Treatment-related adverse events of first-line immunotherapy versus sorafenib for advanced hepatocellular carcinoma: a meta-analysis.

BACKGROUND: Despite all the improvements achieved over the last decade, the use of immune checkpoint inhibitors (ICIs) has been associated to a wide range of adverse drug events, which are frequently markedly different from those observed with cytotoxic chemotherapy and targeted therapies, such as sorafenib. RESEARCH DESIGN AND METHODS: We performed a meta-analysis with the aim to compare grade 3/4 treatment-related adverse events (TRAEs), grade 5 TRAEs, serious TRAEs, and TRAEs leading to discontinuation in ICIs versus sorafenib across phase III clinical trials of first-line treatment for advanced hepatocellular carcinoma (HCC). RESULTS: Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients treated with ICIs showed higher risk of serious TRAEs (OR 1.48, 95% CI = 1.16-1.9) while sorafenib treatment was associated with higher risk of TRAEs leading to discontinuation (OR 0.65, 95% CI = 0.48-0.89). No differences in grade 3/4 TRAEs and grade 5 TRAEs. CONCLUSIONS: Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in HCC.

Antibiotic Abuse and Antimicrobial Resistance in Hospital Environment: A Retrospective Observational Comparative Study.

Background and Objectives: Antimicrobial resistance represents a serious problem, and it may be life-threatening in the case of severe hospital-acquired infections (HAI). Antibiotic abuse and multidrug resistance (MDR) have significantly increased this burden in the last decades. The aim of this study was to investigate the distribution and susceptibility rates of five selected bacterial species (E. coli, K. pneumoniae, P. aeruginosa, S. aureus and E. faecium) in two healthcare settings located in the Apulia region (Italy). Materials and Methods: Setting n.1 was a university hospital and setting n.2 was a research institute working on oncological patients. All the enrolled patients were diagnosed for bacterial HAI. The observation period was between August and September 2021. Clinical samples were obtained from several biological sources, in different hospital wards. Bacterial identification and susceptibility were tested by using the software VITEC 2 Single system. Results: In this study, a higher incidence of multi-drug-resistant K. pneumoniae was reported (42,2% in setting n.1 and 50% in setting n.2), with respect to the Italian 2019 statistics report (30.3%). All the isolates of E. faecium and S. aureus were susceptible to linezolid. All the bacterial isolates of P. aeruginosa and most of K. pneumoniae were susceptible to ceftazidime-avibactam. Amikacin and nitrofurantoin represented a good option for treating E. coli infections. Multidrug-resistant (MDR) P. aeruginosa, methicillin-resistant S. aureus (MRSA) and vancomycin-resistantE. faecium (VRE) had a lower incidence in the clinical setting, with respect to E. coli and K. pneumoniae. Conclusions: The data obtained in this study can support clinicians towards a rational and safe use of antibiotics for treating the infections caused by these resistant strains, to enhance the overall efficacy of the current antibiotic protocols used in the main healthcare environments.

LC-MS/MS Analysis on Infusion Bags and Filled Syringes of Decitabine: New Data on Physicochemical Stability of an Unstable Molecule.

Many anticancer drugs are reported to have low physicochemical stability after dilution; therefore, producers impose short times from reconstitution, dilution, and the end of administration. The precariousness of cancer patients' health in real-life experience within cancer hospitals often forces delays in the drug administration with respect to the standard treatment schedule timing, because of acute toxicities or the need to postpone a control analysis before administration. The public health costs for discarded anticancer drugs due to administration interruptions can be avoided, thanks to independent analytical studies, which integrate the producer's data reported in the technical sheet, referring to the real conditions of preparation in a sterile atmosphere under a cabin in a laboratory dedicated to handling cytotoxic drugs in controlled conditions of temperature, pressure, and particulate contamination. Decitabine is apparently an unstable molecule, whose reported stability is only 3 h at 2-8 °C when diluted, while the mother solution must be immediately used or, otherwise, discarded. This study has investigated the physicochemical stability of decitabine both in diluted infusion bags and in sterile water reconstituted syringes at 4 °C for 0, 24, 48, and 72 h. In all performed studies, the stability-indicating method involves, for the first time, the use of liquid chromatography-tandem mass spectrometry analysis. Unexpectedly, both diluted and reconstituted solutions of decitabine are more stable than previously reported data, with a 48 h-long physicochemical stability at 2-8 °C and protected from light.

