Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out. RESULTS: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

PEOPLE (NCT03447678), a first-line phase II pembrolizumab trial, in negative and low PD-L1 advanced NSCLC: clinical outcomes and association with circulating immune biomarkers.

BACKGROUND: The PEOPLE trial aimed to identify new immune biomarkers in negative and low programmed death-ligand 1 (PD-L1) (0%-49%) advanced non-small-cell lung cancer (aNSCLC) patients treated with first-line pembrolizumab. Here we report the main outcomes and the circulating immune biomarkers analysis. PATIENTS AND METHODS: The primary endpoint of this phase II trial was the identification of immune biomarkers associated with progression-free survival (PFS). Overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety were secondary endpoints. Absolute cell counts for 36 subsets belonging to innate and adaptive immunity were determined by multiparametric flow cytometry in peripheral blood at baseline and at first radiologic evaluation. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyze immune variables and their correlation with clinical endpoints. RESULTS: From May 2018 to October 2020, 65 patients were enrolled. After a median follow-up of 26.4 months, the median PFS was 2.9 months [95% confidence interval (CI) 1.8-5.6 months] and median OS was 12.1 months (95% CI 8.7-17.1 months). The ORR was 21.5%, DCR was 47.7% and median DoR was 14.5 months (95% CI 6.4-24.9 months). Drug-related grade 3-4 adverse events were 9.2%. Higher T cell and natural killer (NK) cell count at baseline and at the first radiologic evaluation were associated with improved PFS, DCR and OS. On the contrary, higher myeloid cell count at baseline or at the first radiologic evaluation was significantly associated with worse OS and DCR. CONCLUSIONS: Circulating immune biomarkers can contribute to predict outcomes in negative and low PD-L1 aNSCLC patients treated with first-line single-agent pembrolizumab.

Clinical management of patients with thymic epithelial tumors: the recommendations endorsed by the Italian Association of Medical Oncology (AIOM).

The Italian Association of Medical Oncology recommendations on thymic epithelial tumors, which have been drawn up for the first time in 2020 through an evidence-based approach, report indications on all the main aspects of clinical management of this group of rare diseases, from diagnosis and staging, to new available systemic treatments, such as targeted therapies and immunotherapies. A summary of key recommendations is presented here and complete recommendations are reported as Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100188.

Diagnostic Accuracy of EndoFaster® and Narrow-Band Imaging Endoscopy in Patients with Impaired Gastric Acid Secretion: A Real-Time Prospective Study.

BACKGROUND: EndoFaster® analyzes gastric juice in real time during gastroscopy allowing the detection of hypo-achlorhydric conditions, like corpus atrophic gastritis. Narrow-band imaging (NBI) endoscopy allows to accurately detect and perform target biopsies in areas of intestinal metaplasia, a histological change often associated to corpus atrophic gastritis. AIMS: To compare the diagnostic accuracy of EndoFaster® with histological evaluation for corpus atrophic gastritis through high-resolution (HR) NBI targeted biopsies. METHODS: Prospective study on consecutive adult patients undergoing gastroscopy between April and November 2018. Patients in therapy with proton pump inhibitors, previous gastric surgery, and/or known gastric neoplasia were excluded. At the beginning of gastroscopy, gastric juice was aspirated and analyzed by EndoFaster® in 15 seconds. Endoscopists were blinded to the report of EndoFaster®. Evaluation of gastric mucosa in HR-white light was firstly performed, then with HR-NBI allowing to perform targeted biopsies on areas suspected for intestinal metaplasia; otherwise, biopsies were performed according to the updated Sydney System protocol and sent for histopathological evaluation. RESULTS: Overall, 124 patients were included [64% F; 56 (18-85) years]. Corpus atrophic gastritis was present in 41.9% of patients. EndoFaster® showed an accuracy for corpus atrophic gastritis diagnosis, compared to histopathological evaluation as gold standard, of 87.1% and a sensitivity, specificity, PPV, and NPV of 78.8%, 93.1%, 89.1%, and 85.9%, respectively. pH showed a positive correlation with the severity score of atrophy (r = 0.67, 95% CI: 0.73-0.81, and p < 0.0001). EndoFaster® allowed to diagnose corpus atrophic gastritis in 3.7% of patients negative to NBI (corpus atrophic gastritis without intestinal metaplasia). CONCLUSION: EndoFaster® seems a promising tool to diagnose corpus atrophic gastritis. The evaluation of hypo-achlorhydria during gastroscopy can address bioptic sampling in corpus atrophic gastritis patients without intestinal metaplasia.

