Trastuzumab-based therapy has been shown to confer overall survival benefit in HER2-positive patients with advanced gastric cancer in a large multicentric trial (ToGA study). Subgroup analysis identified adenocarcinomas of the stomach and gastroesophageal (GE) junction with overexpression of HER2 according to immunohistochemistry (IHC) as potential responders. Due to recent approval of trastuzumab for HER2 positive metastatic gastric and GE-junction cancer in Europe (EMEA) HER2 diagnostics is now mandatory with IHC being the primary test followed by fluorescence in situ hybridization (FISH) in IHC2+ cases. However, in order to not miss patients potentially responding to targeted therapy determination of a HER2-positive status for gastric cancer required modification of scoring as had been proposed in a pre-ToGA study. To validate this new HER2 status testing procedure in terms of inter-laboratory and inter-observer consensus for IHC scoring a series of 547 gastric cancer tissue samples on a tissue microarray (TMA) was used. In the first step, 30 representative cores were used to identify specific IHC HER2 scoring issues among eight French and German laboratories, while in the second step the full set of 547 cores was used to determine IHC HER2 intensity and area score concordance between six German pathologists. Specific issues relating to discordance were identified and recommendations formulated which proved to be effective to reliably determine HER2 status in a prospective test series of 447 diagnostic gastric cancer specimens.

The fluid sign is featured in acute vertebral compression fractures that show bone marrow edema. It can be an additional sign of osteoporosis and rarely occurs in metastatic fractures.

Fluorescence diagnosis aims to improve the management of oral cancer via early detection of the malignant lesions and better delimitation of the tumor margins. This paper presents a comparative study of normal inspection, combined fluorescence diagnosis (CFD) and its 2 main components, autofluorescence and 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPIX) fluorescence. Biopsy-controlled fluorescence imaging and spectral analysis were performed on a total of 85 patients with suspected or histologically proven oral carcinoma both before and after topical administration of 5-ALA (200 mg 5-ALA dissolved in 50 ml of H 2 0). Fluorescence excitation was accomplished using filtered light of a xenon short arc lamp ( ‫؍‬ 375-440 nm). As for CFD, a "streetlight" contrast (red to green) was readily found between malignant and healthy tissue on the acquired images. In terms of tumor localization and delimitation properties, CFD was clearly favorable over either normal inspection or its 2 components in fluorescence imaging. The performance of CFD was found to be impeded by tumor keratinization but to be independent of either tumor staging, grading or localization. In spectral analysis, cancerous tissue showed significantly higher PPIX fluorescence intensities and lower autofluorescence intensities than normal mucosa. There is a great potential for CFD in early detection of oral neoplasms and exact delimitation of the tumors' superficial margins and an advantage over white light inspection and each of its 2 main components. The method is noninvasive, safe and easily reproducible. © 2002 Wiley-Liss, Inc. Key words: combined fluorescence diagnosis; autofluorescence photodetection; protoporphyrin IX; 5-aminolevulinic acid; oral cancer; spectroscopyMalignant neoplasms of the upper aerodigestive tract are of major importance in modern health care. Head and neck cancer is the fifth most common cancer worldwide. 1 In most industrialized countries, both morbidity and mortality rates of squamous cell carcinoma of the oral cavity or oropharynx show an upward tendency. A possible way to increase cure rates of oral cancer lies in early detection followed by radical surgery. 2 However, early lesions are often hard to detect and are sometimes overlooked, even by experienced clinicians. These early invasive carcinomas or carcinomas in situ might simply appear as flat, inconspicuous irregularities of the mucosal surface and may lack typical morphologic characteristics of malignant tumors. At the same time, especially when tongue-like, submucosal spreading of malignancy or diffuse infiltration into surrounding tissue layers is present, superficial demarcation of the tumor borders via simple inspection and/or other common diagnostic procedures often remains unsatisfactory. This may result in prolonged operation times or, in the worst case, might prevent a successful resection in terms of tumorfree borders, along with increased rates of local recurrence and a reduction in 5-year survivals. 3 To facilitate diagnosis of early or secon...

