Breakthrough pain in patients with multiple myeloma: a secondary analysis of IOPS MS study.

OBJECTIVE: The aim of this study was to characterize breakthrough pain (BTcP) in patients with multiple myeloma (MM). PATIENTS AND METHODS: This was a secondary analysis of a large multicenter study of patients with BTcP. Background pain intensity and opioid doses were recorded. The BTcP characteristics, including the number of BTcP episodes, intensity, onset, duration, predictability, and interference with daily activities were recorded. Opioids prescribed for BTcP, time to achieve a meaningful pain relief after taking a medication, adverse effects, and patients' satisfaction were assessed. RESULTS: Fifty-four patients with MM were examined. In comparison with other tumors, in patients with MM BTcP was more predictable (p=0.04), with the predominant trigger being the physical activity (p<0.001). Other BTcP characteristics, pattern of opioids used for background pain and BTcP, satisfaction and adverse effects did not differ. CONCLUSIONS: Patients with MM have their own peculiarities. Given the peculiar involvement of the skeleton, BTcP was highly predictable and triggered by movement.

Grade group system and plasma androgen receptor status in the first line treatment for metastatic castration resistant prostate cancer.

In localized prostate cancer (PCa), Grade Group (GG) and Gleason Score (GS) have a well-established prognostic role. In metastatic castration resistant prostate cancer (mCRPC), the prognostic role of GS and GG is less defined. In first-line treatment of mCRPC, androgen receptor (AR)-directed drugs (abiraterone acetate, enzalutamide) and docetaxel represent the referring options. There is no evidence that the GS/GG systems can add information to guide the choice between AR-directed drugs and docetaxel in the first-line setting of mCRPC. Nowadays there are no validated biomarkers, which define patients who may benefit or not from hormonal treatments or chemotherapy. Androgen receptor (AR) copy number variations (CNV) are predictive factors of poor response to abiraterone and enzalutamide. There are no available data about the association between AR CNV and GG. In this retrospective study, we analysed the association of the highest GG score with AR CNV and their impact on the clinical outcome of AR-directed drugs and docetaxel as first-line therapy for mCRPC patients. Patients benefit from docetaxel, abiraterone or enzalutamide regardless the GG. However, the presence of GG5 and AR CNV gain identifies a subgroup of patients with poor prognosis, which could benefit from front-line docetaxel instead of AR-directed drugs.

Italian SARS-CoV-2 patients in intensive care: towards an identikit for subjects at risk?

OBJECTIVE: To investigate patient characteristics and factors that increase the risk of being admitted to intensive care and that influence survival in cases of SARS-CoV-2 pneumonia. PATIENTS AND METHODS: One-hundred and ninety-one SARS-CoV-2 patients were admitted to the "Fondazione Poliambulanza di Brescia" Hospital (Brescia, Lombardy, Italy) in the period 1st March 2020 to 11th April 2020. Data on demographics, clinical presentation at admission, co-morbidities, pharmacological treatment, admission to intensive care and death was recorded. Logistic regression and survival analysis were carried out to investigate the risk of being admitted to intensive care and the risk of death. RESULTS: The mean age of the study cohort was 64.6±9.9 years (range 20-88). Median BMI was 28.5±5 kg/m2. Fever (81%) and dyspnea (65%) were the most common symptoms on admission. Most of patients (63%) had at least one co-existing disease. The 157 (82%) patients admitted to intensive care were more likely to be of intermediate age (60-69 years; OR 3.23, 95% CI 1.32-8.38), overweight (OR 2.66, 95% CI 1.02-7.07) or obese (OR 5.63, 95% CI 1.73-21.09) and with lymphocytopenia (OR 2.75, 95% CI 1.17-6.89) than the 34 patients admitted to the ordinary ward. During intensive care, 50% of patients died and their death was associated with older age (HR 2.06, 95% CI 1.07-3.97), obesity (HR 2.23, 95% CI 1.15-4.35) and male gender (HR 1.9, 95% CI 1.02-3.57). CONCLUSIONS: We found that admission to intensive care and poor survival were associated with advanced age and higher body mass index, albeit with differences in statistical significance. Pre-existing diseases and symptoms on admission were not associated with different clinical outcomes. Interestingly, male gender was more prevalent among SARS-CoV-2 patients and was related negatively to survival, but it was not associated with more frequent admission to intensive care.

