Clodronate Reduces ATP-Containing Microvesicle Releasing Induced by Nociceptive Stimuli in Human Keratinocytes.

Clodronate (Clod), a first-generation bisphosphonate, acts as a natural analgesic inhibiting vesicular storage of the nociception mediator ATP by vesicular nucleotide transporter (VNUT). Epidermal keratinocytes participate in cutaneous nociception, accumulating ATP within vesicles, which are released following different stimulations. Under stress conditions, keratinocytes produce microvesicles (MVs) by shedding from plasma membrane evagination. MV secretion has been identified as a novel and universal mode of intercellular communication between cells. The aim of this project was to evaluate if two nociceptive stimuli, Capsaicin and Potassium Hydroxide (KOH), could stimulate MV shedding from human keratinocytes, if these MVs could contain ATP, and if Clod could inhibit this phenomenon. In our cellular model, the HaCaT keratinocyte monolayer, both Capsaicin and KOH stimulated MV release after 3 h incubation, and the released MVs contained ATP. Moreover, Clod (5 µM) was able to reduce Caps-induced MV release and abolish the one KOH induced, while the Dansylcadaverine, an endocytosis inhibitor of Clod uptake, partially failed to block the bisphosphonate activity. Based on these new data and given the role of the activation of ATP release by keratinocytes as a vehicle for nociception and pain, the "old" bisphosphonate Clodronate could provide the pharmacological basis to develop new local analgesic drugs.

Correction: Piola et al. 3D Bioprinting of Gelatin-Xanthan Gum Composite Hydrogels for Growth of Human Skin Cells. Int. J. Mol. Sci. 2022, 23, 539.

In the original publication [...].

Aesthetic Rehabilitation Medicine: Enhancing Wellbeing beyond Functional Recovery.

Although rehabilitation medicine emphasizes a holistic health approach, there is still a large gap of knowledge about potential interventions aimed at improving overall wellbeing through cosmetic interventions. Therefore, this narrative review investigates the role of different rehabilitative techniques in enhancing aesthetics, quality of life, and psychosocial wellbeing for patients with disabilities. The study follows the SANRA framework quality criteria for a narrative review. Literature searches across PubMed/Medline, Web of Science, and Scopus identified articles focusing on rehabilitation strategies within the aesthetic rehabilitation domain. The review identified evidence supporting injection procedures, such as Botulinum Toxin, Platelet-Rich Plasma, Hyaluronic Acid, Ozone, and Carboxytherapy, and assessing their applications in several disabling disorders. Additionally, physical therapies like Extracorporeal Shock Wave Therapy, Laser Therapy, Microcurrent Therapy, Tecar Therapy, and physical exercises were explored for their impact on cutaneous microcirculation, cellulite treatment, wound healing, and scar appearance improvement. Lastly, the manuscript underlines the role of manual therapy techniques in addressing both physical discomfort and aesthetic concerns, discussing their effectiveness in adipose tissue therapy, scar tissue mobilization, and regional fat thickness reduction. Taken together, this review emphasizes the role of a multidisciplinary approach, aiming to provide valuable insights into potential benefits for both functional and aesthetic outcomes.

Long-Term Impact of Deep Brain Stimulation in Parkinson's Disease: Does It Affect Rehabilitation Outcomes?