Axillary nodal involvement by primary tumor features in early breast cancer: an analysis of 2600 patients.

BACKGROUND: Primary tumor characteristics, which are readily available to all clinicians, may aid in selecting the optimal adjuvant therapy for patients with breast cancer (BC). Herein, we investigated the relationship between tumor size, hormone receptor and HER2 status, Ki67 and age with axillary lymph node metastases (ALNM) in early-BC patients. METHODS: We analyzed data on consecutive 2600 early-BC cases collected in the registry of Fondazione IRCC Istituto Nazionale dei Tumori, Milano, Italy. Correlation between Ki67 and primary tumor size (T-size) was calculated by Spearman's rank correlation coefficient. Association of ALNM with Ki67 and other tumor characteristics was investigated by logistic regression. Adjusted odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated in all cases, and separately analyzed according to age, T-size and BC subtype. RESULTS: Large tumor size strongly associated to ALNM, with an adjusted odds ratio (OR) for each 5-mm increase of 1.32 (95% CI 1.24-1.41), except for triple-negative BC (TNBC) cases. In tumors =10 mm, without lymphovascular invasion, representing the strongest predictor of ALNM (OR 6.09, 95% CI 4.93-7.53), Ki67 resulted particularly informative, with a fourfold increased odds of ALNM for values > 30%. CONCLUSIONS: These results raise the question whether axillary node status is redundant in cases with exceptionally good features, i.e., small tumors with low Ki67, or in those candidate to adjuvant systemic treatment/radiotherapy anyway including TNBC, and support the incorporation of primary BC tumor characteristics as stratification factors in ongoing trials aiming at de-escalating axillary surgical procedures.

Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out.

Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors.

Correction to: Comparison of three-parameter kinetic model analysis to standard Patlak's analysis in 18F-FDG PET imaging of lung cancer patients.

Following publication of the original article [1], the authors flagged that the author affiliations detailed in the article are incorrect for the authors M. L. Calcagni and A. Giordano.

Comparison of three-parameter kinetic model analysis to standard Patlak's analysis in 18F-FDG PET imaging of lung cancer patients.

BACKGROUND: Patlak's graphical analysis can provide tracer net influx constant (Ki) with limitation of assuming irreversible tracer trapping, that is, release rate constant (kb) set to zero. We compared linear Patlak's analysis to non-linear three-compartment three-parameter kinetic model analysis (3P-KMA) providing Ki, kb, and fraction of free 18F-FDG in blood and interstitial volume (Vb). METHODS: Dynamic PET data of 21 lung cancer patients were retrospectively analyzed, yielding for each patient an 18F-FDG input function (IF) and a tissue time-activity curve. The former was fitted with a three-exponentially decreasing function, and the latter was fitted with an analytical formula involving the fitted IF data (11 data points, ranging 7.5-57.5 min post-injection). Bland-Altman analysis was used for Ki comparison between Patlak's analysis and 3P-KMA. Additionally, a three-compartment five-parameter KMA (5P-KMA) was implemented for comparison with Patlak's analysis and 3P-KMA. RESULTS: We found that 3P-KMA Ki was significantly greater than Patlak's Ki over the whole patient series, + 6.0% on average, with limits of agreement of ± 17.1% (95% confidence). Excluding 8 out of 21 patients with kb > 0 deleted this difference. A strong correlation was found between Ki ratio (=3P-KMA/Patlak) and kb (R = 0.801; P < 0.001). No significant difference in Ki was found between 3P-KMA versus 5P-KMA, and between 5P-KMA versus Patlak's analysis, with limits of agreement of ± 23.0 and ± 31.7% (95% confidence), respectively. CONCLUSIONS: Comparison between 3P-KMA and Patlak's analysis significantly showed that the latter underestimates Ki because it arbitrarily set kb to zero: the greater the kb value, the greater the Ki underestimation. This underestimation was not revealed when comparing 5P-KMA and Patlak's analysis. We suggest that further studies are warranted to investigate the 3P-KMA efficiency in various tissues showing greater 18F-FDG trapping reversibility than lung cancer lesions.