Intra-Arterial Infusion Chemotherapy in Advanced Pancreatic Cancer: A Comprehensive Review.

Advanced pancreatic cancer (PC) has a very poor prognosis due to its chemoresistant nature. Nowadays, only a few therapeutic options are available for PC, and the most effective ones are characterized by low response rates (RRs), short progression-free survival and overall survival, and severe toxicity. To improve clinical results, small series studies have evaluated loco-regional chemotherapy as a treatment option for PC, demonstrating its dose-dependent sensitivity towards the tumor. In fact, pancreatic arterial infusion (PAI) chemotherapy allows higher local concentrations of chemotherapeutic agents, sparing healthy tissues with a lower rate of adverse events compared to systemic chemotherapy. This therapeutic approach has already been evaluated in different types of tumors, especially in primary and metastatic liver cancers, with favourable results. With regard to advanced PC, a few clinical studies have investigated the safety and efficacy of PAI with promising results, especially in terms of RRs compared to systemic chemotherapy. However, clear evidence about its efficacy has not been established yet nor have the underlying mechanisms leading to its success. In this review, we aim to summarize the literature data on the clinical approaches to pancreatic arterial drug administration in terms of techniques, drug pharmacokinetics, and clinical outcomes for advanced PC.

A New Score to Assess the Perioperative Period of the Cancer Patient Undergoing Non-Palliative Elective Surgery: A Retrospective Evaluation of a Case Report by PERIDIA Score.

The complexity of cancer patients and the use of advanced and demolitive surgical techniques frequently need post-operatory ICU hospitalization. To increase safety and to select the best medical strategies for the patient, a multidisciplinary team has performed a new peri-operatory assessment, arising from evidence-based literature data. Verifying that most of the cancer patients, admitted to the intensive care unit, undergo major surgery with localizations in the supramesocolic thoraco-abdominal area, the team focused the attention on supramesocolic peridiaphragmatic cancer surgery. Some scores already in use in clinical practice were selected for the peri-operatory evaluation process. None of them evaluate parameters relating to the entire peri-operative period. In detail, only a few study models were found that concern the assessment of the intra-operative period. Therefore, we wanted to see if using a mix of validated scores, it was possible to build a single evaluation score (named PERIDIAphragmatic surgery score or PERIDIA-score) for the entire peri-operative period that could be obtained at the end of the patient's hospitalization period in post-operative ICU. The main property sought with the creation of the PERIDIA-score is the proportionality between the score and the incidence of injuries, deaths, and the length of stay in the ward. This property could organize a tailor-made therapeutic path for the patient based on pre-rehabilitation, physiotherapy, activation of social assistance services, targeted counseling, collaborations with the continuity of care network. Furthermore, if the pre-operative score is particularly high, it could suggest different or less invasive therapeutic options, and if the intra-operative score is particularly high, it could suggest a prolongation of hospitalization in ICU. The retrospective prospective study conducted on 83 patients is still ongoing. The first data would seem to prove an increase of clinical complications in patients who were assigned a one-third score with respect to the maximum (16/48) of PERIDIA-score. Moreover, patients with a 10/16 score within each phase of the evaluation (pre, peri, and post) more frequently develop injuries. In the light of these evidence, the 29-point score assigned to our patient can be considered as predictive for the subsequent critical and fatal complications the patient faced up.

