Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience.

OBJECTIVES: Cisplatin is essential in the curative treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC) patients. The assessment of risk factors to predict an early cisplatin-induced nephrotoxicity could help in better managing one of the most relevant cisplatin-related dose-limiting factors. MATERIAL AND METHODS: We retrospectively collected data of LA-HNSCC patients treated at our Institution from 2008 to 2019. Patients received cisplatin in a curative setting concurrently with radiation. Acute Kidney Injury (AKI) was assessed as a dichotomous variable (CreaIncr) based on pre-treatment values, and values recorded at days 6-20 post-first cycle of cisplatin. Univariable logistic regression models were performed to investigate associations between CreaIncr and clinical characteristics. A multivariable logistic model on a priori selected putative covariates was performed. RESULTS: Of the 350 LA-HNSCC treated patients, 204 were analyzed. Ninety (44 %) suffered from any grade AKI (grade I 51.1 %): out of them, 84.4 % received high-dose cisplatin (100 mg/m2 q21). On the univariable logistic regression model, male sex, age, serum uric acid, creatinine, concomitant drugs, and cisplatin schedule were significantly associated with a higher rate of AKI. At multivariable model, age (p = 0.034), baseline creatinine (p = 0.027), concomitant drugs (p = 0.043), and cisplatin schedule (one-day bolus or fractionated high-dose vs. weekly; p = 0.001) maintained their significant association. CONCLUSIONS: Identifying pre-treatment risk factors in LA-HNSCC patients may improve decision-making in a setting where cisplatin has a curative significance. A strict monitoring of AKI could avoid cisplatin dose adjustments, interruptions, and treatment delays, thus limiting a negative impact on outcomes.

Assessing suffering of patients on cancer treatment and of those no longer treated using ESAS-Total Care (TC).

AIM: The aim of the study was to assess the suffering of patients on oncologic treatment and of those no longer on treatment. Preliminarily, we aimed to confirm the psychometric properties of Edmonton Symptom Assessment System-Total Care (ESAS-TC) in different stages of the disease. The ESAS-TC screens physical and psychological symptoms, but also spiritual pain, discomfort deriving from financial problems associated with illness, and suffering related to social isolation. METHODS: A sample of consecutive advanced cancer patients on oncologic therapies treated at the Internistic and Geriatric Supportive Care Unit (IGSCU) of Istituto Nazionale dei Tumori, Milano, and of terminal patients no longer on treatment and cared for by the Fondazione ANT palliative home care team were asked to fill the ESAS-TC. In order to strengthen the previous validation study of the ESAS-TC, 3-ULS (to assess social isolation), JSWBS (to assess spiritual well-being), COST-IT (to assess financial distress), and KPS (to assess functional status) were administered too. RESULTS: The questionnaires were self-reported by 108 patients on treatment (52% >60 years old, female 53%, and 61% with KPS 90-100) and by 94 home care patients (71% >60 years old, female 51%, and 68% with KPS 10-50). The sound psychometric characteristics of ESAS-TC were confirmed. Patients on treatment showed lower total ESAS-TC score (19.3 vs 52.7, p<.001) after controlling for age and functional status, and lower financial distress (p.<001). Financial distress, spiritual suffering, and social isolation, after controlling for age, showed a significantly higher score in home care patients. CONCLUSIONS: Only through an adequate routine assessment with validated tools is it possible to detect total suffering, the "Total pain" of patients, and treat it through a multidisciplinary approach. The study confirms the reliability and validity of the Italian version of ESAS-TC and the importance of supportive and early palliative care fully integrated with oncological treatment.

Case report: pseudoendocrine sarcoma, a clinicopathologic report of a newly described soft tissue neoplasm.

Papke et al. recently reported a series of twenty-three soft tissue lesions chiefly arising in older adults featuring distinct morphological and genetic characteristics. Pseudoendocrine sarcoma (PS) is the somewhat descriptive and provisional term adopted for the newly reported mesenchymal neoplasm. Since the publication of the original paper published in January 2022, a single case of PS has been published. Pseudoendocrine sarcoma shows a predilection for the paravertebral deep soft tissues of the trunk, low-grade neuroendocrine-like histological features, and hallmark CTNNB1 activating mutations.Herein, we will discuss a case of a 72-year-old woman presenting with a 4-cm laterocervical mass. Hematoxylin and eosin slides showed a multilobular proliferation of monomorphic epithelioid cells with speckled chromatin arranged in nests and trabeculae. Immunohistochemical staining and molecular analysis were consistent with the newly proposed entity.

