Anemia in patients receiving anticancer treatments: focus on novel therapeutic approaches.

Anemia is common in cancer patients and impacts on quality of life and prognosis. It is typically multifactorial, often involving different pathophysiological mechanisms, making treatment a difficult task. In patients undergoing active anticancer treatments like chemotherapy, decreased red blood cell (RBC) production due to myelosuppression generally predominates, but absolute or functional iron deficiency frequently coexists. Current treatments for chemotherapy-related anemia include blood transfusions, erythropoiesis-stimulating agents, and iron supplementation. Each option has limitations, and there is an urgent need for novel approaches. After decades of relative immobilism, several promising anti-anemic drugs are now entering the clinical scenario. Emerging novel classes of anti-anemic drugs recently introduced or in development for other types of anemia include activin receptor ligand traps, hypoxia-inducible factor-prolyl hydroxylase inhibitors, and hepcidin antagonists. Here, we discuss their possible role in the treatment of anemia observed in patients receiving anticancer therapies.

Reducing agalsidase beta infusion time in Fabry patients: low incidence of antibody formation and infusion-associated reactions in an Italian multicenter study.

BACKGROUND: Fabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated. RESULTS: Twenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study's end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved. CONCLUSIONS: The study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.

Use of non-invasive respiratory supports in high-intensity internal medicine setting during the first two waves of the COVID-19 pandemic emergency in Italy: a multicenter, real-life experience.

During the first two waves of the COVID-19 emergency in Italy, internal medicine high-dependency wards (HDW) have been organized to manage patients with acute respiratory failure (ARF). There is heterogeneous evidence about the feasibility and outcomes of non-invasive respiratory supports (NIRS) in settings outside the intensive care unit (ICU), including in patients deemed not eligible for intubation (i.e., with do-not-intubate, DNI status). Few data are available about the different NIRS modalities applied to ARF patients in the newly assembled internal medicine HDW. The main aim of our study was to describe a real-life experience in this setting of cure, focusing on feasibility and outcomes. We retrospectively collected data from COVID-19 patients with ARF needing NIRS and admitted to internal medicine HDW. Patients were treated with different modalities, that is high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), or non-invasive mechanical ventilation (NIMV). Switching among different NIRS during the hospitalization and the success rate (weaning with the same NIRS) or failure (endotracheal intubation-ETI or in-hospital death) were recorded. Three hundred thirty four ARF patients (median age 74 years), of which 158 (54%) had a DNI status, were included. CPAP, NIMV, and HFNC's success rates were 54, 33, and 13%, respectively. Although DNI status was strongly associated with death (Gehan-Breslow-Wilcoxon test p < 0.001), an acceptable success rate was observed in these patients using CPAP (47%). Multivariate regression models showed older age (odds ratio-OR 4.74), chronic ischemic heart disease (OR 2.76), high respiratory rate after 24 h (OR 7.13), and suspected acute respiratory distress syndrome-ARDS (OR 21.1) as predictors of mortality risk or ETI. Our real-life experience shows that NIRS was feasible in internal medicine HDW with an acceptable success rate. Although DNI patients had a worse prognosis, the use of NIRS represented a reasonable chance of treatment.

Dapaglifozin on Albuminuria in Chronic Kidney Disease Patients with FabrY Disease: The DEFY Study Design and Protocol.