Structural skin changes in elderly people investigated by reflectance confocal microscopy.

BACKGROUND: Reflectance confocal microscopy (RCM) is particularly suitable for the study of skin ageing because it provides nearly histological information in vivo and non-invasively. However, there are no studies that evaluated RCM skin features of a large population older than 70 years. OBJECTIVES: The aim of our investigation was to study age-related skin changes in an elderly population by RCM and to evaluate their topographical and gender differences. METHODS: We obtained RCM images of photoprotected (volar arm) and chronic (face) and intermittently photoexposed (dorsal forearm) body sites of 209 volunteers (105 women and 104 men, mean age: 77.5, range 74-81 years). 15 previously reported and new RCM parameters related to skin ageing were assessed. RESULTS: Photoexposed sites had thicker suprapapillary epidermis, more linear, distant and thin furrows, higher presence of mottled pigmentation, polycyclic papillae and coarse and huddled collagen and lower presence of dermal papillae than the photoprotected site. Irregular honeycomb pattern was not higher in photoexposed sites, indicating that it is probably more dependent on intrinsic ageing. Two ageing scores defined for facial skin ageing (epidermal disarray score and epidermal hyperplasia score) were found useful for the identification of photoageing. Gender differences only concerned some RCM parameters (i.e. thickness of different layers of the epidermis, furrows and collagen score) and some body sites, in line with the fact that women and men of our cohort had no major differences in clinically visible skin ageing. CONCLUSIONS: Our study confirmed that RCM is a powerful non-invasive technique to microscopically quantify ageing signs and our observations contribute to highlight the differences between intrinsic and extrinsic ageing.

Pheromone receptors and their putative ligands: possible role in humans.

Pheromones are ectohormones that play an important role in communication and behavior. Pheromones and pheromone receptor genes are important in mice and other mammals that rely heavily on pheromone cues to survive. Although there is controversy about whether pheromones and pheromone receptor genes have the same importance or are even active in humans, there are some hints that they might have roles in sociosexual behavior and mental disorders. The aim of this qualitative review was to provide an overview of the state of the art regarding pheromones and pheromone receptors in humans and their possible implications in human physiology and pathology. An electronic search was conducted in MEDLINE, PubMed and Scopus databases for articles published in English up to December 2018. The search concerned a possible role of pheromones and pheromone receptors in humans with implications for sociosexual behavior, mental disorders, the menstrual cycle and nutrition. Pheromone communication in humans has not been definitively demonstrated. However, the potential ability of putative pheromones to activate the hypothalamus, which controls the release of many hormones, suggests they could have a role in systemic functions in humans. Future confirmation of the effects of pheromones and pheromone receptors in humans could be useful in the prevention and treatment of various human disorders.

Combination radium-223 therapies in patients with bone metastases from castration-resistant prostate cancer: A review.

Chemotherapeutic agents (docetaxel, cabazitaxel), hormonal therapies (abiraterone, enzalutamide) and radium-223 improve survival in patients with bone metastatic castration-resistant prostate cancer (mCRPC). Combinations of radium-223 with these agents or novel drugs have been investigated in order to improve survival and decrease bone-related morbidity. In mCRPC, clinical and preclinical data indicate that radium-223, abiraterone and enzalutamide have a direct effect on prostate cancer cells and bone microenvironment when administered as single agents. Initial results from studies of radium-223 and abiraterone, enzalutamide or docetaxel demonstrated efficacy without any safety concern in pre-treated mCRPC; however, this safety profile changed when radium-based combination therapies were administered in un-pretreated mCRPC. This review underline the biological rationale for combining radium strategies, investigating their effects on bone in terms of control of skeletal-related events and bone disease progression. The aim is to understand the possible reasons why different radium-based combination treatments can led to different clinical outcomes.

Patient-derived organoids (PDOs) as a novel in vitro model for neuroblastoma tumours.