Hepatic Arterial Infusion of Chemotherapy for Advanced Hepatobiliary Cancers: State of the Art.

Liver functional failure is one of the leading causes of cancer-related death. Primary liver tumors grow up mainly in the liver, and thus happens for liver metastases deriving from other organs having a lower burden of disease at the primary site. Systemic chemotherapy usually offers a modest benefit in terms of disease control rate, progression-free survival, and overall survival at the cost of a significant percentage of adverse events. Liver malignancies are mostly perfused by the hepatic artery while the normal liver parenchyma by the portal vein network. On these bases, the therapeutic strategy consisting of hepatic arterial infusion (HAI) of chemotherapy takes place. In literature, HAI chemotherapy was applied for the treatment of advanced hepatobiliary cancers with encouraging results. Different chemotherapeutic agents were used such as Oxaliplatin, Cisplatin, Gemcitabine, Floxuridine, 5-Fluorouracil, Epirubicin, individually or in combination. However, the efficacy of this treatment strategy remains controversial. Therefore, this review aims to summarize the current knowledge on this approach from different points of view, such as techniques, drugs pharmacology and pharmacokinetics, and clinical outcomes for advanced hepatobiliary cancers.

Mast Cells Positive for c-Kit Receptor and Tryptase Correlate with Angiogenesis in Cancerous and Adjacent Normal Pancreatic Tissue.

BACKGROUND: Mast cells (MCs) contain proangiogenic factors, in particular tryptase, associated with increased angiogenesis in several tumours. With special reference to pancreatic cancer, few data have been published on the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue (PDAT) and adjacent normal tissue (ANT). In this study, density of mast cells positive for c-Kit receptor (MCDP-c-KitR), density of mast cells positive for tryptase (MCDPT), area of mast cells positive for tryptase (MCAPT), and angiogenesis in terms of microvascular density (MVD) and endothelial area (EA) were evaluated in a total of 45 PDAT patients with stage T2-3N0-1M0. RESULTS: For each analysed tissue parameter, the mean ± standard deviation was evaluated in both PDAT and ANT and differences were evaluated by Student's t-test (p ranged from 0.001 to 0.005). Each analysed tissue parameter was then correlated to each other one by Pearson t-test analysis (p ranged from 0.01 to 0.03). No other correlation among MCDP-c-KitR, MCDPT, MCAPT, MVD, EA and the main clinical-pathological characteristics was found. CONCLUSIONS: Our results suggest that tissue parameters increased from ANT to PDAT and that mast cells are strongly associated with angiogenesis in PDAT. On this basis, the inhibition of MCs through tyrosine kinase inhibitors, such as masitinib, or inhibition of tryptase by gabexate mesylate may become potential novel antiangiogenetic approaches in pancreatic cancer therapy.

Peripheral Neuropathy under Oncologic Therapies: A Literature Review on Pathogenetic Mechanisms.

Peripheral neurologic complications are frequent adverse events during oncologic treatments and often lead to dose reduction, administration delays with time elongation of the therapeutic plan and, not least, worsening of patients' quality of life. Experience skills are required to recognize symptoms and clinical evidences and the collaboration between different health professionals, in particular oncologists and hospital pharmacists, grants a correct management of this undesirable occurrence. Some classes of drugs (platinates, vinca alkaloids, taxanes) typically develop this kind of side effect, but the genesis of chemotherapy-induced peripheral neuropathy is not linked to a single mechanism. This paper aims from one side at summarizing and explaining all the scattering mechanisms of chemotherapy-induced peripheral neuropathy through a detailed literature revision, on the other side at finding new approaches to possible treatments, in order to facilitate the collaboration between oncologists, hematologists and hospital pharmacists.

Microvascular Density, Endothelial Area, and Ki-67 Proliferative Index Correlate Each Other in Cat Post-Injection Fibrosarcoma.