Fabry disease (FD) is a rare genetic disorder caused by a deficiency in the α-galactosidase A enzyme, which results in the globotriaosylceramide accumulation in many organs, including the kidneys. Nephropathy is a major FD complication that can progress to end-stage renal disease if not treated early. Although enzyme replacement therapy and chaperone therapy are effective, other treatments such as ACE inhibitors and angiotensin receptor blockers can also provide nephroprotective effects when renal damage is also established. Recently, SGLT2 inhibitors have been approved as innovative drugs for treating chronic kidney disease. Thus, we plan a multicenter observational prospective cohort study to assess the effect of Dapagliflozin, a SGLT2 inhibitor, in FD patients with chronic kidney disease (CKD) stages 1-3. The objectives are to evaluate the effect of Dapagliflozin primarily on albuminuria and secondarily on kidney disease progression and clinical FD stability. Thirdly, any association between SGT2i and cardiac pathology, exercise capacity, kidney and inflammatory biomarkers, quality of life, and psychosocial factors will also be evaluated. The inclusion criteria are age ≥ 18; CKD stages 1-3; and albuminuria despite stable treatment with ERT/Migalastat and ACEi/ARB. The exclusion criteria are immunosuppressive therapy, type 1 diabetes, eGFR < 30 mL/min/1.73 m2, and recurrent UTIs. Baseline, 12-month, and 24-month visits will be scheduled to collect demographic, clinical, biochemical, and urinary data. Additionally, an exercise capacity and psychosocial assessment will be performed. The study could provide new insights into using SGLT2 inhibitors for treating kidney manifestations in Fabry disease.

The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.

Red Blood Cell Morphologic Abnormalities in Patients Hospitalized for COVID-19.

Peripheral blood smear is a simple laboratory tool, which remains of invaluable help for diagnosing primary and secondary abnormalities of blood cells despite advances in automated and molecular techniques. Red blood cells (RBCs) abnormalities are known to occur in many viral infections, typically in the form of mild normo-microcytic anemia. While several hematological alterations at automated complete blood count (including neutrophilia, lymphopenia, and increased red cell distribution width-RDW) have been consistently associated with severity of COVID-19, there is scarce information on RBCs morphological abnormalities, mainly as case-reports or small series of patients, which are hardly comparable due to heterogeneity in sampling times and definition of illness severity. We report here a systematic evaluation of RBCs morphology at peripheral blood smear in COVID-19 patients within the first 72 h from hospital admission. One hundred and fifteen patients were included, with detailed collection of other clinical variables and follow-up. A certain degree of abnormalities in RBCs morphology was observed in 75 (65%) patients. Heterogenous alterations were noted, with spiculated cells being the more frequent morphology. The group with >10% RBCs abnormalities had more consistent lymphopenia and thrombocytopenia compared to those without abnormalities or <10% RBCs abnormalities (p < 0.018, and p < 0.021, respectively), thus underpinning a possible association with an overall more sustained immune-inflammatory "stress" hematopoiesis. Follow-up analysis showed a different mortality rate across groups, with the highest rate in those with more frequent RBCs morphological alterations compared to those with <10% or no abnormalities (41.9%, vs. 20.5%, vs. 12.5%, respectively, p = 0.012). Despite the inherent limitations of such simple association, our results point out towards further studies on erythropoiesis alterations in the pathophysiology of COVID-19.

Assessment of SARS-CoV-2 IgG and IgM antibody detection with a lateral flow immunoassay test.

The dramatic impact of SARS-CoV-2 infection on the worldwide public health has elicited the rapid assessment of molecular and serological diagnostic methods. Notwithstanding the diagnosis of SARS-CoV-2 infection is based on molecular biology approaches including multiplex or singleplex real time RT-PCR, there is a real need for affordable and rapid serological methods to support diagnostics, and surveillance of infection spreading. In this study, we performed a diagnostic accuracy analysis of COVID-19 IgG/IgM rapid test cassette lateral flow immunoassay test (LFIA) assay. To do so, we analyzed different cohorts of blood samples obtained from 151 SARS-CoV-2 RT-PCR assay positive patients (group 1) and 51 SARS-CoV-2 RT-PCR assay negative patients (group 2) in terms of sensitivity, specificity, PPV, NPV and likelihood ratios. In addition, we challenged LFIA with plasma from 99 patients stored during 2015-2017 period. Our results showed that this LFIA detected SARS-CoV-2 IgM and/or IgG in 103 out of 151 (68.21%) samples of group 1, whereas no IgM and/or IgG detection was displayed both in the group 2 and in pre-pandemic samples. Interestingly, IgM and/or IgG positivity was detected in 86 out of 94 (91.49%) group 1 samples collected after 10 days from symptoms onset whereas only 17 out of 57 of group 1 samples obtained before day 10 were positive to SARS-CoV-2 specific antibodies. We also compared the performance of this LFIA test with respect to other four different LFIA assays in 40 serum samples from multiplex RT-PCR positive individuals. Within the limits of the study size, the results demonstrated that COVID-19 IgG/IgM rapid test cassette LFIA assay displayed valid performance in IgM and IgG detection when compared with the other four LFIA assays. Hence, this approach might be considered as an alternative point-of-care procedure for SARS-CoV-2 serological investigation.