Italian version of the Edmonton Symptom Assessment System (ESAS)-Total Care (TC): development and psychometric validation in patients undergoing cancer treatment or follow-up.

INTRODUCTION: The routine use of patient-reported outcomes (PROs) in clinical practice improves quality of care, it helps in reducing the access to emergency services and unscheduled visits, and it can improve cancer patients' time survival. The Edmonton Symptom Assessment System (ESAS) is a PRO largely used in different care settings to monitor physical and psychological symptoms. Nonetheless, along with these symptoms, literature also highlighted the presence and effect of spiritual pain, financial distress, and social isolation on quality of care, treatment effectiveness, and survival. AIM: The aims of the current study were (a) to complete the Italian version of the ESAS validation process by adding the missing symptom "insomnia" and (b) to develop and validate the ESAS-Total Care (ESAS-TC) that is intended to evaluate and screen not only physical and psychological symptoms but also spiritual pain, discomfort deriving from financial problems associated with illness, and suffering related to social isolation. METHODS: A sample of Italian native outpatients, who referred to the dedicated Supportive Care Unit of the Fondazione IRCCS, Istituto Nazionale deiTumori (INT), Milano, were asked to fill the ESAS-TC to assess item properties, factorial structure, internal consistency, test-retest reliability (patients were asked to retake the scale after 2-6 weeks), and external validity. Concerning the latter, other self-administered scales were employed to assess perceived stress (Perceived Stress Scale), unmet needs (using theNeed Evaluation Questionnaire that describes informative, assistance/care, relational, needs for psycho-emotional support, material needs), and perceived social support (administering the Multidimensional Scale of Perceived Social Support that evaluates perceived support of family, friends, and significant others in the wider social field). RESULTS: The scales were administered to 243 patients with solid (90%) and hematologic (10%) cancers, mean age 62.6, female 76.5%. Analysis suggested that a single factor better represents the structure of the ESAS scales, their internal consistency and test-retest reliability were good, and evidence of construct and criterion validity were provided. Additionally, incremental validity of the ESAS-TC was proved showing that the added items offer a unique contribution in predicting the patient's stress. Finally, known groups validity was confirmed testing the differences in the ESAS scores due to the Karnofsky Performance Status. CONCLUSIONS: The current study allowed to complete the validation of the Italian version of the ESAS and to develop a psychometrically sound scale, the ESAS-Total Care, that potentially helps in moving cancer research toward personalized total cancer care.

Clear cell sarcoma-like/malignant gastrointestinal neuroectodermal tumor of the tongue: a clinicopathologic and molecular case report.

Malignant gastrointestinal neuroectodermal tumor (M-GNET) and clear cell sarcoma (CCS) of soft tissue represent closely related, extremely rare, malignant mesenchymal neoplasm of uncertain differentiation. Both entities are characterized genetically by the same molecular alterations represented by the presence of EWSR1-ATF1 and, more rarely, EWSR1-CREB1 fusion genes. The latter translocation seems to be more represented in M-GNET that, despite significant morphologic overlap with CCS, tends to lack overt features of melanocytic differentiation. Most M-GNET occur in the lower gastrointestinal tract, whereas occurrence in the upper tract has been reported only exceptionally. The differential diagnosis represents a major challenge, and accurate diagnosis impact significantly on therapeutic planning. We herein report the clinicopathologic features of a molecularly confirmed M-GNET that arose at the base of the tongue and review the pertinent literature.

Primary malignant ossifying fibromyxoid tumour of the bone. A clinicopathologic and molecular report of two cases.

OBJECTIVE: To report the exceptional occurrence of ossifying fibromyxoid tumour (OFMT) as a primary bone lesion. OFMT is a rare soft tissue tumour of uncertain differentiation and variable malignant potential, that occurs in adults with a slight male predominance. It is typically located in the subcutis or in the skeletal muscles of the extremities, followed by trunk or head and neck. METHODS: Two cases of OFMT proven to arise from bone are presented. The first is a 65-year old female with a history of rib "osteosarcoma", presenting with an inferior lobe left lung mass. The second is a man with a lytic lesion of the 5th cervical vertebra that recurred shortly after resection. Following H&E and immunohistochemical examination, tumour samples were analysed by NGS and by break-apart FISH to detect rearrangement of the PHF1 and TFE3 genes. RESULTS: PHF1 gene-rearrangement was identified by FISH on both the primary and the metastatic lesion of first patient. NGS identified a PHF1(intron1) and EPC1 (exon 10) fusion transcript later confirmed by positive PHF1 rearrangement on FISH in the second case. CONCLUSIONS: The demonstration of PHF1 gene rearrangements represents a fundamental ancillary diagnostic test when presented with challenging examples of OFMT.