Soft tissue sarcomas are a large group of different tumor types both in humans and in animals. Among them, fibrosarcoma is the most frequent malignant mesenchymal tumoral form in cats, representing up to 28% of all cat skin tumors, while human fibrosarcoma, fortunately, only represents 5% of all sarcomas and 0.025% of the world-wide burden of tumors. This low incidence in humans leads to consideration of this group of tumoral diseases as rare, so therapeutic options are few due to the difficulty of starting clinical trials. In this context, the identification of research models for fibrosarcomas could be of great interest to deepen knowledge in this field and recognize new or possible biological pathways involved in tumor progression and metastasis. Angiogenesis is considered a fundamental scattering cause of tumor aggressiveness and progression in all forms of cancer, but only a few research parameters were developed and reported to express them quantitatively and qualitatively. The role in angiogenesis of microenvironmental stromal cells, such as fibroblasts, lymphocytes, mast cells, and macrophages, was largely demonstrated since this topic was first approached, while quantification of new vessels and their blood capacity in tumoral area is a relatively recent approach that could be well developed thanks to expertise in immunohistochemistry and image analysis. In this paper, a crossing study evaluating microvascular density (MVD), endothelial area (EA), and Ki-67 proliferative index was reported for a series of formalin-fixed and paraffin-embedded tissue samples from 99 cat patients, affected by cat post-injection fibrosarcoma, by using a till ×400 magnification light microscopy. We aim to demonstrate that cat pets may be considered a useful animal model for better studying the correspondent human diseases and we report, for the first time to our knowledge, experimental data in terms of correlation among MVD, EA, and Ki-67 strictly involved in aggressiveness and tumoral progression.

Case Report: Lymphocytosis Associated With Fatal Hepatitis in a Thymoma Patient Treated With Anti-PD1: New Insight Into the Immune-Related Storm.

Recent advances in tumor immunotherapy have made it possible to efficiently unleash immune effectors, reacting against neoplastic cells. Although these approaches primarily aim to eradicate malignancy, immune-related adverse events (irAEs) often influence patients' prognosis, constituting a new spectrum of side effects. Taking into account the typical microenvironment and the intricate equilibrium between the anti-tumor response and the immune cells, the thymoma constitutes a unicum in the immune-oncology field. We report a fatal immune-mediated adverse events' storm in a thymoma patient treated with Pembrolizumab, leading to hepatotoxicity accompanied by lymphocytosis, thrombocytopenia, and thyroid dysfunction, unveiling a novel potential pathophysiological effect of immunotherapy. The clinical proficiency of the immune checkpoint inhibitors in thymoma patients warrants timely prevention and management of off-target consequences in order to optimize this promising therapeutic option. This case report describes a unique consequence of irAEs, emerging as a red flag warranting a multidisciplinary approach.

Bevacizumab Plus FOLFOX-4 Combined With Deep Electro-Hyperthermia as First-line Therapy in Metastatic Colon Cancer: A Pilot Study.

