Papers by Alfredo Berruti
Endocrinology, Diabetes & Metabolism Case Reports, Sep 1, 2014
Insulinoma is a rare form of insulin-secreting pancreatic islet cell neuroendocrine (NE) tumor. T... more Insulinoma is a rare form of insulin-secreting pancreatic islet cell neuroendocrine (NE) tumor. The medical treatment of the malignant NE disease of the pancreas deeply changed in the last years, thanks to the introduction of new target molecules, as everolimus. Even if the exact mechanism is not actually known, one of the side effects of everolimus, hyperglycemia, has been demonstrated to be useful to contrast the typical hypoglycemia of the insulinoma. We report the case of a patient with a metastatic malignant insulinoma treated with intermittent everolimus, obtaining an important improvement in the quality of life; this suggests the necessity of preclinical studies to analyze the cellular pathways involved in insulin-independent gluconeogenesis. Learning points: † Effect of somatostatin analogs is long-lasting in the control of functioning NE tumors. † Persistent everolimus control of hypoglycemia despite serum insulin levels and disease progression. † Open issue: are disease progression and the increase in serum markers the only valid criteria to reject a treatment? This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.
Cancer, Jun 1, 2000
Circulating neuroendocrine markers were measured in patients with prostate carcinoma (PC), prosta... more Circulating neuroendocrine markers were measured in patients with prostate carcinoma (PC), prostatic intraepithelial neoplasia (PIN), and benign prostatic hypertrophy (BPH) with the goal to: 1) evaluate the differences in the expression of these markers in patients with benign, premalignant, and primary or metastatic PC; 2) evaluate their prognostic significance; 3) compare values in patients with hormone-naive and hormone-refractory disease; and 4) assess changes after androgen deprivation or chemotherapy. Serum neuron specific enolase (NSE) (immunoradiometric assay) and plasma chromogranin A (CgA) (enzyme-linked immunoadsorbent assay) were evaluated in 141 patients with BPH, 54 patients with PIN, and 159 patients with PC; 119 patients were bearing hormone-naive disease and 40 were bearing hormone-refractory disease. CgA was monitored in 31 patients submitted to androgen deprivation and in 24 patients receiving chemotherapy. Supranormal CgA was observed more frequently in patients with American Urologic Association (AUA) Stage D2 disease (45.5%) compared with those with Stage D1 disease (33.3%), Stage C disease (16.7%), Stage A/B disease (18.8%), PIN (25.9%), and BPH (17.0%) (P < 0.02). Supranormal NSE did not change in any of the patient subgroups. Elevated CgA was observed in 36.0% of patients with metastases who had hormone-naive disease and in 45.0% of patients with hormone-refractory disease (P value not significant). Supranormal NSE and CgA values were predictors for poor prognosis in patients with hormone-refractory disease. Elevated baseline CgA values decreased > 50% in 1 of 12 patients who received luteinizing hormone-releasing hormone analogs and in 2 of 12 patients who underwent chemotherapy. CgA appears to reflect the neuroendocrine activity of PC better than NSE. Elevated CgA values correlate with poor prognosis and are scarcely influenced by either endocrine therapy or chemotherapy.
Annals of Oncology, Sep 1, 2020
Frontiers in Endocrinology, 2021
Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplasti... more Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER-β over the ER-α.Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER-α/β signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC50: MUC-1 cells: 67.58 µM (95%CI: 63.22–73.04), ACC115m cells: 51.76 µM (95%CI: 46.45–57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC50: 5.43 µM (95%CI: 5.18–5.69 µM) mainly involving ER-β, as their nuclear localizati...
Frontiers in Immunology, 2021
BackgroundRare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 p... more BackgroundRare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 people each year. The International Rare Cancer Consortium defines rare cancer incidence as less than six per 100,000 per year. There is a growing number of reports of the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with rare tumours, and hence, we conducted a comprehensive review to summarise and analyse the available literature.MethodsA literature search of PubMed was performed on January 31, 2021, using the following ICI names as keywords: ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. Studies on patients with rare tumours who were being treated with ICIs were included. We plotted the overall response rate against the corresponding median survival across a variety of cancer types using linear regression.ResultsFrom 1,255 publications retrieved during the primary search, 62 publications were selected (with a ...
Journal of Experimental & Clinical Cancer Research, 2015
Purpose: Aim of this study was to investigate for the presence of existing prognostic factors in ... more Purpose: Aim of this study was to investigate for the presence of existing prognostic factors in patients with bone metastases (BMs) from RCC since bone represents an unfavorable site of metastasis for renal cell carcinoma (mRCC). Materials and methods: Data of patients with BMs from RCC were retrospectively collected. Age, sex, ECOG-Performance Status (PS), MSKCC group, tumor histology, presence of concomitant metastases to other sites, time from nephrectomy to bone metastases (TTBM, classified into three groups: <1 year, between 1 and 5 years and >5 years) and time from BMs to skeletal-related event (SRE) were included in the Cox analysis to investigate their prognostic relevance. Results: 470 patients were enrolled in this analysis. In 19 patients (4%),bone was the only metastatic site; 277 patients had concomitant metastases in other sites. Median time to BMs was 16 months (range 0 − 44y) with Median OS of 17 months. Number of metastatic sites (including bone, p = 0.01), concomitant metastases, high Fuhrman grade (p < 0.001) and non-clear cell histology (p = 0.013) were significantly associated with poor prognosis. Patients with TTBM >5 years had longer OS (22 months) compared to patients with TTBM <1 year (13 months) or between 1 and 5 years (19 months) from nephrectomy (p < 0.001), no difference was found between these two last groups (p = 0.18). At multivariate analysis, ECOG-PS, MSKCC group and concomitant lung or lymph node metastases were independent predictors of OS in patients with BMs. Conclusions: Our study suggest that age, ECOG-PS, histology, MSKCC score, TTBM and the presence of concomitant metastases should be considered in order to optimize the management of RCC patients with BMs.