Multifocal Medulloblastoma in an Adult Patient: Description of a Rare Presentation and Review of the Literature.

Medulloblastoma is an embryonal neuroepithelial tumor that affects mainly childhood and more rarely adults. Medulloblastoma occurring as multiple nodules at diagnosis is a rare and tricky presentation. Here, we describe the case of a previously healthy 47-year-old woman with multiple posterior fossa cerebellar tumors. Histological, immunohistochemical, and molecular analyses were performed to best characterize the two excised lesions. The histopathological analysis revealed different variants of medulloblastoma in the excised nodules, one being extensive nodularity, rare in adults, and the other desmoplastic/nodular with areas of anaplasia. Immunostains and molecular analysis classified both nodules as SHH medulloblastoma. Adult medulloblastoma is extremely rare. Important differences exist between adult medulloblastoma and medulloblastoma arising in children and infants. Such differences are in location, distribution of histological variants and of molecular subgroups, survival rates, and therapeutic options. An extensive morphological and molecular characterization of such rare tumors is necessary to choice the best-tailored therapy.

The validation of the Italian version of the COmprehensive Score for financial Toxicity (COST).

PURPOSE: Financial toxicity (FT) is the unintended, potential economic harm or damage of oncologic treatments that has become a medical problem with political implications. To assess FT, the COmprehensive Score for financial Toxicity (COST) questionnaire was developed. Since an Italian version is not available yet, we aimed to validate the Italian version of the COST questionnaire in a population of cancer patients during oncologic treatments or follow-up. METHODS: A sample of Italian native outpatients were asked to fill the Italian version of the COST and five other self-administered questionnaires to assess quality of life, treatment-related symptoms, hope, distress, and unmet needs. Additionally, a subsample of patients was asked to retake the COST after 2-6 weeks. RESULTS: A single factor better represents the scale structure. Internal consistency and test-retest reliability were good. Evidence of convergent and discriminant validity was provided and criterion validity was established, showing that financial toxicity predicts the patient's distress. Finally, known-groups validity was confirmed, testing the differences related to treatment-related expenses, sociodemographic characteristics, stage of the disease, and performance status. CONCLUSION: The current findings suggest the Italian version of the COST is a psychometrically sound scale that potentially offers an added value in assessing FT in patients with cancer.

Interferon-Gamma and Tumor Necrosis Factor-Related Weak Inducer of Apoptosis Expression in Neoangiogenesis in Colorectal Polypoid Lesions.

BACKGROUND: Interferon gamma (IFNγ) and tumor necrosis factor-related weak inducer of apoptosis (TWEAK) molecules seem to have a potential effect on angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of this study was to assess a possible interplay between IFNγ and TWEAK cytokines and VEGF machinery in the different steps of colorectal carcinogenesis. METHODS: A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Polypoid lesion tissue samples were collected and frozen. Real-time reverse transcription polymerase chain reaction for IFNγ, TWEAK, and VEGF-A mRNA expression was performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Nonparametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. RESULTS: IFNγ and TWEAK mRNA expression was higher in patients with T2 or more advanced colorectal cancer than in those with adenomas or T1 cancer (p < 0.001 and p = 0.01, respectively). IFNγ and TWEAK mRNA expression levels directly correlated with VEGF-A mRNA expression levels (rho = 0.44, p < 0.001 and rho = 0.29, p = 0.004, respectively). On the contrary, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGF-C protein levels (rho = -0.29, p = 0.04 and rho = -0.31, p = 0.03, respectively). Similarly, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGFR2 protein levels (rho = -0.38, p = 0.033 and rho = -0.40, p = 0.025, respectively). CONCLUSION: This study showed that in colorectal polypoid lesions, IFNγ and TWEAK expressions are directly correlated to VEGF-A expression but inversely correlated with VEGFR2 levels, suggesting a possible feedback mechanism in the regulation of VEGF-A expression.

Assessment of the interlaboratory variability and robustness of JAK2V617F mutation assays: A study involving a consortium of 19 Italian laboratories.