[Usefulness of thiopurine methyltransferase polymorphism study and metabolites measurement for patients treated by azathioprine]. / Intérêt de la recherche du polymorphisme de la thiopurine méthyltransférase et du dosage des métabolites chez les patients traités par azathioprine.

Azathioprine is widely used in internal medicine and frequently implicated in occurrence of adverse events. Among these adverse events the bone marrow suppression, a dose-related one, is the most serious because of is potential morbidity and mortality. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism that results in a high variability of its activity with 89% of patients with a normal activity, 11% with an intermediate activity, and 0.3% with very low activity leading to a very high risk of bonne marrow suppression. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques to identify patients for which the standard dose is not advisable. Furthermore, azathioprine metabolites monitoring is helpful for the follow up of patients, especially in therapeutic failure, to distinguish non-compliant patients from under-dosed, "shunters" or resistant patients.

The use of breast imaging for predicting response to neoadjuvant lapatinib, trastuzumab and their combination in HER2-positive breast cancer: Results from Neo-ALTTO.

AIM: To determine the value of mammography and breast ultrasound (US) in predicting outcomes in HER2 positive breast cancer patients (pts) within Neo-ALTTO trial. PATIENTS AND METHODS: Mammography and US were required at baseline, week 6 and surgery. Two independent blinded investigators reviewed the measurements and assigned the corresponding response category. Pts showing complete or partial response according to RECIST (v1.1) were classified as responders. The association between imaging response at week 6 or prior to surgery was evaluated with respect to pathological complete response (pCR) and event-free Survival (EFS). RESULTS: Of the 455 pts enrolled in the trial, 267 (61%) and 340 (77%) had evaluable mammography and US at week 6; 248 (56%) and 309 (70%) pts had evaluable mammography and US prior to surgery. At week 6, 32% and 43% of pts were classified as responders by mammography and US, respectively. pCR rates were twice as high for responders than non-responders (week 6: 46% versus 23% by US, p < 0.0001; 41% versus 24% by mammography, p = 0.007). Positive and negative predictive values of mammography and US prior to surgery were 37% and 35%, and 82% and 70%, respectively. No significant correlation was found between response by mammography and/or US at week 6/surgery and EFS. CONCLUSIONS: Mammography and US were underused in Neo-ALTTO although US had the potential to assess early response whereas mammography to detect residual disease prior to surgery. Our data still emphasise the need for further imaging studies on pts treated with neoadjuvant HER2-targeted therapy.

Metformin plus proton pump inhibitors therapy: the cobalamin deficiency challenge.

OBJECTIVE: It is known in literature that metformin and proton pump inhibitors (PPIs) are associated to cobalamin levels reduction independently but still very little is known about the combination of the two drugs in cobalamin levels decrease. Currently there are no published data concerning the management of patients with cobalamin deficiency related to the concomitant use of the aforementioned drugs. CASE REPORT: We present the case of a 65 year-old white man with an history of renal cell carcinoma, melanoma and hepatic nodular sclerosis Hodgkin's lymphoma, who was under treatment with metformin because of diabetes and with pantoprazole because of Barrett's esophagus. He came to our attention because of a progressive reduction of cobalamin levels without related anemia. We decided to continue metformin and pantoprazole therapy and we treated the patient with intramuscular injection of cobalamin to avoid the vitamin deficiency consequences. DISCUSSION: Up to now no published data are available concerning the management of patients with cobalamin deficiency related to the concomitant use of metformin and PPIs. Our case report faces this clinical problem in terms of therapeutic management.

Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization.

Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.

Disease progression pattern in metastatic breast cancer patients treated with anti-HER2 therapies.