Iron metabolism in infections: Focus on COVID-19.

Iron is a micronutrient essential for a wide range of metabolic processes in virtually all living organisms. During infections, a battle for iron takes place between the human host and the invading pathogens. The liver peptide hepcidin, which is phylogenetically and structurally linked to defensins (antimicrobial peptides of the innate immunity), plays a pivotal role by subtracting iron to pathogens through its sequestration into host cells, mainly macrophages. While this phenomenon is well studied in certain bacterial infections, much less is known regarding viral infections. Iron metabolism also has implications on the functionality of cells of the immune system. Once primed by the contact with antigen presenting cells, lymphocytes need iron to sustain the metabolic burst required for mounting an effective cellular and humoral response. The COVID-19 pandemic has boosted an amount of clinical and translational research over the possible influences of nutrients on SARS-CoV-2 infection, in terms of either susceptibility or clinical course. Here we review the intersections between iron metabolism and COVID-19, belonging to the wider domain of the so-called "nutritional immunity". A better understanding of such connections has potential broad implications, either from a mechanistic standpoint, or for the development of more effective strategies for managing COVID-19 and possible future pandemics.

Anatomic reconstruction of the coracoclavicular and acromioclavicular ligaments with semitendinosus tendon graft for the treatment of chronic acromioclavicular joint dislocation provides good clinical and radiological results.

PURPOSE: To evaluate clinical and radiographic outcomes of anatomical reconstruction of the coracoclavicular and acromioclavicular ligaments with single-strand semitendinosus tendon graft for the treatment of chronic acromioclavicular joint dislocation. METHODS: Patients affected by chronic type III-V acromioclavicular joint dislocations were included. Exclusion criteria were: age under 18 years, concomitant rotator cuff tears, previous surgery to the same shoulder, degenerative changes of the glenohumeral joint, infections, neurologic diseases, patients with a previous history of ligament reconstruction procedures that had required harvesting of the semitendinosus tendon from the ipsilateral or contralateral knee. All patients underwent the same surgical technique and rehabilitation. Primary outcome was the normalized Constant score. Secondary outcomes were: DASH score, radiographic evaluation of loss of reduction and acromioclavicular joint osteoarthritis. RESULTS: Thirty patients with a mean age of 28.9 ± 8.3 years were included. Mean time to surgery was 12.8 ± 10 months. Mean follow-up was 28.1 ± 2.4 months (range: 24-32). Comparison between pre- and postoperative functional scores showed significant clinical improvement (p < 0.001). Time to surgery was independently associated with a poorer Constant score (p < 0.0001). On radiographs, 4 patients (13.3%) showed asymptomatic partial loss of reduction. CONCLUSION: Anatomic reconstruction of coracoclavicular and acromioclavicular ligaments using a semitendinosus tendon graft for the treatment of chronic acromioclavicular joint dislocation provided good clinical and radiological results at minimum 2-year follow-up. LEVEL OF EVIDENCE: Level III.

Biologic and synthetic ligament reconstructions achieve better functional scores compared to osteosynthesis in the treatment of acute acromioclavicular joint dislocation.