Bevacizumab plus FOLFOX-4 regimen represents the first-line therapy in patients affected by metastatic colorectal cancer (mCRC). Hyperthermia has been considered an effective ancillary treatment for cancer therapy through several anti-tumor mechanisms, sharing with Bevacizumab the inhibition of angiogenesis. Up to now, scientific literature offers very few clinical data on the combination of bevacizumab plus oxaliplatin-based chemotherapy with deep electro-hyperthermia (DEHY) for metastatic colon cancer (mCC) patients. Therefore, we aimed at evaluating the efficacy of this combination based on the possible interaction between the DEHY and bevacizumab anti-tumor mechanisms. We conducted a retrospective analysis on 40 patients affected by mCC treated with the combination of bevacizumab plus FOLFOX-4 (fluorouracil/folinic acid plus oxaliplatin) and DEHY (EHY2000), between January 2017 and May 2020. DEHY treatment was performed weekly, with capacitive electrodes at 80-110 W for 50 min, during and between subsequent bevacizumab administrations, on abdomen for liver or abdominal lymph nodes metastases and thorax for lung metastases. Treatment response assessment was performed according to the Response Evaluation Criteria for Solid Tumors (RECIST). The primary endpoints were disease control rate (DCR) and progression-free survival (PFS). The secondary endpoint was overall survival (OS). DCR, counted as the percentage of patients who had the best response rating [complete response (CR), partial response (PR), or stable disease (SD)], was assessed at 90 days (timepoint-1) and at 180 days (timepoint-2). DCR was 95% and 89.5% at timepoint-1 and timepoint-2, respectively. The median PFS was 12.1 months, whereas the median OS was 21.4 months. No major toxicity related to DEHY was registered; overall, this combination regimen was safe. Our results suggest that the combined treatment of DEHY with bevacizumab plus FOLFOX-4 as first-line therapy in mCC is feasible and effective with a favorable disease control, prolonging PFS of 2.7 months with respect to standard treatment without DEHY for mCC patients. Further studies will be required to prove its merit and explore its potentiality, especially if compared to conventional treatment.

PARP inhibitors and epithelial ovarian cancer: Molecular mechanisms, clinical development and future prospective.

Epithelial ovarian cancer (EOC) has a poor prognosis. Since the introduction of paclitaxel as antineoplastic agent >20 years ago, only a few phase III randomized trials have shown challenging data regarding different therapeutic options for facing its aggressive clinical course and granting active therapies to patients. Different studies have shown the utility of poly(ADP-ribose) polymerase (PARP) inhibitors in women with EOC with or without BRCA mutations, both germline and somatic. Three PARP inhibitors, olaparib, rucaparib and niraparib, have been recently approved by the Food and Drug Administration for clinical use in EOC patients, though with different clinical indications and profiles of toxicity, while two other molecules, veliparib and talazoparib, are still under clinical investigation. The aim of the present paper is to evaluate the current status of PARP inhibitors in terms of molecular activity, pharmacodynamic properties and clinical applications.

Pharmacotherapy in Mast Cell Leukemia.

INTRODUCTION: Mast cell leukemia (MCL) is one of the most aggressive forms of Systemic Mastocytosis (SM), a complex family of rare diseases, for which standard therapies are very few. MCL represents only <1% cases of SM and this is the reason why there are no specific clinical trials to better explore this disease. As a consequence, MCL is treated and grouped within other forms of SM, being all KIT-driven diseases; however, its KIT dysregulation leads to uncontrolled activation of mast cells (MCs), which correlates with forms of myeloid acute leukemia (AML). AREAS COVERED: Different therapeutic approaches can be followed in the treatment of MCL. The authors look at both symptomatic therapies along with other approaches including targeted therapy. Further, the authors provide their expert opinion. EXPERT OPINION: In the scenario of mast cell leukemia treatment, the key approach to achieve clinical results is, more than other similar pathologies, personalizing the therapy. It could be interesting or desirable to introduce for instance KIT mutant forms as minor criteria for the diagnosis of advanced SM, considering the small patient population with MCL and the relatively large panel of activating mutations for KIT and other important proteins involved in MCs' regulation.

Corrigendum: Bevacizumab Plus FOLFOX-4 Combined With Deep Electro-Hyperthermia as First-line Therapy in Metastatic Colon Cancer: A Pilot Study.

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An evaluation of masitinib for treating systemic mastocytosis.