Background and Objectives: Although the growing literature is now focusing on the long-term effects of Deep Brain Stimulation (DBS) in Parkinson's disease (PD), there is still a large gap of knowledge about its long-term implications in rehabilitation. Therefore, this study aimed at investigating the effects of rehabilitation in PD patients years after DBS implantation. Materials and Methods: This retrospective case-control study analyzed records from Moriggia-Pelascini Hospital, Italy from September 2022 to January 2024. Data of PD patients (n = 47) with (DBS group, n = 22) and without (control group, n = 25) DBS were considered. All study participants underwent a daily rehabilitation program lasting four weeks, including warm-up, aerobic exercises, strength training, postural exercises, and proprioceptive activities. The outcomes assessed were the Unified Parkinson's Disease Rating Scale (UPDRS), Berg Balance Scale (BBS), Timed Up and Go (TUG), 6 Min Walk Test (6MWT), and Self-Assessment Parkinson Disease Scale (SPDDS). Results: DBS group showed significant improvements in terms of all outcome measures after the rehabilitation intervention (UPDRS III: -7.0 (-11.5 to -1.0); p = 0.001; UPDRS I II IV: -12.0 (-19.0 to -4.5); p = 0.001; BBS: 7.0 (3.8 to 10.3); p < 0.001; TUG (s): -2.8 (-5.7 to -1.1); p < 0.001; SPDDS: -8 (-13.0 to -4.0); p < 0.001; 6MWT (m): 81 (37.3 to 132.3); p < 0.001). No differences were reported in the between-group analysis (p: NS). Conclusions: This study emphasizes positive rehabilitation effects on PD patients irrespective of DBS status. Further research is essential to elucidate long-term effects of DBS on rehabilitation outcomes of PD patients.

Role of the Flexion Relaxation Phenomenon in the Analysis of Low Back Pain Risk in the Powerlifter: A Proof-of-Principle Study.

INTRODUCTION: Unlike the most common training approaches for bodybuilding, powerlifting programs are generally based on maximum and submaximal loads, putting enormous stresses on the lumbar spine. The flexion relaxation phenomenon evaluation is a clinical tool used for low back pain (LBP) assessment. This study aimed to evaluate the role of the flexion relaxation phenomenon in the analysis of LBP in the powerlifters. METHODS: Healthy professional powerlifters participated in the study. In fact, we divided the participants into a LBP-low-risk group and a LBP-high-risk group, based on a prior history of LBP. Outcome measures included flexion relaxation ratio (FRR) and trough surface electromyography collected during trunk maximum voluntary flexion; furthermore, during a bench press lifting, we measured the height of the arched back (ARCH), using a camera and the Kinovea video editing software, to consider a potential correlation with the risk of LBP. RESULTS: We included a group of 18 male (aged 24-39 y) powerlifters of 93 kg category. We measured a nonsignificant mean difference of ARCH between low-risk LBP group and high-risk LBP subjects. Curiously, maximum voluntary flexions were both above the threshold of 3.2 µV; therefore, with an absence of appropriate myoelectric silence, on the contrary, the FRR ratios were higher than 9.5, considering the presence of the phenomenon, exclusively for the low-risk group. The lumbar arched back measurement data did not report any association with the LBP risk, regarding the maximum voluntary flexion value, and even more than the FRR there is a relationship with the presence or the absence of LBP risk. CONCLUSIONS: FRR could be considered as a useful parameter for studying the risk of LBP in powerlifting. The FRR index not only refers to the possible myoelectric silence of the lumbar muscles in trunk maximum forward flexion but also takes into account the energy value delivered by the lumbar muscles during the flexion. Furthermore, we can indicate that the size of the powerlifter ARCH may not be a determining factor in the occurrence of LBP.

Technological advances and digital solutions to improve quality of life in older adults with chronic obstructive pulmonary disease: a systematic review.