Human Pathology, Dec 1, 2015
The correct pathological classification of adrenocortical carcinoma is relevant to establish an e... more The correct pathological classification of adrenocortical carcinoma is relevant to establish an early therapeutic strategy of this rare malignancy. Aim of the study was to assess the most frequent pitfalls in adrenocortical carcinoma diagnosis reviewing a large consecutive series of 300 cases with an original diagnosis or a clinical suspect of adrenocortical carcinoma, that were sent in
Journal of Clinical Oncology, Feb 20, 2022
1 Background: The ESE-ENSAT guidelines on ACC management suggest adjuvant mitotane for patients a... more 1 Background: The ESE-ENSAT guidelines on ACC management suggest adjuvant mitotane for patients at high risk of recurrence. This indication has limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane or observation. The primary endpoint of the study was RFS. Patients who refused randomization were eligible for the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in ADIUVO except for randomization. A total of 91 patients were enrolled in ADIUVO, 45 in the mitotane and 46 in the observation arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with mitotane and observation groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohort was analyzed in parallel to deal with the lower than expected recruitment in ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55-3.32, p = 0.54) and HR for death 2.171 (95%CI, 0.52-12.12, p = 0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed that of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-yr RFS is 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care. Clinical trial information: NCT00777244.
Annals of Oncology, Sep 1, 2020
Conclusions: Our study demonstrates that MUC1/16 overexpressing HNSCC are "inflamed". Moreover, H... more Conclusions: Our study demonstrates that MUC1/16 overexpressing HNSCC are "inflamed". Moreover, HRAS overexpression and RAS oncogenic mutations are associated with MUC1/16 overexpression. In this context, Ras-targeted therapeutic approaches may sensitize this cluster of tumors to immunotherapy.
Endocrine Abstracts, May 3, 2017
Journal of Clinical Oncology, Jun 1, 2022
Background: In advanced ACC, no significant progress has been made since introduction of mitotane... more Background: In advanced ACC, no significant progress has been made since introduction of mitotane and cisplatin-based therapy. EO2401 (EO) was designed to activate existing commensal memory T cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived, synthetically produced peptides corresponding to HLA-A2 restricted epitopes with molecular mimicry to three TAAs upregulated in ACC, IL13Rα2, BIRC5 and FOXM1, with the CD4 helper peptide UCP2 and the adjuvant Montanide. Pre-clinically EO generates strong immune responses and cross-reactive CD8 cells recognizing the TAAs. Methods: This Phase 1/2 trial (NCT04187404) investigated EO + nivolumab (N) (EO + N = EN) in pts with ACC. Cohort 1 lead-in established safety of EN. Cohort 2 includes pts with metastatic ACC, with (C2a), or without (C2b) prior systemic therapy. EN was given 4 times q2 w, followed by boosters q4 w until PD (iRECIST). Results: 33 pts with ACC started study treatment: C2a 26 pts (58% 1; 42% 2 prior lines), C2b 7 pts. Median age 47; 24% men; ECOG 0/52%, 1/42%, 2/6%; 61% ≥2 organs involved by metastases (61% liver, 76% lung). EN was well tolerated. The combination safety profile was consistent with the profile of N monotherapy except for higher local administration site reactions (any erythema/pain/induration in 35% of pts). Overall (n = 33), best RECIST response was PR 12%, SD 24%, PD 45%, NE 18%; median PFS was 1.9 mo (range 0.4-7.6+); median survival not reached, and survival rate at 6-mo 63% (median FU 4.9 mo, range 0.9-12.0). Strong CD8 T cell ELISPOT responses against the vaccine peptides (9/9 pts) and cross-reactivity against targeted TAAs (8/8 evaluable pts) was observed. Tetramer staining of specific CD8 cells for all 3 peptides was detected in 7/8 tested. When investigated, positive staining against BIRC5 was detected as early as 4 w after the first vaccination. In C2a, a group of pts (n = 10) with SD at the first CT (incl. 4 pts with PR) seemed to fare well; all investigated tumor samples in this group showed a low level of TMB, low MSI, and low PDL1 expression. In contrast, 10 pts had PD < 2mo and died < 6mo. There was no correlation between clinical benefit and a large panel of cytokines/chemokines. However, post-hoc analysis identified several clinical factors (prior mitotane, ECOG ≤ 1, ACC 1st diagnosis > 9 mo, max lesion ≤125 mm, ≤3 organs involved, lymphocytes ≤ grade 1) that excluded 90% of pts without benefit to EN. In the post-hoc selected group (n = 14) with median FU 6.9 mo (12 pts censored) the DCR was 64% (4 PR, 5 SD), 6-mo PFS was 42% and 6-mo survival rate 93%. Conclusions: EO2401 in combination with nivolumab was well tolerated and induced a specific immune response in all tested pts. In addition, efficacy was seen in a subpopulation of pts with ACC defined by clinical parameters in a post-hoc analysis. A randomized phase 2 study based on the findings of Cohort 2a is being planned. Clinical trial information: NCT04187404. Research Sponsor: Enterome.
