D. Santini

Retrospective studies of early gastric cancer in a high incidence area of Italy

Frequency and characteristics of early gastric cancer (egc) were evaluated in a retrospective study of 511 surgical specimens of gastric carcinoma. We observed a total of 46 egc in 40 patients. The predominant macroscopic type was IIc, followed by I and III. On the basis of histological appearance, 25 egc were of intestinal type and 15 of diffuse type. Seventy‐six per cent of egc were localized at the lesser curvature of the stomach and in particular at the pyloric antrum. Twenty‐two egc were limited to the mucosal layer. No relationship was observed between macroscopic type or histological characters, and tumour staging. As Italy can be considered a high‐risk country for gastric carcinoma and because this disease is in many respects similar to that observed in Japan, it seems possible to obtain a reduction of the death rate for gastric cancer by increasing, as in Japan, the number of cancers diagnosed in the early phase.

Microscopic margins of resection influence primary gastrointestinal stromal tumor survival

Background: Primary gastrointestinal stromal tumors (GISTs) are stromal tumors that arise from the gastrointestinal tract. Both surgical resection and molecular therapy are crucial in the treatment of these tumors. This study analyzes the outcomes of 151 patients with GIST treated at 3 institutions. These institutions comprise the GISTologist Study Group and provided follow-up data. Patients and Methods: 151 patients with primary GIST were admitted and treated at the St. Orsola-Malpighi University Hospital in Bologna, Italy, the Catholic University Hospital in Rome, Italy, and the Modena University Hospital and National Cancer Institute in Naples, Italy, over the past 11 years. Patient data as well as tumor and therapy variables were studied to identify factors predicting survival with a focus on the microscopic margins of resection. Results: All 151 patients had primary disease without metastasis and underwent complete resection of gross disease. The 5-year disease-free survival rate was 77%. Disease-free survival was predicted by tumor size, mitotic count, and margins of resection. Recurrence of disease after resection was predominantly intra-abdominal. Conclusions: Tumor size, mitotic count, and microscopic margins of resection predict disease-free survival in patients with primary GIST.

Determination of Mammalian Target of Rapamycin Hyperactivation as Prognostic Factor in Well-Differentiated Neuroendocrine Tumors

Purpose To evaluate the role of the activation of mTOR (phosphorylated mTOR, p-mTOR) and the expression SSTR2A and IGF-1R as prognostic factor in well-differentiated neuroendocrine tumors. Methods A retrospective study was conducted on data from patients with diagnosis of neuroendocrine tumor originated from pancreas (pNET) or gastrointestinal tract (stomach, appendix, and ileus; GI-NET) made between January 2003 and December 2004 and followed up at our institution. Archival material should be available for revision according to WHO 2010 neuroendocrine tumor classification and for p-mTOR, SSTR2A, and IGF-1R immunostaining, calculating a quantitative score (QS). We evaluated clinical, pathological, and immunohistochemistry features for association with the presence of advanced disease at diagnosis and disease relapse in patients who have undergone radical surgery. Results Archival material from 64 patients was analyzed (37 pNETs and 27 GI-NETs). In these patients, G2 grading, low SSTR2A QS, and high p-mTOR QS were associated with advanced disease at diagnosis at multivariate analysis. Risk of recurrence in 49 patients with R0-resected tumors was higher for G2 grading, stage IIIB-IV, low IGF-1R QS, and high p-mTOR QS at univariate analysis. Conclusions With the limits of retrospective data, activation of m-TOR is correlated with advanced disease at diagnosis and with shorter disease-free survival after R0 resection. Validation through prospective studies is needed.

‘All action no talk’: the role of HER2/neu in adjuvant therapy choice for gastric cancer