To date, a plenty of techniques for the detection of JAK2V617F is used over different laboratories, with substantial differences in specificity and sensitivity. Therefore, to provide reliable and comparable results, the standardization of molecular techniques is mandatory.A network of 19 centers was established to 1) evaluate the inter- and intra-laboratory variability in JAK2V617F quantification, 2) identify the most robust assay for the standardization of the molecular test and 3) allow consistent interpretation of individual patient analysis results. The study was conceived in 3 different rounds, in which all centers had to blindly test DNA samples with different JAK2V617F allele burden (AB) using both quantitative and qualitative assays.The positivity of samples with an AB < 1% was not detected by qualitative assays. Conversely, laboratories performing the quantitative approach were able to determine the expected JAK2V617F AB. Quantitative results were reliable across all mutation loads with moderate variability at low AB (0.1 and 1%; CV = 0.46 and 0.77, respectively). Remarkably, all laboratories clearly distinguished between the 0.1 and 1% mutated samples.In conclusion, a qualitative approach is not sensitive enough to detect the JAK2V617F mutation, especially at low AB. On the contrary, the ipsogen JAK2 MutaQuant CE-IVD kit resulted in a high, efficient and sensitive quantification detection of all mutation loads. This study sets the basis for the standardization of molecular techniques for JAK2V617F determination, which will require the employment of approved operating procedures and the use of certificated standards, such as the recent WHO 1st International Reference Panel for Genomic JAK2V617F.

Colorectal polypoid lesions and expression of vascular endothelial growth factor in a consecutive series of endoscopic and surgical patients.

Colorectal cancer incidence in patients undergoing screening protocols is decreasing because of the higher rate of discovered preneoplastic colonic lesions; however, adenomatous polyps may not always be removable endoscopically and surgery may still be necessary. The aim of this study was to assess the vascular endothelial growth factor expression in the different steps of colorectal carcinogenesis to explore its potential role as a marker of malignancy in polypoid lesions. A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Real-time reverse transcription polymerase chain reaction for VEGF-A messenger RNA expression and immunohistochemistry for VEGF-A were performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Non-parametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. VEGF-A messenger RNA expression was higher in patients with high-grade dysplasia or colorectal cancer than in those with low-grade dysplasia adenomas (p = 0.01). At immunohistochemistry, VEGF-A expression was significantly higher in colorectal cancer patients compared to dysplastic adenomas (p < 0.001), and the accuracy of VEGF-A expression for prediction of malignancy was 91.7 (95% confidence interval = 78.7-97.9). VEGF-C protein expression was lower in colorectal cancer patients than in simple adenomas (p = 0.02). VEGF-A levels were directly correlated to polyp size (rho = 0.73, p = 0.0062). Multivariate analysis demonstrated that malignancy and polyp size were independent predictors of VEGF-A mucosal levels. This study demonstrated that the VEGF-A expression changes along the colorectal carcinogenesis pathway showing a neat step up at the passage from high-grade dysplasia to invasive cancer. This feature might potentially be useful to stratify colorectal polyps in different risks of progression classes. Moreover, the high level of VEGF-A expression predicted the presence of lymphovascular invasion with good accuracy.

Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors.

AIM: The BRAF mutation is a rare pathogenetic alternative to KIT/PDGFRA mutation in GIST and causes Imatinib resistance. A recent description of KIT and BRAF mutations co-occurring in an untreated GIST has challenged the concept of their being mutually exclusive and may account for ab initio resistance to Imatinib, even in the presence of Imatinib-sensitive KIT mutations. BRAF sequencing is generally limited to KIT/PDGFRA wild-type cases. Hence, the frequency of concomitant mutations may be underestimated. METHODS: We screened for KIT (exon 9, 11 ,13 ,17), PDGFRA (exon 12,14, 18) and BRAF (exon 15) mutations a series of 407 GIST. Additionally, we evaluated the BRAF V600E mutation-specific antibody, VE1, as a surrogate for V600E mutation, on a series of 313 GIST (24 on whole sections, 288 cases on tissue array), including 6 cases molecularly ascertained to carry the BRAF V600E mutation. RESULTS: No concomitant KIT/BRAF or PDGFRA/BRAF mutations were detected. BRAF mutation was detected only in one case, wild-type for KIT/PDGFRA. All the 6 BRAF-mutant cases stained positive with the VE1 antibody. A weak VE1 expression was observed in 14/287 (4.9%) BRAF wild-type cases, as observed also in 2/6 BRAF-mutant cases. Overall in our series, sensitivity and specificity of the VE1 antobody were 100% and 95.1%, respectively. CONCLUSIONS: The concomitance of BRAF mutation with either KIT or PDGFRA mutation is rare in GIST. In these tumors, moderate/strong VE1 immunoreactivity is a valuable surrogate for molecular analysis. Instead, genotyping is warranted in the presence of weak VE1 staining.

