Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view.

BACKGROUND:  Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE:  The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.

Diabetes management in cancer patients. An Italian Association of Medical Oncology, Italian Association of Medical Diabetologists, Italian Society of Diabetology, Italian Society of Endocrinology and Italian Society of Pharmacology multidisciplinary consensus position paper.

Cancer management has significantly evolved in recent years, focusing on a multidisciplinary team approach to provide the best possible patient care and address the various comorbidities, toxicities, and complications that may arise during the patient's treatment journey. The co-occurrence of diabetes and cancer presents a significant challenge for health care professionals worldwide. Management of these conditions requires a holistic approach to improve patients' overall health, treatment outcomes, and quality of life, preventing diabetes complications and cancer treatment side-effects. In this article, a multidisciplinary panel of experts from different Italian scientific societies provide a critical overview of the co-management of cancer and diabetes, with an increasing focus on identifying a novel specialty field, 'diabeto-oncology', and suggest new co-management models of cancer patients with diabetes to improve their care. To better support cancer patients with diabetes and ensure high levels of coordinated care between oncologists and diabetologists, 'diabeto-oncology' could represent a new specialized field that combines specific expertise, skills, and training.

Impact of different typologies of smoking on ovarian reserve and oocyte quality in women performing ICSI cycles: an observational prospective study.

OBJECTIVE: Within the last few years smoking activities, as well as infertility, have increased in Italy, and so has the consumption of alternative cigarette devices among women of childbearing age. The aim of this observational study was to evaluate the impact of the consumption of cigarettes and alternatives devices, such as electronic cigarettes and heat-not-burn (HnB) products, on infertile women performing in vitro fertilization (IVF), in specific on the quality of oocytes retrieved in women performing intracytoplasmic sperm injection (ICSI) cycles. PATIENTS AND METHODS: Prospective observational longitudinal study involving 410 women referring to the Reproductive Physiopathology and Andrology Unit, Sandro Pertini Hospital, Rome, from 2019-2022. All the women enrolled filled out an elaborate questionnaire investigating smoking consumption, before the beginning of ovarian stimulation by antagonist protocol, ovarian pick-up, and subsequent ICSI technique. The outcomes of the study were the evaluation of clinical and ICSI features between the groups of smokers and non-smokers: the number of retrieved oocytes, immature oocytes, and fertilization rate were confronted between the two groups and between cigarette smokers vs. e-cigarette and heat-not-burn (HnB) products smokers. RESULTS: Clinical parameters were comparable between the group of smokers compared to one of the non-smokers, except for anti-Müllerian hormone (AMH), which was statistically lower in smokers (p<0.05). Regarding IVF hormonal stimulations it appears that the total dose of gonadotropin was statistically lower in the non-smoker's group, compared to smokers (1850±860 UI vs. 1,730±780 p<0.05). Regarding ICSI techniques interestingly the number of oocytes retrieved was lower in the smokers' group compared to non-smokers (5.21±0.9 vs. 6.55±3.5, p<0.001), and the number of empty zona pellucida oocytes was statistically higher in the smokers' group (0.51±0.1 vs. 0.2±0.1, p<0.05). On the other hand, the fertilization rate (FR) was statistically higher in non-smokers compared to the smokers' group (72.16±3.05 vs. 68.12±2.21, p=0.03). Out of the 203 smokers, overall, any statistically significant difference, regarding ICSI results, has been found between the group of cigarette smokers, compared to the group of e-cigarettes plus HnB products smokers. CONCLUSIONS: Smoking negatively impacts human fertility, leading to a reduction of ovarian reserve and ovarian quality, which can negatively impact results in women performing ICSI cycles. Despite the limitation of the study, our results underline that consumption of cigarette alternative devices seems to have a similar negative impact on the quantity and quality of oocytes retrieved in ICSI cycles. Clinicians should emphasize the reduction of exposure to harmful substances derived from the combustion of tobacco smoking, as well as alternative devices, in women of childbearing age.

MiRNA dysregulation underlying common pathways in type 2 diabetes and cancer development: an Italian Association of Medical Oncology (AIOM)/Italian Association of Medical Diabetologists (AMD)/Italian Society of Diabetology (SID)/Italian Society of Endocrinology (SIE)/Italian Society of Pharmacology (SIF) multidisciplinary critical view.