HER2 protein is a transmembrane tyrosine kinase receptor belonging to the HER family. HER2 is known to be involved in the pathogenesis of several human cancers and its overexpression and/or amplification, in the last three decades, has been robustly associated with poor prognosis in breast cancer, leading to the use of trastuzumab and other anti-HER2 targeted agents as the backbone of HER2-positive patients’ treatment [1]. The interest in studying the role of HER2 in gastric cancers has developed differently. The pivotal work [2] demonstrating the prognostic value of the HER2 gene in gastric cancer was published at the beginning of 1990s, but for the following 20 years, a large variation in the rate of HER2 positivity (ranging from 44 to 53.4%) across different studies [3] was found. This lack of consistency can be partly attributed to the differences in study populations, but especially to the use of non-standardized methodology (mainly based on IHC) and different scoring criteria. Things changed when the majority of researchers adopted the scoring criteria developed by Hofmann et al. for the ToGA trial [4], which reduced the variation to a range of 9.4%– 15.7% [5–9]. However, it is not surprising that the potential prognostic role of HER2 in gastric cancer is still under debate [10, 11]. Although most of the authors have found significant correlation between HER2positive status and poor outcomes, others have not demonstrated any association between HER2 expression and prognosis [3]. The results from the ToGA [5] trial further complicated this issue as the study showed a longer than expected (historical controls) overall survival of patients who received chemotherapy alone, leading the authors to take into account a possible role of HER2 overexpression in conferring a better prognosis. Therefore, the authors concluded that further studies were needed to obtain a definitive answer about the prognostic role of HER2 in gastric cancer. Although trastuzumab is, so far, the only targeted therapy that has demonstrated in a randomized trial a modest but clinically significant improvement in survival when combined with chemotherapy as first-line treatment in metastatic gastric cancer, further research aiming to elucidate the actual biological and prognostic role of HER2 overexpression in this disease would seem to be mandatory. The contribution provided by Gordon et al. [12] interestingly describes the role of HER2 status in an unexplored landscape of the chemo-radiation adjuvant setting. In particular, the authors investigated the potential prognostic and/or predictive role of HER2 amplification/overexpression using the population of the SWOG9008/INT-0116 trial. In this phase III trial 582 patients with resected stage IB-IV(M0) gastric and gastroesophageal (GE) junction cancer were randomly assigned to postoperative adjuvant therapy with 5-fluorouracil (5-FU)/leucovorin plus external beam radiation versus observation. After a median follow-up of 10 years, a survival advantage was observed in all subsets of patients treated with postoperative chemoradiation (except for cases with diffuse histology) and HER2 positivity status was able to independently predict a lack of benefit from adjuvant chemo-radiation, especially considering that none of the 28 HER2-positive cancers had diffuse histology [13]. These data are in accordance with previously reported preclinical evidence suggesting a possible role of HER2-mediated PI3K/ AKT pathway activation in reducing cytotoxicity of 5-FU and radiation in breast cell lines [14–17] and with the reported reduction in resistance of HER2 overexpressing gastric cancer cell lines treated with trastuzumab [18]. Therefore, this study could represent a step forward in understanding the clinical utility of HER2 assessment in gastric cancer patients as it elucidates for the first time in the literature a predictive role in the adjuvant setting in a phase III prospective trial. Furthermore, despite not being able to reach a conclusion regarding the prognostic role of HER2 status in the postoperative setting, given the low number of HER2-positive cases, these results support the rationale to further consider this biological marker as one of the possible parameters to guide clinical decisions regarding adjuvant treatment. To note, despite the paper by Gordon et al. having a robust methodology, some factors should be taken into consideration in order to better understand the global value of this analysis. The first concern is related to the molecular analysis which was done retrospectively and was not planned in this clinical trial: <50% (258 of 559) of the enrolled patients had pathological specimens available and this could reflect a selection bias. Second, the balance of the main clinical and pathological characteristics between the two arms has not been analysed in the HER2/neu-positive patients. Third, the number of HER2-amplified cases is lower than the findings in previous reports [10]. This result is particularly relevant if we take into account that GE junction cancers. It is well documented that GE junction cancers show a higher rate of HER2 amplification, in contradistinction to the results reported by Gordon et al. Finally, it is also worth pointing out that the level of concordance between in situ hybridization methods (FISH and SISH) and IHC positivity seems to be considerably lower compared with the ones in ‘post ToGa era’ studies. One explanation for this weak correlation could be related to the IHC scoring criteria used for the study. As mentioned by the authors, the common breast cancer scoring system (BCSS) [19] has been applied to carry out the work instead of using the ed ito ria ls editorials Annals of Oncology 24: 1715–1717, 2013 doi:10.1093/annonc/mdt172 Published online 12 May 2013

Successful treatment with personalized dosage of imatinib in elderly patients with gastrointestinal stromal tumors.

