues affected by WG. CONCLUSIONS CD4(+)CD25(+) effector memory T-cells expressing CD134 and GITR seem to play a role in disease mechanisms, as suggested by their close association with disease activity and their participation in inflammatory process.

Immunohistochemical demonstration of chromogranins A and B in neuroendocrine tumors of the lung

Fifty neuroendocrine tumors of the lung (16 carcinoids, two atypical carcinoids/well-differentiated neuroendocrine carcinomas [WDNCs], 13 neuroendocrine carcinomas of intermediate cell type [SCNCs], and 19 neuroendocrine carcinomas of small cell type [SCNs]) were immunohistochemically investigated with antibodies against chromogranins A and B. All carcinoids and WDNCs were positive for both chromogranins A and B, whereas in cases of ICNC and SCNC both markers were only expressed in six and five cases, respectively. One ICNC was only positive for chromogranin A. In cases of SCNC five tumors were exclusively positive for chromogranin A and six were positive only for chromogranin B. Chromogranins are therefore excellent markers for the immunohistochemical demonstration of carcinoids and WDNCs. It may be speculated that expression of chromogranins in cases of ICNC and SCNC represents a higher degree of differentiation in these tumors.

Rapid detection of mycobacterial DNA in clinical samples by multiplex PCR.

Triplex-polymerase chain reaction technique (PCR) was developed for the detection and identification of mycobacterial DNA sequences in uncultured clinical samples. A 123 bp fragment corresponding to a specific Mycobacterium tuberculosis sequence complex, a 383 bp DNA fragment encoding for part of the 65 kD mycobacterial surface antigen, and a 268 bp fragment of the human (3-globin gene to demonstrate the presence of suitable DNA were amplified by triplex PCR. To demonstrate the applicability of this method, 206 alcohol-fixed, paraffin-embedded sputum samples from 47 patients with culture-proven tuberculosis were investigated. Of 206 samples, 157 were PCR positive, resulting in correct diagnosis of tuberculosis in 46 of 47 (97.8%) patients. Furthermore, 165 alcohol-fixed, auramin-stained sputum smears were examined in a blind trial. Triplex PCR revealed tuberculosis in 20 of 21 samples from patients with tuberculosis. In comparison, cultures were positive in 20 of 21 samples. and acid-fast organisms were found by microscopy in 18 of 21 samples. We conclude that triplex PCR is a rapid and sensitive technique for the detection of mycobacterial DNA in uncultured clinical samples and offers equivalent sensitivity (95.2%) and specificity (98.6%) as do culture methods.

Pathologie des Schilddrüsenkarzinoms

ZusammenfassungSchilddrüsenkarzinome machen etwa 1% aller menschlichen Malignome aus und stellen somit einen eher seltenen Tumortyp dar. Sowohl die Abgrenzung der Karzinome von gutartigen Läsionen (Hyperplasien, Adenome) als auch die für die weitere Therapie notwendige exakte Klassifizierung der Schilddrüsenkarzinome stellen in der täglichen Routinepathologie mitunter eine diagnostische Herausforderung dar. Schilddrüsenkarzinome mit Follikelzellursprung werden nunmehr auch in der kürzlich erschienenen WHO-Klassifikation der Schilddrüsentumoren aufgrund ihres biologischen Verhaltens in papilläre, follikuläre, gering differenzierte und anaplastische Karzinome unterteilt. Während die differenzierten Karzinome (papilläre und follikuläre Karzinome) ganz überwiegend eine hervorragende Prognose aufweisen, zeigt das gering differenzierte Karzinom eine deutlich schlechtere und das anaplastische Karzinom in der Regel eine infauste Prognose. Das von den C-Zellen ausgehende medulläre Karzinom tritt in einer sporadischen und familiären Form auf. Das familiäre medulläre Karzinom wird autosomal-dominant vererbt und kann heute in fast allen Fällen durch entsprechende Mutationen des RET-Protoonkogens nachgewiesen werden.AbstractThyroid carcinoma accounts for approximately 1% of all human malignancies and is thus a rather rare tumour. Both its differential diagnosis from benign lesions (thyroid hyperplasia and adenoma) and exact classification may cause substantial difficulties in daily routine diagnostic pathology. Due to their different biological behaviour the recently published WHO classification of thyroid tumours subdivides thyroid carcinomas of follicular cell origin into well-differentiated carcinomas (papillary and follicular carcinoma), poorly differentiated carcinomas and anaplastic carcinomas. Whereas papillary and follicular carcinomas are usually associated with good prognosis, poorly differentiated carcinoma shows a significantly less favourable and anaplastic carcinoma even a devastating outcome. Thyroid medullary carcinoma, originating from calcitonin-producing C cells, occurs in a sporadic and familial form; the familial type is inherited in an autosomal dominant manner and shows specific germ line mutations of the RET proto-oncogene.