Increasing evidence suggests that patients with diabetes, particularly type 2 diabetes (T2D), are characterized by an increased risk of developing different types of cancer, so cancer could be proposed as a new T2D-related complication. On the other hand, cancer may also increase the risk of developing new-onset diabetes, mainly caused by anticancer therapies. Hyperinsulinemia, hyperglycemia, and chronic inflammation typical of T2D could represent possible mechanisms involved in cancer development in diabetic patients. MicroRNAs (miRNAs) are a subset of non-coding RNAs, ⁓22 nucleotides in length, which control the post-transcriptional regulation of gene expression through both translational repression and messenger RNA degradation. Of note, miRNAs have multiple target genes and alteration of their expression has been reported in multiple diseases, including T2D and cancer. Accordingly, specific miRNA-regulated pathways are involved in the pathogenesis of both conditions. In this review, a panel of experts from the Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), and Italian Society of Pharmacology (SIF) provide a critical view of the evidence about the involvement of miRNAs in the pathophysiology of both T2D and cancer, trying to identify the shared miRNA signature and pathways able to explain the strong correlation between the two conditions, as well as to envision new common pharmacological approaches.

Epidemiologic trend of pediatric inflammatory bowel disease in Latin America: The Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN) Working Group.

INTRODUCTION AND AIMS: The primary aim was to explore the epidemiologic trend of pediatric inflammatory bowel disease in Latin America, and the secondary aims were to obtain an overview of the diagnostic/therapeutic focus of the members of the LASPGHAN and examine the relation of case frequency to year, during the study period. MATERIALS AND METHODS: Latin American pediatric gastroenterologists participated in an online survey, conducted through the SurveyMonkey platform, that investigated the yearly frequency of new inflammatory bowel disease patients within the time frame of 2005-2016, their disease variety, the gastrointestinal segments affected, and the diagnostic and treatment methods utilized. The correlation of new case frequency with each study year was evaluated. RESULTS: A total of 607 patients were studied. The diagnoses were ulcerative colitis in 475 (78.3%) cases, Crohn's disease in 104 (17.1%), and inflammatory bowel disease D unclassified in 28 (4.6%). The trend in ulcerative colitis was a lineal increase in the frequency of new cases related to each study year, with a significant correlation coefficient. Pancolitis was found in 67.6% of the patients. The diagnostic methods included clinical data, endoscopy, and biopsies in more than 99% of the cases, and imaging studies were indicated selectively. Drug regimens were limited to 5-aminosalicylic acid derivatives, azathioprine, 6-mercaptopurine, infliximab, and adalimumab. CONCLUSIONS: Pediatric inflammatory bowel disease in Latin America appears to have increased during the years included in the study period, with a predominance of moderate or severe ulcerative colitis. That lineal trend suggests the predictive likelihood of a gradual increase in the coming years, with possible epidemiologic and clinical implications.

Antineoplastic dosing in overweight and obese cancer patients: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper.

Most anticancer molecules are administered in body-size-based dosing schedules, bringing up unsolved issues regarding pharmacokinetic data in heavy patients. The worldwide spread of obesity has not been matched by improved methods and strategies for tailored drug dosage in this population. The weight or body surface area (BSA)-based approaches may fail to fully reflect the complexity of the anthropometric features besides obesity in cancer patients suffering from sarcopenia. Likewise, there is a lack of pharmacokinetic data on obese patients for the majority of chemotherapeutic agents as well as for new target drugs and immunotherapy. Therefore, although the available findings point to the role of dose intensity in cancer treatment, and support full weight-based dosing, empirical dose capping often occurs in clinical practice in order to avoid toxicity. Thus a panel of experts of the Associazione Italiana Oncologia Medica (AIOM), Associazione Medici Diabetologi (AMD), Società Italiana Endocrinologia (SIE), and Società Italiana Farmacologia (SIF), provides here a consensus statement for appropriate cytotoxic chemotherapy and new biological cancer drug dosing in obese patients.

Early prediction of pancreatic cancer from new-onset diabetes: an Associazione Italiana Oncologia Medica (AIOM)/Associazione Medici Diabetologi (AMD)/Società Italiana Endocrinologia (SIE)/Società Italiana Farmacologia (SIF) multidisciplinary consensus position paper.