Imatinib is the standard first-line therapy for metastatic gastrointestinal stromal tumors. It has markedly improved the prognosis and outcome of patients affected by gastrointestinal stromal tumors, especially in the case of exon 11 KIT mutations. Imatinib-associated adverse events are generally mild to moderate; however, in clinical practice, intolerance caused by chronic toxicities frequently leads to breaks in treatment. This is particularly true in elderly patients in whom age, decline in drug metabolism, and polypharmacy, with a possible drug–drug interaction, may influence the tolerability of imatinib. In the present article, we report our extensive experience with the management of imatinib therapy in a ‘real’ population, in particular in very elderly patients, discussing whether the use of personalized imatinib dosage could be a safe and advantageous option, enabling continuous administration, thus ensuring effective treatment. Only a few case reports in the literature provide data on outcome with low tailored dosage of imatinib and none of them has been carried out on a Western population. Here, we report four cases treated with low imatinib dosage as a safe and useful option enabling continued treatment with imatinib, improving tolerance, and maintaining good and lasting disease control.

Hyaline globules in ovarian tumours

therefore believe this is a quick, simple, inexpensive and reliable means of provisionally distinguishing gold from other black granular deposits. A confirmatory history of chrysotherapy should be obtainable with ease. We fully accept the valuable role of X-ray microanalysis in such circumstances, but few units have direct access to this facility which also has significant associated costs. All our cases have been biopsied within the past 2-3 years, with the skin cases forming part of a research programme in the Department of Rheumatology locally. Whilst we agree that chrysiasis is not a common condition, we should point out that gold deposits in lymph nodes draining injection sites may occur in the absence of established chrysiasis. Awareness of this feature of gold should be of significant value to all practising pathologists who may encounter such cases.

Identification of single nucleotide variants in gastrointestinal stromal tumor KIT/PDGFRA wild-type (WT GISTs) by massively parallel sequencing.

10046 Background: Recently SDH variations were identified in KIT and PDGFRA wild type GISTs. However the causative genomic alterations of these GISTs still remain unknown. Massively parallel sequencing allows identifying novel putative variants. METHODS Whole transcriptome paired-end RNA sequencing was performed by Illumina GAIIx system using a 75 bases paired-end strategy on tumor samples of two young adults patients (P1 and P2) affected by gastric WT-GIST (age 28 and 30 years). Sequences were aligned with BWA against exon+junction references. SNVmix2 was used for SNP calling, identifying by this 2045 and 1780 coding non-synonymous novel single nucleotide variants (SNVs) in P1 and P2, respectively. After checking misalignments by SAMTools, the variants were filtered to increasing SNPcall confidence: SNVs with quality read score > 30 (error probability of 0.1%), total coverage > 40, and ratio between coverage of alterate base and total coverage >0.3 were labeled high confidence. Single point mutations were translated at the protein level and their likelihood of being disease-associated was computed with SNP&GO and confirmed with Sanger sequencing. RESULTS In both patients common mutations in SDHA and different private SNV were highlighted. Among the private disease-related SNVs we identified mutations in MYH9 (myosin heavy chain 9) and TPI1 (triosephosphate isomerase 1) in patient P1, and a mutation in OGDHL (oxoglutarate dehydrogenase-like) in P2. MYH9 is involved in cell motility and cytokinesis, while OGDHL is an enzyme of the Krebs cycle, as the SDH complex, and TPI1 is involved in glycolysis. Ongoing validation by Sanger sequencing on DNA from tumor and peripheral blood (PB) already confirmed the presence of heterozygous MYH9 K1775E in P1 and OGDHL V815M in P2, both in tumor and PB, showing that these mutations are germinal. CONCLUSIONS Massively parallel RNA sequencing, followed by data analysis, allows to discover novel single nucleotide variants and to identify new potential target genes in WT-GIST.

Etude de la prolifération cellulaire de la muqueuse rectale à différents stades évolutifs de la colite ulcéreuse

RésuméLes biopsies rectales de 12 patients atteints de colite ulcéreuse (UC) et de 3 sujets contrôle témoins ont été incubées in vitro avec un précurseur marqué du DNA dans le but d’observer les modifications des paramètres de prolifération cellulaire décrits par d’autres auteurs à différents stades évolutifs de la maladie. Nos résultats indiquent que les paramètres de la cinétique cellulaire observés sont en relation avec le degré de sévérité de l’inflammation. Une extension du compartiment prolifératif vers la surface muqueuse a été observé dans tous les cas de colite ulcéreuse en phase active (modérée ou sévère) et dans un cas de colite quiescente.SummaryRectal biopsies from 12 ulcerative colitis (UC) patients and three controls were incubated in vitro with a labelled precursor of the DNA in order to see if the changes of proliferation patterns described by other Authors vary in different stages of the disease. Our results indicate that kinetic parameters of mucous cells seen to be correlated to the severity of inflammation. It was also observed an upward extension of the proliferative compartment in all cases of active (moderate or sevare) colitis and in one case of quiescent colitis.