BACKGROUND: Several technological advances and digital solutions have been proposed in the recent years to face the emerging need for tele-monitoring older adults with Chronic Obstructive Pulmonary Disease (COPD). However, several challenges have negatively influenced an evidence-based approach to improve Health-Related Quality of Life (HR-QoL) in these patients. AIM: To assess the effects of tele-monitoring devices on HR-QoL in older adults with COPD. METHODS: On November 11, 2022, PubMed, Scopus, Web of Science, and Cochrane were systematically searched for randomized controlled trials (RCTs) consistent with the following PICO model: older people with COPD as participants, tele-monitoring devices as intervention, any comparator, and HR-QoL as the primary outcome. Functional outcomes, sanitary costs, safety, and feasibility were considered secondary outcomes. The quality assessment was performed in accordance with the Jadad scale. RESULTS: A total of 1845 records were identified and screened for eligibility. As a result, 5 RCTs assessing 584 patients (423 males and 161 females) were included in the systematic review. Tele-monitoring devices were ASTRI telecare system, WeChat social media, Pedometer, SweetAge monitoring system, and CHROMED monitoring platform. No significant improvements in terms of HR-QoL were reported in the included studies. However, positive effects were shown in terms of the number of respiratory events and hospitalization in patients telemonitored by SweetAge system and CHROMED platform. DISCUSSION: Although a little evidence supports the role of tele-monitoring devices in improving HR-QoL in older patients, positive effects were reported in COPD exacerbation consequences and functional outcomes. CONCLUSION: Tele-monitoring solutions might be considered as sustainable strategies to implement HR-QoL in the long-term management of older patients with COPD.

Efficacy of Proprioceptive Training on Plantar Pressure and Jump Performance in Volleyball Players: A Proof-of-Principle Study.

Volleyball players are often subject to micro-traumatisms of the heel fat pad and ankle injuries. Recently, mat-based proprioceptive training has assumed a key role in recovery from these disorders. Therefore, this proof-of-principle study aimed to assess the efficacy of proprioceptive mat training on plantar pressures and athletic performance in volleyball players. The participants included adult semi-professional volleyball players allocated into two groups: an experimental group, with mat-based proprioceptive and balance training, and a control group, with a sham protocol. For the outcome, we evaluated the barefoot plantar pressure, performing an analysis on a baropodometric resistive platform. The countermovement jump and squat jump were measured using an inertial measurement unit. Nineteen subjects were included in the two groups: the active proprioceptive group (n = 10) or the control group (n = 9). The results show a more uniform redistribution of loads with pressure hindfoot relief in the experimental group compared to the control group (p = 0.021, RBC = 0.67). Moreover, we observed a significant increase in peak landing force and high concentric power development in the experimental group compared to the controls. Focused proprioceptive management provided hindfoot load attenuation by stimulating higher peaks of concentric force in the experimental group compared to the sham group. Even though the study included a small sample, the results obtained in this proof-of-principle study suggest a positive role of proprioceptive stimulation in the inter-seasonal scenario for volleyball players to improve their jump performance and reduce the micro-traumatisms of the heel fat pad and the ankle injury rate. However, further studies performed on larger samples are needed to confirm these preliminary results.

Novel Approach to the Treatment of Neuropathic Pain Using a Combination with Palmitoylethanolamide and Equisetum arvense L. in an In Vitro Study.

Neuropathic pain is a typical patient disorder resulting from damage and dysfunction of the peripheral neuraxis. Injury to peripheral nerves in the upper extremities can result in a lifelong reduction in quality of life and a devastating loss of sensory and motor function. Since some standard pharmaceutical therapies can cause dependence or intolerance, nonpharmacological treatments have gained great interest in recent years. In this context, the beneficial effects of a new combination of palmitoylethanolamide and Equisetum arvense L. are evaluated in the present study. The bioavailability of the combination was initially analyzed in a 3D intestinal barrier simulating oral intake to analyze its absorption/biodistribution and exclude cytotoxicity. In a further step, a 3D nerve tissue model was performed to study the biological effects of the combination during the key mechanisms leading to peripheral neuropathy. Our results demonstrate that the combination successfully crossed the intestinal barrier and reached the target site, modulating the nerve recovery mechanism after Schwann cell injury and offering the initial response of relieving pain. This work supported the efficacy of palmitoylethanolamide and Equisetum arvense L. in reducing neuropathy and modifying the major pain mechanisms, outlining a possible alternative nutraceutical approach.

Impact of Physical Rehabilitation on Bone Biomarkers in Non-Metastatic Breast Cancer Women: A Systematic Review and Meta-Analysis.