PURPOSE: Over the last decade a dramatic improvement in the treatment and prognosis of human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC) has been achieved. This study aimed to describe pattern, timing of metastases, and time to progression (TTP) of MBC patients (pts) treated with multiple lines of therapy with trastuzumab and/or lapatinib. METHODS: Clinical-pathologic features, treatment-lines and metastatic sites were collected from the institutional database; TTP was evaluated for each treatment-line. A meta-analysis of treatment-line estimates was performed; Q test and I (2)-index were used to detect and estimate heterogeneity. Cox's proportional hazards model and Fine and Gray's proportional subhazards model in a competing risks setting were used to detect differences in hazard rate and to estimate relative risks. RESULTS: 112 pts were analyzed. The median number of treatment-lines administered was 6 (range 1-17) and 524 (86 %) disease progression events were observed (median follow up 4.2 years). Distribution of metastases at baseline remained consistent across all lines. Having a given site affected by metastasis was a major risk factor of progression in that site. Hormone-receptor-positive pts resulted more likely to progress on bone (HR = 1.88). Elderly pts were less likely to progress on CNS (HR = 0.73). Median TTP resulted superior to 5 months up to the 6th line of treatment, reaching a plateau at the 9th treatment-line. CONCLUSIONS: These data suggest that risk factors for progression in HER2 positive MBC do not significantly differ between various distributions of metastases, and that MBC pts benefit from anti-HER2 therapy even in late treatment-lines.

Histological recovery and gluten-free diet adherence: a prospective 1-year follow-up study of adult patients with coeliac disease.

BACKGROUND: Adequate gluten-free diet (GFD) is the only treatment for coeliac disease (CD). However, no agreement has been reached on either how and when to assess patient adherence to GFD or its effectiveness on villous atrophy. AIM: To assess, in a prospective study, patient adherence to and efficacy of GFD on histological recovery after 1-year of GFD. METHODS: Between 2009 and 2012, we enrolled 65 consecutive newly-diagnosed adult patients (median age 38 years, 18-70) with biopsy-proven atrophic CD. Patients were re-evaluated after 1 year of GFD with duodenal histology, serological assays, symptoms and a dietary interview based on a validated questionnaire. Complete histological recovery was defined as the absence of villous atrophy and ≤30/100 intraepithelial lymphocytes. RESULTS: Overall, 81.5% of patients had adequate adherence (ADA) to GFD, whereas 18.5% had an inadequate adherence (IADA); 66% of ADA patients and no IADA patients achieved complete histological recovery (P < 0.00001). Among ADA patients, antibody seroconversion and symptoms were not significantly different between patients who achieved complete histological recovery and those who achieved partial histological recovery with P = 0.309 and P = 0.197, respectively. Multivariate analysis showed that Marsh 3C was a risk factor for incomplete histological recovery in ADA patients (OR 8.74, 95% CI: 1.87-40.83). CONCLUSIONS: This study shows that complete histological recovery after 1-year of GFD in adult patients, who are assessed as adherent to the GFD, can be obtained in 66% of patients. Patients with severe histological damage at diagnosis are at risk for incomplete histological recovery 1 year later.

Prdm5 suppresses Apc(Min)-driven intestinal adenomas and regulates monoacylglycerol lipase expression.

PRDM proteins are tissue-specific transcription factors often deregulated in diseases, particularly in cancer where different members have been found to act as oncogenes or tumor suppressors. PRDM5 is a poorly characterized member of the PRDM family for which several studies have reported a high frequency of promoter hypermethylation in cancer types of gastrointestinal origin. We report here the characterization of Prdm5 knockout mice in the context of intestinal carcinogenesis. We demonstrate that loss of Prdm5 increases the number of adenomas throughout the murine small intestine on an Apc(Min) background. By using the genome-wide ChIP-seq (chromatin immunoprecipitation (ChIP) followed by DNA sequencing) and transcriptome analyses we identify loci encoding proteins involved in metabolic processes as prominent PRDM5 targets and characterize monoacylglycerol lipase (Mgll) as a direct PRDM5 target in human colon cancer cells and in Prdm5 mutant mouse intestines. Moreover, we report the downregulation of PRDM5 protein expression in human colon neoplastic lesions. In summary, our data provide the first causal link between Prdm5 loss and intestinal carcinogenesis, and uncover an extensive and novel PRDM5 target repertoire likely facilitating the tumor-suppressive functions of PRDM5.

Ribozyme-mediated compensatory induction of menin-oncosuppressor function in primary fibroblasts from MEN1 patients.