BACKGROUND: Neuroblastoma (NB) is a paediatric tumour of the sympathetic nervous system. Half of all cases are defined high-risk with an overall survival less than 40% at 5 years from diagnosis. The lack of in vitro models able to recapitulate the intrinsic heterogeneity of primary NB tumours has hindered progress in understanding disease pathogenesis and therapy response. METHODS: Here we describe the establishment of 6 patient-derived organoids (PDOs) from cells of NB tumour biopsies capable of self-organising in a structure resembling the tissue of origin. RESULTS: PDOs recapitulate the histological architecture typical of the NB tumour. Moreover, PDOs expressed NB specific markers such as neural cell adhesion molecules, NB84 antigen, synaptophysin (SYP), chromogranin A (CHGA) and neural cell adhesion molecule NCAM (CD56). Analyses of whole genome genotyping array revealed that PDOs maintained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p and gain of chromosome 17q. Furthermore, the PDOs showed stemness features and retained cellular heterogeneity reflecting the high heterogeneity of NB tumours. CONCLUSIONS: We were able to create a novel preclinical model for NB exhibiting self-renewal property and allowing to obtain a reservoir of NB patients' biological material useful for the study of NB molecular pathogenesis and to test drugs for personalised treatments.

The use of SAMe in chemotherapy-induced liver injury.

Drug-induced liver injury (DILI) remains the most common cause of acute liver failure in the Western world. Chemotherapy is one of the major class of drugs most frequently associated with idiosyncratic DILI. For this reason, patients who receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate and which drug doses should be modified. S-adenosylmethionine (SAMe) is an endogenous agent derived from methionine. Its supplementation is effective in the treatment of liver disease, in particular intrahepatic cholestasis (IHC). The target of this review is to analyze the mechanisms of hepatotoxicity of the principal anticancer agents and the role of SAMe in the prevention of this complication.

Bone metastases in biliary cancers: A multicenter retrospective survey.

•Natural history of biliary cancers metastatic to bone•The role of skeletal events in patients with biliary cancer•Biliary cancer and bone metastases: role of bisphosphonates.

Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO.

Background: Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status. Patients and methods: Patients were randomized to receive upfront 5-fluoruracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or 5-fluoruracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. Tumors were defined as right- or left-sided if they originated from the caecum to the transverse colon or within the splenic flexure and beyond, respectively. Patients with available information about both primary sidedness and RAS and BRAF status were included in the present analysis. Progression-free survival (PFS), overall survival (OS) and RECIST response rate were assessed according to tumor location and RAS and BRAF mutational status. Results: Information about primary sidedness and RAS and BRAF status was available for 358 (70.5%) out of 508 randomized patients. Patients with right-sided tumors (N = 173) presented shorter OS [23.7 versus 31.0 months, HR = 1.42 (95% CI 1.09-1.84), P = 0.010] and a trend toward shorter PFS [10.2 versus 11.5 months, HR = 1.24 (95% CI: 0.98-1.56), P = 0.083] than those with left-sided tumors (N = 185), but these associations were no longer evident when adjusting for RAS and BRAF status. Patients with right-sided tumors achieved more relative benefit from the intensification of the chemotherapy backbone in terms of both PFS (HR = 0.59 versus 0.89, P for interaction = 0.099) and OS (HR = 0.56 versus 0.99, P for interaction = 0.030) and this advantage was independent of their RAS and BRAF status. Conclusions: FOLFOXIRI plus bevacizumab may be regarded as a preferred first-line treatment option for clinically selected patients with right-sided metastatic colorectal cancer irrespective of their RAS and BRAF mutational status. Trial registration: clinicaltrials.gov identifier NCT00719797.

Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment.

Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signaling pathways. Furthermore, CBZ leads to the inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor κB (RANK), due to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment.

New findings in non-invasive imaging of cutaneous endometriosis: Dermoscopy, high-frequency ultrasound and reflectance confocal microscopy.