Rehabilitation might improve bone health in breast cancer (BC) patients, but the effects on bone biomarkers are still debated. Thus, this meta-analysis of randomized controlled trials (RCTs) aims at characterizing the impact of rehabilitation on bone health biomarkers in BC survivors. On 2 May 2022, PubMed, Scopus, Web of Science, Cochrane, and PEDro were systematically searched for RCTs assessing bone biomarker modifications induced by physical exercise in BC survivors. The quality assessment was performed with the Jadad scale and the Cochrane risk-of-bias tool for randomized trials (RoBv.2). Trial registration number: CRD42022329766. Ten studies were included for a total of 873 patients. The meta-analysis showed overall significant mean difference percentage decrease in collagen type 1 cross-linked N-telopeptide (NTX) serum level [ES: -11.65 (-21.13, -2.17), p = 0.02)] and an increase in bone-specific alkaline phosphatase (BSAP) levels [ES: +6.09 (1.56, 10.62). According to the Jadad scale, eight RCTs were considered high-quality studies. Four studies showed a low overall risk of bias, according to RoBv.2. The significant effects of rehabilitation on bone biomarkers suggested a possible implication for a precision medicine approach targeting bone remodeling. Future research might clarify the role of bone biomarkers monitoring in rehabilitation management of cancer treatment induced bone-loss.

Oral-Gut Microbiota, Periodontal Diseases, and Arthritis: Literature Overview on the Role of Probiotics.

Periodontal diseases are oral inflammatory diseases affecting the tissues supporting and surrounding the teeth and include gingivitis and periodontitis. Oral pathogens may lead to microbial products spreading into the systemic circulation and reaching distant organs, while periodontal diseases have been related to low-grade systemic inflammation. Gut and oral microbiota alterations might play a role in the pathogenesis of several autoimmune and inflammatory diseases including arthritis, considering the role of the gut-joint axis in the regulation of molecular pathways involved in the pathogenesis of these conditions. In this scenario, it is hypothesized that probiotics might contribute to the oral and intestinal micro-ecological balance and could reduce low-grade inflammation typical of periodontal diseases and arthritis. This literature overview aims to summarize state-of-the-art ideas about linkages among oral-gut microbiota, periodontal diseases, and arthritis, while investigating the role of probiotics as a potential therapeutic intervention for the management of both oral diseases and musculoskeletal disorders.

Multidisciplinary Rehabilitation after Hyaluronic Acid Injections for Elderly with Knee, Hip, Shoulder, and Temporomandibular Joint Osteoarthritis.

Osteoarthritis (OA) is a prevalent degenerative joint condition characterized by cartilage deterioration, joint inflammation, and functional limitations, particularly impacting the elderly population. Rehabilitation and hyaluronic acid (HA) injections are common therapeutic approaches routinely used in clinical practice, but their synergistic potential is far from being fully characterized. Thus, the aim of this narrative review was to elucidate the multilevel benefits and synergies of integrating these two approaches in multidisciplinary OA rehabilitation. This narrative review follows the scale for the assessment of narrative review articles (SANRA) criteria and involves a comprehensive literature search from July to August 2023. Two independent reviewers screened studies, including those involving human subjects with OA, rehabilitation strategies, and outcomes following HA injection, published in English. Results: HA injections might improve joint biomechanics, reducing friction, absorbing shocks, and potentially regulating inflammation. Rehabilitation plays a pivotal role in strengthening muscles, increasing the range of motion, and enhancing overall function. Optimizing rehabilitation following HA injection might provide additional benefits in joint health. OA management requires a multidisciplinary approach integrating HA injections, rehabilitation, and personalized care. Challenges in patient adherence and healthcare resources currently exist, but emerging technologies offer opportunities to enhance patient engagement and monitoring optimizing sustainability and outcomes of patients with knee, hip, shoulder, and temporomandibular joint OA.