PURPOSE: To systematically review the outcomes of surgical treatments of acute acromioclavicular joint dislocation. METHODS: Studies were identified by electronic databases (Ovid, PubMed). All studies reporting functional and radiological outcomes of surgical treatments of acute acromioclavicular joint dislocations were included. Following data were extracted: authors and year, study design, level of evidence, number of patients, age, classification of acromioclavicular joint dislocation, time to surgery, surgical technique, follow-up, clinical and imaging outcomes, complications, and failures. Descriptive statistics was used, when a data pooling was not possible. Comparable outcomes were pooled to generate summary outcomes reported as frequency-weighted values. Quality appraisal was assessed through the MINORS checklist. RESULTS: One hundred and thirty-three studies were included for a total of 4473 shoulders. Mean age of participants was 36.9 years. Mean follow-up was 42.06 months. Arthroscopy showed better ASES (p < 0.0001) and lower VAS pain score (p = 0.0249) compared to an open approach. Biologic and synthetic reconstructions demonstrated better results over osteosynthesis techniques. Biologic techniques showed overall better Constant (p = 0.0001) and DASH (p = 0.0215) scores, while synthetic reconstruction showed better UCLA score (p = 0.0001). Among suture buttons, triple button showed overall better results in Constant (p = 0.0001) and VAS (p = 0.0001) scores, while better results in DASH score (p = 0.0003) were achieved by 2 double button techniques. Overall, the level of evidence was low. CONCLUSION: Biological and synthetic reconstructions achieved better functional scores compared to osteosynthesis. Among suture buttons, the triple button showed better functional performance. LEVEL OF EVIDENCE: IV.

A Novel ALAS2 Missense Mutation in Two Brothers With Iron Overload and Associated Alterations in Serum Hepcidin/Erythroferrone Levels.

Iron loading anemias are characterized by ineffective erythropoiesis and iron overload. The prototype is non-transfusion dependent ß-thalassemia (NTDT), with other entities including congenital sideroblastic anemias, congenital dyserythropoietic anemias, some hemolytic anemias, and myelodysplastic syndromes. Differential diagnosis of iron loading anemias may be challenging due to heterogeneous genotype and phenotype. Notwithstanding the recent advances in linking ineffective erythropoiesis to iron overload, many pathophysiologic aspects are still unclear. Moreover, measurement of hepcidin and erythroferrone (ERFE), two key molecules in iron homeostasis and erythropoiesis, is scarcely used in clinical practice and of uncertain utility. Here, we describe a comprehensive diagnostic approach, including next-generation sequencing (NGS), in silico modeling, and measurement of hepcidin and erythroferrone (ERFE), in two brothers eventually diagnosed as X-linked sideroblastic anemia (XLSA). A novel pathogenic ALAS2 missense mutation (c.1382T>A, p.Leu461His) is described. Hyperferritinemia with high hepcidin-25 levels (but decreased hepcidin:ferritin ratio) and mild-to-moderate iron overload were detected in both patients. ERFE levels were markedly elevated in both patients, especially in the proband, who had a more expressed phenotype. Our study illustrates how new technologies, such as NGS, in silico modeling, and measurement of serum hepcidin-25 and ERFE, may help in diagnosing and studying iron loading anemias. Further studies on the hepcidin-25/ERFE axis in additional patients with XLSA and other iron loading anemias may help in establishing its usefulness in differential diagnosis, and it may also aid our understanding of the pathophysiology of these genetically and phenotypically heterogeneous entities.

Arthroscopic Superior Capsule Reconstruction With Doubled Autologous Semitendinosus Tendon Graft.

Massive and irreparable rotator cuff tears remain a difficult condition to treat. Fatty infiltration of the muscles and excessive retraction of the tendons predispose to high failure rates of arthroscopic repair techniques. In recent years, studies on the superior capsule have shown that it plays a key role in reducing superior humeral head translation and restoring balance to the force couples required for dynamic shoulder function. Superior capsule reconstruction has become common in clinical practice. Several techniques with different types of grafts have been described, such as fascia lata autograft, dermal allograft patch, and long head of the biceps tendon autograft. More recently, an open technique with semitendinosus tendon autograft has been proposed. Our aim is to describe an all-arthroscopic technique for superior capsule reconstruction using a doubled semitendinosus tendon autograft in a box-shaped configuration. We believe that the technique can combine the advantages of other techniques, such as graft availability, low harvest-site morbidity, limited cost, and mechanical strength.