Multiple endocrine neoplasia type 1 (MEN1) syndrome is characterized by the occurrence of tumors of parathyroids, neuroendocrine cells of the gastro-enteropancreatic tract and anterior pituitary. MEN1 gene encodes menin-oncosuppressor protein. Loss of heterozygosity at 11q13 is typical of MEN1 tumors. We have analyzed the MEN1 mRNA and menin expression in fibroblasts from normal skin biopsies and from MEN1 patients (two with a frameshift 738del4 (exon 3) mutation, introducing a premature stop codon, and an individual with an R460X (exon 10) nonsense mutation). The expression of full-length menin protein did not differ between MEN1 and normal fibroblasts. Wild-type alleles mRNAs were expressed in MEN1 patients, whereas mutant alleles were partially degraded by nonsense-mediated mRNA decay pathway, suggesting a mechanism of compensation for allelic loss by the up-regulation of wild-type menin expression at a post-transcriptional level. Small-interfering RNA silencing of the wild-type mRNA allele abolished menin compensation, whereas the ribozyme silencing of the MEN1-mutated mRNA allele resulted in strongly enhanced wild-type menin expression. Gel-retardation analysis showed that in vitro-specific RNA-protein complexes bound to MEN1 mRNA. These findings contribute to the understanding of tumorigenesis in MEN1, offering the basis for the development of RNA-based therapies in MEN1 gene mutation carriers.

Stabilization effects of kosmotrope systems on ornithine carbamoyltransferase.

In the present article the influence of salts and additives, such as trehalose, NaCl, ornithine, sodium phosphate and ammonium sulphate, on ornithine carbamoyltransferase (OCTase) is investigated in order to study the OCTase stabilization process as a function of solutes and to point out the fundamental role played by an enhancement of hydrophobic interactions. The synergic use of different techniques, such as neutron spectroscopy, UV-vis spectroscopy, activity and thermal measurements, allows to highlight the cosolute capability to avoid thermal inactivation, to induce important changes in secondary and tertiary enzyme structure and to stabilize biological macromolecules.

[Prevention and therapy of critical ischemia in hemodialyzed patients]. / Prevenzione e terapia dell'ischemia critica nell'uremico in terapia dialitica.

The cardiovascular disease is largely increased in chronic renal failure and the patients have a 10-20 times higher mortality respect normal population. Besides habitual risk-factors they add the mineral metabolism alterations, iperomocisteine and chronical vessel flogosis. In these patients the vascular disease is often lately diagnosed, but early diagnosis would be extremely important to establish appropriate pharmacologic or surgical treatment (PTA or by pass). The basic diagnostic methods are still digital angiography, angio-NMR or angio-CT. In our experience appears that dialysed patients present high total mortality and re-vascolarization (particularly for peripheral occlusive disease) gives less guarantee of success. During last years endovascular surgery procedures extremely improved short-term prognosis for these patients. When there is no space for the re-vascolarization and the situation is strongly compromised by the presence of extended gangrene or infected lesion, amputation is still indicated and can be considered the only possible solution.

Characterization of the functional and growth properties of long-term cell cultures established from a human somatostatinoma.

In somatostatinoma, a rare malignant somatostatin (SST)-secreting neoplasia, tumour regression is rarely observed, implying the need for novel antiproliferative strategies. Here, we characterized a long-term culture (SST-secreting cancer (SS-C cells)) established from a human somatostatinoma. High concentrations of SST and chromogranin A were released by SS-C cells and SST release was stimulated by depolarizing stimuli and inhibited by the SST analogue, octreotide. SS-C cells expressed mRNA for SST receptor (SSTR) subtypes 1, 2 and 4, being also able to bind native SST. Moreover, SS-C cells were positively stained with an antibody to SSTR2. SS-C cells also expressed interferon-gamma (IFN-gamma) receptor mRNA and measurable telomerase activity. Our findings indicate that in vitro exposure of SS-C cells to native SST-28, to octreotide, to IFN-gamma, or to 3'-azido-3'deoxythymidine (AZT), a telomerase inhibitor, results in inhibition of SS-C cell proliferation. Concomitant with growth inhibition, apoptosis was detected in SST-, octreotide-, IFN-gamma- or AZT-treated SS-C cell cultures. Taken together our results characterized native SST, SST analogues, IFN-gamma and a telomerase inhibitor as growth-inhibiting and proapoptotic stimuli in cultured human somatostatinoma cells. Based on these findings, the potential of SST analogues, IFN-gamma and AZT, alone or in combination, should be further explored in the medical treatment of somatostatinoma.