Impact of exercise training on muscle mitochondria modifications in older adults: a systematic review of randomized controlled trials.

BACKGROUND: Previous evidence showed that cellular aging is a multifactorial process that is associated with decline in mitochondrial function. Physical exercise has been proposed as an effective and safe therapeutical intervention to improve the mitochondria network in the adult myocytes. AIMS: The aim of this systematic review of randomized controlled trials (RCTs) was to assess the exercise-induced muscle mitochondria modifications in older adults, underlining the differences related to different exercise modalities. METHODS: On November 28th, 2021, five databases (PubMed, Scopus, Web of Science, Cochrane, and PEDro) were systematically searched for RCTs to include articles with: healthy older people as participants; physical exercise (endurance training (ET), resistance training (RT), and combined training (CT)) as intervention; other different exercise modalities or physical inactivity as comparator; mitochondrial modifications (quality, density and dynamics, oxidative, and antioxidant capacity) as outcomes. The quality assessment was performed according to the PEDro scale; the bias risk was evaluated by Cochrane risk-of-bias assessment tool. RESULTS: Out of 2940 records, 6 studies were included (2 assessing ET, 2 RT, 1 CT, and 1 both ET and RT). Taken together, 164 elderly subjects were included in the present systematic review. Significant positive effects were reported in terms of mitochondrial quality, density, dynamics, oxidative and antioxidant capacity, even though with different degrees according to the exercise type. The quality assessment reported one good-quality study, whereas the other five studies had a fair quality. DISCUSSION: The overall low quality of the studies on this topic indicate that further research is needed. CONCLUSION: RT seems to be the most studied physical exercise modality improving mitochondrial density and dynamics, while ET have been related to mitochondrial antioxidant capacity improvements. However, these exercise-induced specific effects should be better explored in older people.

Impact of nutraceuticals and dietary supplements on mitochondria modifications in healthy aging: a systematic review of randomized controlled trials.

BACKGROUND: To date, the mitochondrial function has been related to several pathways involved in the cellular aging process. Dietary supplements might have reciprocal and multilevel interactions with mitochondria network; however, no systematic review assessed the role of different nutraceuticals in mitochondria modification of healthy older adults. AIM: To assess the effects of different dietary supplements on mitochondria modifications in older adults. METHODS: On February 22, 2022, PubMed, Scopus, Web of Science, and Cochrane were systematically searched from inception for randomized controlled trials (RCTs). According to PICO model, we considered healthy older adults as participants, nutraceutical treatment as intervention, any treatment as comparator, mitochondrial modifications as outcome. Jadad scale was used for the quality assessment. RESULTS: Altogether, 8489 records were identified and screened until 6 studies were included. A total of 201 healthy older adults were included in the systematic review (mean age ranged from 67.0 ± 1.0 years to 76.0 ± 5.6 years). The dietary supplements assessed were sodium nitrite, N-3 polyunsaturated fatty acids, hydrogen-rich water, nicotinamide riboside, urolithin A, and whey protein powder. Positive effects were reported in terms of mitochondrial oxidative and antioxidant capacity, volume, bioenergetic capacity, and mitochondrial transcriptome based on the nutritional supplements. The quality assessment underlined that all the studies included were of good quality. DISCUSSION: Although dietary supplements might provide positive effects on mitochondria modifications, few studies are currently available in this field. CONCLUSION: Further studies are needed to better elucidate the reciprocal and multilevel interactions between nutraceuticals, mitochondria, and environmental stressors in healthy older adults.

The prevention of falls in patients with Parkinson's disease with in-home monitoring using a wearable system: a pilot study protocol.