BACKGROUND: Cutaneous endometriosis (CE) is rare and its dermoscopic features were reported only in 3 patients. The aim of this study was to examine a case of pigmented CE with multiple non-invasive imaging techniques, to compare the obtained images with histopathology and to define their utility in an early diagnosis of the disease. CASE REPORT: We performed dermoscopy, high-frequency ultrasound (HFUS), in vivo and ex vivo reflectance confocal microscopy (RCM) of a pigmented CE arising on the caesarean scar of a phototype IV patient, along with histologic studies. Dermoscopy showed a greyish background and a brownish pigmentation. HFUS shows well-demarcated anechoic areas corresponding to ectopic endometrial tissue at histopathologic examination. RCM and OCT only showed the alterations of the epidermis. CONCLUSION: High-frequency ultrasound could represent a very useful tool for an early diagnosis of CE and its usefulness could be tested in patients with unusual cyclical pain, even before skin lesion appearance. RCM allowed the visualization of skin surface modification due to underlying endometriosic tissue. Dermoscopy showed a new aspect that was probably related to the mix of blood extravasation (ie, greyish background) and epidermal pigmentation (ie, brown pigmentation).

Prognostic and predictive role of neutrophil/lymphocytes ratio in metastatic colorectal cancer: a retrospective analysis of the TRIBE study by GONO.

Background: Neutrophil/lymphocyte ratio (NLR), defined as absolute neutrophils count divided by absolute lymphocytes count, has been reported as poor prognostic factor in several neoplastic diseases but only a few data are available about unresectable metastatic colorectal cancer (mCRC) patients (pts). The aim of our study was to evaluate the prognostic and predictive role of NLR in the TRIBE trial. Patients and methods: Pts enrolled in TRIBE trial were included. TRIBE is a multicentre phase III trial randomizing unresectable and previously untreated mCRC pts to receive FOLFOXIRI or FOLFIRI plus bevacizumab. A cut-off value of 3 was adopted to discriminate pts with low (NLR < 3) versus high (NLR ≥ 3) NLR, as primary analysis. As secondary analysis, NLR was treated as an ordinal variable with three levels based on terciles distribution. Results: NLR at baseline was available for 413 patients. After multiple imputation at univariate analysis, patients with high NLR had significantly shorter progression-free survival (PFS) [hazard ratio (HR) 1.27 (95% CI 1.05-1.55), P = 0.017] and overall survival (OS) [HR 1.56 (95% CI 1.25-1.95), P < 0.001] than patients with low NLR. In the multivariable model, NLR retained a significant association with OS [HR 1.44 (95% CI 1.14-1.82), P = 0.014] but not with PFS [HR 1.18 (95% CI 0.95-1.46), P = 0.375]. No interaction effect between treatment arm and NLR was evident in terms of PFS (P for interaction = 0.536) or OS (P for interaction = 0.831). Patients with low [HR 0.84 (95% CI 0.64-1.08)] and high [HR 0.73 (95% CI 0.54-0.97)] NLR achieved similar PFS benefit from the triplet and consistent results were obtained in terms of OS [HR 0.83 (95% CI 0.62-1.12) for low NLR; HR 0.82 (95% CI 0.59-1.12) for high NLR]. Conclusion: This study confirmed the prognostic role of NLR in mCRC pts treated with bevacizumab plus chemotherapy in the first line, showing the worse prognosis of pts with high NLR. The advantage of the triplet is independent of NLR at baseline.

Tramadol hydrochloride 75 mg/dexketoprofen 25 mg oral fixed-dose combination in moderate-to-severe acute pain: sustained analgesic effect over a 56-h period in the postoperative setting.