Pancreatic cancer (PC) is a common cause of cancer-related death, due to difficulties in detecting early-stage disease, to its aggressive behaviour, and to poor response to systemic therapy. Therefore, developing strategies for early diagnosis of resectable PC is critical for improving survival. Diabetes mellitus is another major public health problem worldwide. Furthermore, diabetes can represent both a risk factor and a consequence of PC: nowadays, the relationship between these two diseases is considered a high priority for research. New-onset diabetes can be an early manifestation of PC, especially in a thin adult without a family history of diabetes. However, even if targeted screening for patients at higher risk of PC could be a promising approach, this is not recommended in asymptomatic adults with new-onset diabetes, due to the much higher incidence of hyperglycaemia than PC and to the lack of a safe and affordable PC screening test. Prompted by a well-established and productive multidisciplinary cooperation, the Italian Association of Medical Oncology (AIOM), the Italian Medical Diabetologists Association (AMD), the Italian Society of Endocrinology (SIE), and the Italian Society of Pharmacology (SIF) here review available evidence on the mechanisms linking diabetes and PC, addressing the feasibility of screening for early PC in patients with diabetes, and sharing a set of update statements with the aim of providing a state-of-the-art overview and a decision aid tool for daily clinical practice.

Bone metastases from differentiated thyroid carcinoma: current knowledge and open issues.

Bone represents the second most common site of distant metastases in differentiated thyroid cancer (DTC). The clinical course of DTC patients with bone metastases (BM) is quite heterogeneous, but generally associated with low survival rates. Skeletal-related events might be a serious complication of BM, resulting in high morbidity and impaired quality of life. To achieve disease control and symptoms relief, multimodal treatment is generally required: radioiodine therapy, local procedures-including surgery, radiotherapy and percutaneous techniques-and systemic therapies, such as kinase inhibitors and antiresorptive drugs. The management of DTC with BM is challenging: a careful evaluation and a personalized approach are essential to improve patients' outcomes. To date, prospective studies focusing on the main clinical aspects of DTC with BM are scarce; available analyses mainly include cohorts assembled over multiple decades, small samples sizes and data about BM not always separated from those regarding other distant metastases. The aim of this review is to summarize the most recent evidences and the unsolved questions regarding BM in DTC, analyzing several key issues: pathophysiology, prognostic factors, role of anatomic and functional imaging, and clinical management.

The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype.

In addition to their detection in typical X-linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)-2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4-year-old boy with lethal Epstein-Barr virus-related lymphoma and his asymptomatic 8-month-old brother with a Tlow B+ natural killer (NK)+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. After confirming normal IL-2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription-1 (STAT-5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γc ), which showed partially preserved function. Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc . Here, we describe how the R328X mutation in IL-2RG may allow partial phosphorylation of STAT-5 through a JAK3-independent pathway. We identified a region of three amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes.

Differential activity pattern of c-Fos in the nucleus accumbens between adult and aged rats during flavor recognition memory.

Previous studies have addressed the role of the nucleus accumbens core (NAcbC) and shell (NAcbSh) in taste aversion learning and in the processing of taste palatability which is affected by aging. However, little is known about its implication in safe taste memory and the aging impact. To explore the role of the NAcb in flavor neophobia and its attenuation during aging, we applied c-Fos immunohistochemistry as an index of neural activity of the NAcbC and NAcbSh. Twenty one adult (5-month-old) and 24 aged (24-month-old) male Wistar rats were exposed to a 3% cider vinegar solution for 1, 2 or 6 consecutive days (n = 7 adult and n = 8 aged rats per group). Aged rats exhibited slower attenuation of flavor neophobia than adult rats. Adult rats showed increased NAcbSh c-Fos activity on day 2 compared to days 1 and 6, while this increase was delayed to day 6 in aged rats. There were no differences in the number of NAcbC c-Fos positive cells. This suggests that changes in the activity of neural circuits of palatability processing during normal aging could contribute to the slower attenuation of flavor neophobia in aged rats.

Flavor recognition memory related activity of the posterior piriform cortex in adult and aged rats.