KIT, PDGFRA, and BRAF mutational spectrum impacts on the natural history of imatinib-naive localized GIST: a population-based study.

The mutation status of KIT or PDGFRA notoriously affects the response of advanced gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors. Conversely, it is currently still unclear whether mutation status impinges on the prognosis of localized, untreated GISTs. Hence, at present, this variable is not included in decision making for adjuvant therapy. A series of 451 primary localized GISTs were analyzed for KIT, PDGFRA, and BRAF mutations. Univariable and multivariable analyses and a backward selection procedure were used to assess the impact of mutation status on overall survival and to identify prognostically homogenous groups. Mutation was a significant prognostic indicator of overall survival in naive, localized GISTs (P<0.001): KIT-mutated patients had a worse outcome than PDGFRA-mutated or triple-negative (KIT, PDGFRA, BRAF wild-type) cases. Multivariable Cox regression models allowed us to identify 3 molecular risk groups: group I exhibited the best outcome and included PDGFRA exon 12, BRAF, and KIT exon 13-mutated cases; group II, of intermediate clinical phenotype (HR=3.06), included triple-negative, KIT exon 17, PDGFRA exon 18 D842V, and PDGFRA exon 14-mutated cases; group III displayed the worst outcome (hazard ratio=4.52), and comprised KIT exon 9 and exon 11 and PDGFRA exon 18 mutations apart from D842V. This study highlights the prognostic impact of mutation status on the natural course of GIST and suggests that the molecular prognostic grouping may complement the conventional clinicopathologic risk stratification criteria in decision making for adjuvant therapy.

Impact of molecular analysis on the final sarcoma diagnosis: a study on 763 cases collected during a European epidemiological study.

Sarcomas are rare, heterogenous, and often difficult to classify. A large proportion of sarcomas are associated with specific molecular genetic lesions such as translocations, mutations, and amplifications, which are helpful in the diagnosis of individual cases. However, the exact impact of molecular genetics on the final diagnosis of sarcomas is unknown. In this study, all soft tissue and visceral sarcomas arising in patients living in 3 European regions in 2 countries (representing 13 million inhabitants) were collected and reviewed during 2 consecutive years. A molecular analysis was performed for all suspicions of sarcomas with specific genetic lesions [mutations of KIT/PDGFRA in gastrointestinal stromal tumors (GISTs), reciprocal translocation, or amplification of MDM2 in atypical lipomatous tumors, well-differentiated liposarcoma-dedifferentiated liposarcoma (ALT/WDLPS-DDLPS)]. To evaluate the impact of molecular tests, a premolecular analysis diagnosis was proposed with 3 categories of certainty: certain, probable, or possible. A molecular analysis was performed in 763/1484 tumors corresponding to 295 cases in which GIST was suspected, 248 sarcomas with a suspicion of translocation, and 220 cases in which ALT/WDLPS-DDLPS was suspected. Molecular analysis was found to be useful (confirms a probable diagnosis) in 11 (4%) GISTs, 62 (26%) suspicions of translocation, and 66 (31%) suspicions of ALT/WDLPS-DDLPS; and necessary (allows a possible diagnosis) in 2 (<1%) GISTs, 31 (12%) suspicions of translocation, and 19 (9%) suspicions of ALT/WDLPS-DDLPS. This study performed in an epidemiological setting demonstrates the significant impact of molecular analysis on the final sarcoma diagnosis and favors such an analysis on any tumor with a suspicion of a specific genomic abnormality and for which the diagnosis is uncertain.

Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables.

Gastrointestinal stromal tumor (GIST) natural history per se has not been extensively investigated yet, with most data being drawn from large studies with a relevant referral bias. Hence, the estimation of prognosis still remains a critical issue. We retrospectively evaluated 929 GISTs resected between 1980 and 2000 in 35 Italian institutions. A total of 526 patients were found to be suitable for refining risk assessment through the development of a survival nomogram. Median follow-up was 126 months. On testing for potential prognostic parameters, age, tumor site, size, and mitotic index proved to be predictors of OS on both univariable and multivariable Cox model analyses, whereas necrosis and cytonuclear atypia were significant on univariable analysis only. The discriminative ability of the model, including the parameters selected after a backward procedure (C=0.72), improved compared with the National Institutes of Health 2002 (C=0.64) and the National Comprehensive Cancer Network 2007 (C=0.63). On the basis of these data we developed a prognostic nomogram for survival that considers site, size, and mitotic index as continuous variables, providing estimates stratified for patients aged ≤65 and >65 years. This nomogram is a tool based on survival. It overcomes problems that result from artificial categorization of continuous variables. We believe that in the future this should also be attempted by nomograms based on the risk of relapse.