Augmented Repair of Large to Massive Delaminated Rotator Cuff Tears With Autologous Long Head of the Biceps Tendon Graft: The Arthroscopic "Cuff-Plus" Technique.

An anatomic and tension-free repair is the goal of arthroscopic rotator cuff repair. However, this purpose is not always achievable in large and massive tears, and sometimes, even when intraoperative results seem acceptable, clinical and radiologic outcomes can be disappointing shortly afterward. Superior capsule reconstruction has been claimed as a valid and viable joint-preserving option for treating irreparable rotator cuff tears. However, the role of the superior capsule in repairable cuff tears has also been questioned. The aim of this article is to present the so-called arthroscopic cuff-plus technique. This technique consists of superior capsule reconstruction using the proximal part of the long head of the biceps tendon associated with a tension-free repair of the rotator cuff tendons in large to massive delaminated tears.

Cytomegalovirus-Induced Gastrointestinal Bleeding and Pancreatitis Complicating Severe Covid-19 Pneumonia: A Paradigmatic Case.

COVID-19 is a new pandemic disease whose pathophysiology and clinical description are still not completely defined. Besides respiratory symptoms and fever, gastrointestinal (GI) symptoms (including especially anorexia, diarrhea, and abdominal pain) represent the most frequent clinical manifestations. Emerging data point out that severe SARS-CoV-2 infection causes an immune dysregulation, which in turn may favor other infections. Here we describe a patient with severe COVID-19 pneumonia who developed in the resolving phase abdominal pain associated with cytomegalovirus (CMV)-induced duodenitis with bleeding and pancreatitis. A high level of suspicion toward multiple infections, including CMV, should be maintained in COVID-19 patients with heterogeneous clinical manifestations.

Cobalamin Deficiency in the Elderly.

Older people are at risk for cobalamin (vitamin B12) deficiency because of a number of common disorders (e.g., autoimmune gastritis) and drugs (e.g., antacids) that may alter its absorption and utilization. The prevalence of cobalamin deficiency increases with age, resulting, particularly elevated, in frail and institutionalized subjects. At variance with common sense, the diagnosis is far from simple. It requires a high degree of suspicion, due to heterogeneity and non-specificity of the signs and symptoms, ranging from macrocytosis (with or without anemia) to neuropsychiatric manifestations, that characterize several other aging-related disorders, like hematological malignancies, diabetes, hypothyroidism or vasculopathy. Furthermore, the detection of low levels of serum vitamin B12 appears poorly sensitive and specific. Other biomarkers, like serum homocysteine or methylmalonic acid, have improved the diagnostic possibilities but are expensive, not widely available, and may be influenced by some confounders (e.g., folate deficiency, or chronic renal failure). Early recognition and treatment are crucial since a proportion of patients develop severe complications, such as bone marrow failure and irreversible neurological impairment. High-dose oral treatment has proven to be as effective as the parenteral route, even in subjects with malabsorption, ensuring the complete resolution in the majority of cases. In this review, we trace the essential role of cobalamin in humans, the possible causes and impact of deficiency, the diagnostic challenges and the therapeutic options, between old and emerging concepts, with a particular focus on the elderly.

Practical implications of the 2019 Nobel Prize in Physiology or Medicine: from molecular adaptation to hypoxia to novel anti-anemic drugs in the clinic.

The 2019 Nobel Prize for Medicine or Physiology was assigned to three prestigious physician-scientists, Gregg L. Semenza, William G. Kaelin, and Peter J. Ratcliffe, who clarified the molecular mechanisms of hypoxia adaptation. This viewpoint traces their fundamental findings, which have paved the way for the development of innovative drugs for a wide range of common diseases, including cancer and anemia.