Multimodal analgesia constitutes a common strategy in pain management. A tramadol hydrochloride 75 mg/dexketoprofen 25 mg oral fixed combination (TRAM/DKP 75 mg/25 mg) has been recently registered and released in Europe for the treatment of moderate-to-severe acute pain. This paper provides additional analyses on the results of two phase III clinical trials (DEX-TRA-04 and DEX-TRA-05) on postoperative pain to document its sustained effect. The analysis was applied to a modified intention-to-treat population (mITT, n = 933) of patients undergoing active treatment from the first dose, to assess the sustained effect of TRAM/DKP 75 mg/25 mg on pain intensity (PI-VAS 0-100) over 56 h from first drug intake. The superior analgesic effect of TRAM/DKP 75 mg/25 mg over 56 h in terms of difference in PI-VAS (mean [SE]) was shown for DEX-TRA-04 (-11.0 [0.55] over dexketoprofen 25 mg and -9.1 [0.55] over tramadol 100 mg, P ≤ 0.0001) and for DEX-TRA-05 (-10.4 [0.51] over dexketoprofen 25 mg and -8.3 [0.51] over tramadol 100 mg, P ≤ 0.0001). The statistical analysis performed on data coming from both studies confirms the superior sustained analgesia of TRAM/DKP 75 mg/25 mg over tramadol 100 mg and dexketoprofen 25 mg. These results are consistent with the previously published data obtained on the ITT population and strongly support the role of this oral fixed-dose combination in the treatment of moderate-to-severe acute pain.

Propolis in the prevention of oral mucositis in breast cancer patients receiving adjuvant chemotherapy: A pilot randomised controlled trial.

Chemo-induced oral mucositis (OM) is associated with significant symptoms, treatment delays and increased costs. This pilot randomised controlled trial aimed at evaluating the safety, tolerability and compliance with propolis in breast cancer patients receiving doxorubicin and cyclophosphamide, testing preliminary clinical efficacy of propolis in the prevention of OM, and prospectively evaluating the incidence of OM. Sixty patients were randomised to receive either a dry extract of propolis with 8%-12% of galangin plus mouth rinsing with sodium bicarbonate (experimental arm), or mouth rinsing with sodium bicarbonate (control arm). OM was evaluated with the NCI-CTCAE v4.0 after 5, 10, 15 and 21 days of treatment. Compliance with, tolerability of propolis and adverse events were recorded. The incidence of OM was also prospectively evaluated for 6 months. Two patients (6.7%) manifested a suspected skin reaction to propolis. No patient in the experimental arm developed OM > G1, while in the control arm OM > G1 was 16.7% (p = .02). The incidence of OM ≥ G1 at the end of cycles 2-8 was higher at the second (25%) and fifth cycles (45.8%). Propolis plus bicarbonate was safe, well tolerated and promisingly effective in the prevention of OM in patients with breast cancer.

A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation.

BACKGROUND: Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. METHODS: This was a multicentre, phase 2 trial, planned according to a two-stage Simon's optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150-200 mg m-2 per day on days 1-5 every 28 days. RESULTS: From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. CONCLUSIONS: Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS.

BACKGROUND: Tachykinins have been implicated in the pathophysiology of IBS with diarrhoea (IBS-D). Our aim was to study the efficacy and safety of ibodutant, a selective neurokinin-2 (NK2) receptor antagonist, in patients with IBS-D. METHODS: This multinational double-blind, placebo-controlled study recruited 559 patients with IBS-D according to Rome III criteria. After a 2-week treatment-free run-in, patients were randomised to ibodutant 1 mg, 3 mg, 10 mg or placebo once daily for eight consecutive weeks. Responders were those with a combined response of satisfactory relief (weekly binary question yes/no) of overall IBS symptoms and abdominal pain/discomfort on ≥75% weeks (primary end point). Secondary end points included abdominal pain and stool pattern. Data were also analysed according to US Food and Drug Administration (FDA)-approved interim end points (improvement of pain and stool consistency). Safety was assessed by monitoring adverse events and laboratory tests. Prespecified statistical analysis involved the whole group as well as gender subgroups. RESULTS: Demographics and baseline characteristics were comparable for all treatment arms. In the overall population, responsiveness tended to increase with escalating ibodutant doses. In the prespecified analysis by gender, ibodutant 10 mg demonstrated significant superiority over placebo in females (p=0.003), while no significant effect occurred in males. This was confirmed for secondary end points and for the responder analysis according to FDA-approved end points. The tolerability and safety of ibodutant was excellent at all doses. CONCLUSIONS: Ibodutant showed dose-dependent efficacy response in IBS-D, reaching statistical significance at the 10 mg dose in female patients. The safety and tolerability profile of ibodutant was similar to placebo. TRIAL REGISTRATION NUMBER: NCT01303224.