Annals of Oncology, Jul 1, 2022
Annals of Oncology, Dec 1, 2019
Journal of Clinical Oncology, Jun 1, 2022
AACE clinical case reports, 2016
ABSTRACT Objective: Adrenocortical carcinoma (ACC) is a rare disease often associated with hormon... more ABSTRACT Objective: Adrenocortical carcinoma (ACC) is a rare disease often associated with hormonal hypersecretion. Hypercortisolism is the most common endocrine syndrome associated with ACC. Abiraterone acetate is a selective and irreversible inhibitor of cytochrome P450 17A1 that is currently used in the treatment of metastatic castration-resistant prostate cancer. The drug induces a profound suppression of both androgen and cortisol secretion and it is a plausible candidate for medical treatment of Cushing's syndrome. We evaluated the hormonal effects of abiraterone administration in a patient with Cushing's syndrome induced by heavily pre-treated metastatic ACC. Methods: A 50-year-old woman with ACC, suffering from severe and unmanageable Cushing's syndrome despite mitotane therapy, received oral abiraterone at 500 mg/day. Results: After 9 days of treatment, the patient experienced a dramatic improvement in autonomy and deambulation, reduction of edema, better control of blood pressure and glycemia, s...
In Vivo
Background/Aim: Chemotherapy-induced taste alterations (TAs) affect approximately 53-84% of breas... more Background/Aim: Chemotherapy-induced taste alterations (TAs) affect approximately 53-84% of breast cancer patients with significant consequences on flavor perception, possibly leading to food aversion and changes in daily dietary habits. The aim of this study was to investigate the relationship between TAs and changes in food habits and body weight among early breast cancer (EBC) patients undergoing adjuvant chemotherapy. Patients and Methods: TAs were prospectively evaluated in 182 EBC patients from April 2014 to June 2018. TAs, dietary habits, and body weight were collected by a trained dietician. TAs were classified into different subtypes according to the following basic taste perception: metallic, sweet, bitter, salty, sour, and umami taste. Results: During adjuvant chemotherapy, a significant reduction in the consumption of bread, breadsticks, red meat, fat salami, snacks, added sugar, milk, and alcoholic beverages was observed, regardless of TAs onset. No correlation between these dietary changes and different TAs subtypes was found. Body weight remained stable in most EBC patients (71.4%) and was not influenced by TAs onset and by different TAs subtypes. Conclusion: EBC patients change their dietary habits during adjuvant chemotherapy, mostly following the World Cancer Research Fund recommendations, irrespective of TAs onset and without affecting body weight. Dysgeusia is variably defined as an abnormal or impaired sense of taste, an unpleasant alteration of taste sensation, or a distortion or perversion of the sense of taste (1). Taste sensation is primarily based on the following basic qualities, namely sweet, bitter salty, sour; recently savory or umami (the taste of glutamate) was added as a new basic taste quality (2). Dysgeusia affects approximately 53-84% of breast cancer patients treated with chemotherapy (3, 4) and taxanes are the cytotoxic drugs more frequently associated with the onset of this symptom (5). It has been shown that the main mechanism for taxane-related taste alteration is a neurological damage (6) involving both cranial nerves (VII, IX, and X) and taste receptors (7-9). Chemotherapy-induced taste alterations (TAs) may have significant consequence on flavor perception leading to food aversion, which in turn may lead to changes in daily dietary intake of certain foods (10), and consequently in body weight variation. It has been suggested that TAs are linked to a change in food-related behaviors in order to self-manage this unpleasant side-effect and some examples are eating strongly flavored food, eating candy before meals, drinking sweetened drinks (3). The high caloric intake correlated to this eating-behavior could justify weight gain reported frequently in early breast cancer (EBC) patients during adjuvant chemotherapy (11-15). The aim of the study was to investigate the relationship between TAs and changes in dietary habits and in body weight among a consecutive series of EBC patients undergoing adjuvant chemotherapy and followed up to 12 months after the end of the treatment. Patients and Methods Trial oversight. A prospective, single-center trial was conducted at the Medical Oncology and Breast Unit of the ASST Spedali Civili of Brescia, registered in "ClinicalTrials.gov database" (NCT identification number: NCT03210441) and approved by the local Ethic Committee of Brescia.
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Papers by Alfredo Berruti