The relationship between the piriform cortex and flavor recognition memory was investigated in adult and aged rats. By using c-Fos immunohistochemistry, we assessed the piriform cortex activity induced by flavor familiarity. The results indicated increased activity in the rostral region of the posterior piriform cortex elicited by the most familiar cider vinegar solution after six exposures. Aged rats exhibited overall increased activity in the posterior, but not the anterior piriform cortex, which was not related to flavor familiarity. This suggests that the posterior piriform cortex is related to flavor recognition memory and that aging modifies its activity pattern which might underlie their slower attenuation of flavor neophobia.

Feasibility and oncological safety of sentinel node biopsy in breast cancer patients with a local recurrence.

OBJECTIVES: To investigate the role and feasibility of sentinel lymph node biopsy (SLNB) in breast cancer patients with a local recurrence and no clinically positive axillary lymph nodes. MATERIALS AND METHODS: A total of 71 patients underwent SLNB for breast cancer recurrence. At first surgery, they had received SLNB (46.5%), axillary lymph node dissection (ALND) (36.6%) or no axillary surgery (16.9%). RESULTS: Lymphatic migration was successful in 53 out of 71 patients (74.6%) and was significantly higher in patients with previous SLNB or no axillary surgery than in those with previous ALND (87.9% vs. 53.8%; p = 0.009). Aberrant lymphatic migration pathways were observed in 7 patients (13.2%). The surgical SLNB was successfully performed in 51 patients (71.8%). In 46 patients (90.2%) the SLN was histologically negative, in 3 patients (5.9%) micrometastastatic and in 2 patients (3.9%) macrometastatic. The 2 patients with a macrometastates in SLN underwent ALND, In 4 out of the 18 patients with failure of tracer migration ALND, performed as surgeon's choice, did not find any metastatic node. After a median follow-up period of 39 months (range: 2-182 months), no axillary recurrence has been diagnosed. CONCLUSION: A SLNB in patients with locally recurrent breast cancer, no previous ALND and negative axillary lymph nodes is technically feasible and impacts on the ALND rate. In patients who at primary surgery received ALND, migration rate is significantly lower, aberrant migration is frequent and no clinically useful information has been obtained.

Modalities for assessing the nutritional status in patients with diabetes and cancer.

Epidemiological data have shown that an increased body mass index (BMI) is associated with a higher risk of various cancers, especially in obese diabetic patients. However, oncologic patients often present nutritional alterations that can worsen their prognosis. The aim of this review is to propose the use of cheaper and easy to use tools to assess the nutritional status of patients with cancer with altered glucose metabolism. Based on a literature review, we propose anthropometric measures to classify the degree of malnutrition. Moreover, the Karnofsky Performance Status (KPS) and the Eastern Cooperative Oncology Group's performance index (ECOG) are useful to assess the functional status of the body; the achievement of nutritional needs can be analysed with the PG-SGA questionnaire, while the quality of life can be investigated using the DTSQ, SF36, EQ-5D questionnaires and the Edmonton Symptom Assessment System. Pre-albumin dosage and lymphocyte count are proposed as nutritional parameters. The degree of hydration can be evaluated through the Bio-Impedance Test (BIA), and energy intake through the dairy food diary, which considers the type of nutrition and the consistency of the meals. It is possible to use a score for each tool used, which is useful to plan an adequate nutritional intervention.

Exposure to polychlorinated biphenyls and hexachlorobenzene, semen quality and testicular cancer risk.

PURPOSE: We carried out a case-control study to investigate the possible role of occupational and environmental exposure to endocrine disruptors in the onset of testicular cancer (TC). METHODS: We evaluated 125 TC patients and 103 controls. Seminal fluid examination and organochlorine analysis were performed in all subjects. Cases and controls were also interviewed using a structured questionnaire to collect demographic information, residence, andrological medical history and dietary information. RESULTS: We found that a higher level of reproductive tract birth defects was associated with a higher risk of TC. With regard to diet, cases reported a higher consumption of milk and dairy products than controls. Overall, there was a statistically significant increase in TC risk in cases with detectable values of total polychlorinated organic compounds against controls (14.4 vs. 1.0 %; p < 0.001). TC patients with detectable levels of organochlorines had lower mean semen parameters than those with undetectable levels, although this difference was not statistically significant. CONCLUSION: The International Agency for Research on Cancer recently included dioxin-like polychlorinated biphenyls (PCBs) in Group 1 of known human carcinogens. Our study confirmed and identified various risk factors for testicular cancer: cryptorchidism, consumption of milk and dairy products, parents' occupation and serum concentration of hexachlorobenzene and PCBs and, for the first time, we showed the correlation between semen quality and the serum concentration of these pollutants.