Molecular and clinicopathologic characterization of gastrointestinal stromal tumors (GISTs) of small size.

Although Gastrointestinal stromal tumors (GISTs) affect about 0.0014% of the population, GISTs smaller than 1 cm (microGISTs) are detectable in about 20% to 30% of elderly individuals. This suggests that microGISTs likely represent premalignant precursors that evolve only in a minute fraction of cases toward overt GISTs. We sought histopathologic and molecular explanations for the infrequent clinical progression in small GISTs. To investigate the mechanisms of GIST progression and identify subsets with differential malignant potential, we carried out a thorough characterization of 170 GISTs <2 cm and compared their KIT/PDGFRA status with overt GISTs. The proliferation was lower in microGISTs compared with GISTs from 1 to 2 cm (milliGISTs). In addition, microGISTs were more frequently incidental, gastric, spindle, showed an infiltrative growth pattern, a lower degree of cellularity, and abundant sclerosis. The progression was limited to 1 ileal and 1 rectal milliGISTs. KIT/PDGFRA mutations were detected in 74% of the cases. The overall frequency of KIT/PDGFRA mutation and, particularly, the frequency of KIT exon 11 mutations was significantly lower in small GISTs compared with overt GISTs. Five novel mutations, 3 in KIT (p.Phe506Leu, p.Ser692Leu, p.Glu695Lys) 2 in PDGFRA (p.Ser847X, p.Ser667Pro), plus 4 double mutations were identified. Small GISTs share with overt GIST KIT/PDGFRA mutation. Nevertheless, microGISTs display an overall lower frequency of mutations, particularly canonical KIT mutations, and also carry rare and novel mutations. These molecular features, together with the peculiar pathologic characteristics, suggest that the proliferation of these lesions is likely sustained by weakly pathogenic molecular events, supporting the epidemiologic evidence that microGISTs are self-limiting lesions.

DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours.

AIMS: The histopathological diagnosis of gastrointestinal stromal tumours (GIST) is typically made based on a combination of clinical and morphological features supported by immunohistochemistry studies. The aim of this study was to examine the staining quality, sensitivity, specificity and utility of antibodies used commonly in GIST diagnosis. METHODS AND RESULTS: Immunohistochemistry with a panel of antibodies [CD117, DOG1, protein kinase C (PKC)-theta, nestin, CD34, smooth muscle actin (SMA), desmin, S100 and CD171] was performed on whole sections from 187 GIST and 29 gastrointestinal mesenchymal tumours, and on several microarrays including 355 GISTs and 120 soft tissue sarcomas. Results showed that DOG1 and CD117 were the most sensitive and specific antibodies used in GIST diagnosis. PKC-theta and nestin were sensitive, but less specific, also staining other spindle cell tumours commonly considered in the differential diagnosis of GIST. CD34 staining was less sensitive than many of the other antibodies and of limited aid in diagnosis. The smooth muscle markers SMA and desmin, together with the neural marker S100, were unhelpful in confirming a diagnosis of GIST, but were particularly useful in the exclusion/diagnosis of other gastrointestinal mesenchymal tumour types. CONCLUSIONS: In the majority of histologically suspected GISTs a combination of CD117 and DOG1 immunostaining is sufficient to confirm the histological diagnosis.

A novel missense mutation in the Connexin 26 gene associated with autosomal recessive nonsyndromic sensorineural hearing loss in a consanguineous Tunisian family.

Nonsyndromic sensorineural hearing impairment is inherited in a predominantly autosomal recessive manner in up to 70% of cases. The gene more often involved is GJB2, encoding the gap junction protein Connexin 26. We report here a novel missense mutation in the GJB2 gene found in a Tunisian family. A homozygous change C/G at nucleotide 263 was detected in the 4-year-old girl of this family, affected by congenital moderate hearing loss. This transversion leads to the replacement of a highly conserved alanine with glycine at codon 88 (A88G). The consanguineous parents of the child are healthy carriers of the mutation.