Introduction: Systemic Mastocytosis (SM) is a complex family of rare diseases, against which pharmacological therapies are still very few. It is a c-kit driven disease, whose disregulation leads to uncontrolled activation and proliferation of mast cells (MCs) with consequent release of effector molecules which are responsible for its clinical manifestations. Areas covered: Masitinib is a relatively new potential drug against SM and its chemical structure strictly derives from imatinib, the first tyrosine kinase inhibitor which entered the pharmaceutical market about 15 years ago. In this review, the authors present masitinib in all its properties, from chemistry to pharmacology and toxicity to its potential clinical application in SM, focusing the discussion on the few clinical trials in which it has been involved, with a particular attention on the still open challenge to determine how to measure the response to therapy. Expert opinion: In spite of their similarity in chemistry and biological activity against submolecular targets, masitinib is much more selective towards c-kit receptors than other tyrosine kinases, such as Bcl-Abl. Furthermore, its ability to inhibit degranulation, cytokine production and MCs migration from bone marrow gives it a great chance to become an important therapeutic option for selected SM patients.

Oxaliplatin-Based Intra-arterial Chemotherapy in Colo-Rectal Cancer Liver Metastases: A Review from Pharmacology to Clinical Application.

Liver metastases (LM) are often consequences of colo-rectal cancer (CRC)and the majority of patients have unresectable LM. Oxaliplatin-based intravenous chemotherapy represents the gold standard treatment for CRC. Intravenous oxaliplatin has several side effects i.e., nephrologic, hematologic and neurological toxicity. Moreover, hepatic arterial infusion (HAI) of antitumor drugs deeply modifies the treatment of LMCRC due to the knowledge that LM are perfused by the hepatic artery network, whereas healthy tissue is perfused by the portal vein. Therefore, oxaliplatin-based HAI becomes an interesting possibility to treat LMCRC. The aim of this review is to shed light on the important impact of the oxaliplatin-based chemotherapy from a non-conventional clinical point of view, considering that, being universally accepted its antitumor effect if administered intravenously, fragmentary information are known about its clinical applications and benefits deriving from intra-arterial administration in loco-regional chemotherapy.

Platinum complexes can inhibit matrix metalloproteinase activity: platinum-diethyl[(methylsulfinyl)methyl]phosphonate complexes as inhibitors of matrix metalloproteinases 2, 3, 9, and 12.

Platinum complexes able to inhibit matrix metalloproteinases (MMPs) through a noncompetitive mechanism are reported for the first time in this study. [PtCl2(SMP)] and [Pt(dimethylmalonato)(SMP)], characterized by the bisphosphonate-analogue ligand diethyl[(methylsulfinyl)methyl]phosphonate (SMP), are slight inhibitors of MMP-2 (IC50 = 258 +/- 38 and 123 +/- 14 microM, respectively) but markedly inhibit MMP-9 (IC50 = 35.5 +/- 6 and 17 +/- 4 microM), MMP-3 (IC50 = 5.3 +/- 2.9 and 4.4 +/- 2.2 microM), and MMP-12 (IC50 = 10.8 +/- 3 and 6.2 +/- 1.8 microM). In contrast, cisplatin, carboplatin, and the SMP ligand are inactive, and the bisphosphonate clodronate shows a broad-spectrum inhibitory activity in the high micromolar range (mean IC50 > 200 microM). These results, along with mechanistic investigations (DNA interaction and tumor cell growth inhibition), demonstrate that ligand modifications of platinum compounds can be exploited to target also biological substrates distinct from DNA.

Two polymorphs of potassium trichloro[diethyl (methylsulfinylmethyl)phosphonate-kappaS]platinum(II) with Z' = 1 and 3 in the space group P2(1)2(1)2(1).

Two new polymorphs of the title compound, K[PtCl(3)(C(6)H(15)O(4)PS)], already known in the monoclinic form, were obtained by crystallization from acetone-n-pentane solutions of different composition. Both polymorphs are orthorhombic in the space group P2(1)2(1)2(1), with Z' = 1 (solvent ratio 1:4) and 3 (solvent ratio 1:9). In both polymorphs, electrostatic interactions link K(+) cations and [PtCl(3)(SMP)](-) anions [SMP is diethyl (methylsulfinylmethyl)phosphonate] in infinite chains, while adjacent chains are held together by weak C-H...Cl and C-H...O hydrogen-bond interactions.