Testicular cancer and sperm DNA damage: short- and long-term effects of antineoplastic treatment.

The aim of this study was to investigate sperm DNA damage induced by chemo- and radiotherapy in patients with testicular cancer to provide data on the extent and persistence of nuclear damage that might affect individual reproductive potential. We evaluated pre- and post-antineoplastic treatment sperm DNA integrity, expressed as DNA Fragmentation Index (DFI), in a large caseload of testicular cancer patients by sperm chromatin structure assay. The mean total DFI for all patients at T0 was 18.0 ± 12.5%. Sperm chromatin profile was markedly impaired at T3 (27.7 ± 17.4%) and T6 (23.2 ± 15.3%), improving considerably at T12 and T24 (14.0 ± 8.9% and 14.4 ± 10.3%). After chemotherapy, we found a marked increase in DFI at T3 and T6 and a significant reduction at T12 and T24 in comparison with the baseline. In contrast, DFI increased at T3 and T6 after radiotherapy but the subsequent reduction was far less marked, reaching baseline values at T12 and T24. Finally, post-treatment DNA damage was not age or histotype dependent, but was more marked in the advanced stage of cancer. In this study, we showed that the chromatin profile may be affected in the months immediately following the end of the treatment, improving after 12-24 months. Our results thus indicate that post-treatment DNA damage is influenced both by the type and intensity of the therapy and by the pathological and clinical stage of the disease.

Altered perirhinal cortex activity patterns during taste neophobia and their habituation in aged rats.

Perirhinal cortex (PRh) pathology and chemosensory identification dysfunction are early signs of Alzheimer's disease. We have assessed the impact of normal aging on PRh activity during flavor recognition memory using c-Fos immunoreactivity as a marker for neuronal activity. Adult (5-month-old) and aged (24-month-old) Wistar male rats were exposed to a vinegar solution on a daily basis for a period of six days. Behavioral assessment indicated similar performance in both age groups but suggested slower attenuation of neophobia in aged rats. Regarding c-Fos immunoreactivity, an opposite pattern of PRh activity was found in adult and aged groups drinking the flavor solution during the first (Novel), second (Familiar I) or sixth (Familiar II) exposure as the flavor became familiar. While adult rats exhibited a higher number of PRh c-Fos-positive neurons during the presentation of the novel flavor than during the second and sixth presentation, in aged rats the number of PRh c-Fos-positive neurons was higher during the presentation of the familiar flavor in the last session than in the first and second. The results suggest that the role of the PRh changes during aging and can help to dissociate PRh dysfuntions induced by neurodegenerative diseases and normal aging.

Novel and atypical splicing mutation in a compound heterozygous UNC13D defect presenting in Familial Hemophagocytic Lymphohistiocytosis triggered by EBV infection.

Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3) is a genetic disorder caused by mutations in UNC13D gene, coding the granule priming factor Munc13-4 that intervenes in NK and T cell cytotoxic function. Here we report the case of a 17-month-old girl with prolonged symptomatic EBV infectious mononucleosis and clinical symptoms of hemophagocytic syndrome. In vitro functional analysis pointed to a degranulation defect. The genetic analysis of UNC13D gene identified initially a heterozygous mutation (c.753+1G>T) in the donor splice-site that resulted in exon 9 skipping (maternal allele). Mutations in other genes were considered, but additional analysis of UNC13D cDNA revealed in the paternal allele a heterozygous transition from G to A (c.2448-13G>A) at the 3' acceptor splice-site in intron 25, generating a new acceptor splice-site that leads to a frameshift and a premature STOP codon. Allele specific amplification of the cDNA confirmed the absence of a functional mRNA from the paternal allele. This case illustrates an atypical compound heterozygous UNC13D mutation affecting the RNA splicing that generates a typical FHL3 phenotype.