Objectives: Ea rly cance r d e tection is the best way to improve the prognosis of patie nts with oral cancer. Ther efore this study presents qua ntita tive fluorescence m ea sure ments and r esults in the visualization of cancerous oral mucosa with 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PPOO. Methods: Time progression and type of porphyrin accumulation were analyzed in n eoplastic and surrounding h ealthy ti ssu e of 58 p a tients with a suspected cancer of the oral ca vity by measuring emission spectra of 5-ALA-induced PPIX fluore ce nce. Fluorescen ce im· a ges in the r ed and green spectral range from the tumor tissu e wer e r ecorded with a charge-coupled d evice camera. R esults: After topical application of 0.4% 5-ALA and incubation for 1 to 2.5 hours, all patients r evealed high er inten sities of r ed fluoresce nce in n eoplastic tissu e compared with the surrounding normal tissu e. Maximum contrast w as r eached after 1.5 hours of incuba tion. In 13.8% (n = 8) of the patie nts, additional findings like dysplasia, carcinoma in situ, primary tumor, secondary carcinomas, and tumor branch es w er e found by means of fluorescence marking in contrast to white light examination. An evaluation of the biopsy specimen s r esulted in a sp ecificity of 60% and a sens itivity of 99o/o. Conclusions: As a fluorescent m ark er, PPIX could r epresent a possible n ew dia gnostic tool to det ect early malignant and s condary lesions in the oral cavity. In addition, 5-ALA-induced PPIX fluorescen ce is promising a s a u sefuJ intraoperative tool for d etermining ad equate Pres nted in port at the Fourth International Symposium on Predictive Oncology and Therapy, Nie , Fronce, 0 tobcr 24 -27, 1998.From the D partmcnt ofOtorhinolaryngology-Head and Neck Surg ry (A.L., c.B ., o.o.l, the Laser R s~a rch. Labo reto~ (H.s. , ~~.M., R.B.), and th e In stitute of Pathology (S.A.)

Based on the concept that ischemia is an important factor in the pathogenesis of acute pancreatitis, we developed a new model of complete ischemia/reperfusion of the pancreas in the rat. The aim of this study was to investigate the microcirculation of the pancreas after complete and reversible ischemia at different times after reperfusion by using intravital fluorescence microscopy. In addition, the effect of ischemia/reperfusion on the pancreas was assessed by means of light and electron microscopy and measurement of serum pancreas amylase concentration. In 35 adult Sprague-Dawley rats ischemia of the pancreas was induced by temporary occlusion of the four supplying arteries. Sham-operated animals served as controls (group A). After periods of 30 min (group B), 60 min (group C) or 120 min (group D) of ischemia the organ was reperfused. To exclude the influence of hypovolemia on microcirculation in group E (120 min ischemia) hydroxyethylstarch (HES) was given i.v. to maintain central venous pressure at baseline values. For intravital fluorescence microscopy the pancreas was exteriorized on a stage and quantitative analysis of microcirculation, including functional capillary density and leukocyte-endothelium interaction, was performed after 30 min, 1 h and 2 h of reperfusion. Serum pancreas-amylase was measured at control (prior ischemia) and at 2 h after reperfusion. Tissue samples for light and electron microscopy were taken 2 h after reperfusion. In sham-operated animals, functional capillary density (FCD) remained within baseline values (FCD 407.7 +/- 9 cm-1) during reperfusion. Dependent on the time of ischemia and time of reperfusion a gradual reduction in functional capillary density was observed; after 2 h of ischemia only 35% of capillaries were perfused (FCD 140.9 +/- 28.3 cm-1). Reduced functional capillary density was associated with an increase of perfusion heterogeneity to a maximum of 0.65 +/- 0.12, as against 0.13 +/- 0.02 in control animals. With a 2 h ischemia leukocyte-endothelium interaction was enhanced after 0.5 h of reperfusion (8-fold increase of adherent leukocytes in comparison to control) followed by a further significant increase until 2 h after the beginning of reperfusion. Amylase concentration after ischemia of 2 h (2967 +/- 289 U/l) was significantly higher as compared to controls (1857 +/- 99 U/l). Differences between group E and D were not observed. Pancreatic tissue injury was ascertained by histopathological studies. These results indicate that complete ischemia/reperfusion of the pancreas induces pancreatic microvascular failure. The severity of changes depends on duration of ischemia and duration of reperfusion. The morphological and biochemical changes suggest that ischemia/reperfusion causes an inflammatory reaction as observed in acute pancreatitis.