BACKGROUND: Parkinson's disease (PD) is a chronic, progressive neurodegenerative condition that gradually worsens motor function and leads to postural instability and, eventually, falls. Several factors may influence the frequency of future falls, such as slowness, freezing of gait, loss of balance, and mobility problems, cognitive impairments, and the number of previous falls. The TED bracelet is an advanced technological wearable device able to predict falls. AIMS: This principal aim is to investigate the feasibility of a full-scale research project that uses the TED bracelet to identify whether individuals with PD are at risk of falling. METHODS: This study will involve a pilot prospective observational study design; the subjects will include 26 patients suffering from mild PD and 26 others with no PD and no gait problems. Data will be collected from the TED bracelet and then compared to a paper-based fall diary. The enrolled participants will have a scheduled outpatient evaluation to collect both clinical and instrumental data as well as biological samples. DISCUSSION: This pilot study could then be implemented in a larger form to further evaluate the effectiveness of the TED device. Finally, it will help further develop gait monitoring systems for people with Parkinson's disease and other neurodegenerative diseases that can affect physical function and mobility, such as dementia and Alzheimer's. CONCLUSIONS: Preventing falls and their complications could lead to major advancements in the quality of home care for patients with PD, which would significantly impact the quality of life of both these patients and their caregivers.

3D Bioprinting of Gelatin-Xanthan Gum Composite Hydrogels for Growth of Human Skin Cells.

In recent years, bioprinting has attracted much attention as a potential tool for generating complex 3D biological constructs capable of mimicking the native tissue microenvironment and promoting physiologically relevant cell-cell and cell-matrix interactions. The aim of the present study was to develop a crosslinked 3D printable hydrogel based on biocompatible natural polymers, gelatin and xanthan gum at different percentages to be used both as a scaffold for cell growth and as a wound dressing. The CellInk Inkredible 3D printer was used for the 3D printing of hydrogels, and a glutaraldehyde solution was tested for the crosslinking process. We were able to obtain two kinds of printable hydrogels with different porosity, swelling and degradation time. Subsequently, the printed hydrogels were characterized from the point of view of biocompatibility. Our results showed that gelatin/xanthan-gum bioprinted hydrogels were biocompatible materials, as they allowed both human keratinocyte and fibroblast in vitro growth for 14 days. These two bioprintable hydrogels could be also used as a helpful dressing material.

Oxygen-Ozone Therapy for Reducing Pro-Inflammatory Cytokines Serum Levels in Musculoskeletal and Temporomandibular Disorders: A Comprehensive Review.

To date, the application of oxygen-ozone (O2O3) therapy has significantly increased in the common clinical practice in several pathological conditions. However, beyond the favorable clinical effects, the biochemical effects of O2O3 are still far from being understood. This comprehensive review aimed at investigating the state of the art about the effects of O2O3 therapy on pro-inflammatory cytokines serum levels as a modulator of oxidative stress in patients with musculoskeletal and temporomandibular disorders (TMD). The efficacy of O2O3 therapy could be related to the moderate oxidative stress modulation produced by the interaction of ozone with biological components. More in detail, O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune overactivation. In this context, most musculoskeletal and temporomandibular disorders (TMD) share these two pathophysiological processes. Despite the paucity of in vivo studies, this comprehensive review suggests that O2O3 therapy might reduce serum levels of interleukin 6 in patients with TMD, low back pain, knee osteoarthritis and rheumatic diseases with a concrete and measurable interaction with the inflammatory pathway. However, to date, further studies are needed to clarify the effects of this promising therapy on inflammatory mediators and their clinical implications.

Efficacy of kinesio taping on hand functioning in patients with mild carpal tunnel syndrome. A double-blind randomized controlled trial.

STUDY DESIGN: Double-blind randomized controlled trial. INTRODUCTION: Carpal tunnel syndrome (CTS) is a common mononeuropathy that causes pain and disability in the affected hand. Kinesio taping (KT) has been recently proposed as a promising conservative approach in CTS patients. PURPOSE OF THE STUDY: To investigate the effectiveness of KT compared to a sham taping on symptoms and hand function in patients affected by mild CTS. METHODS: Patients affected by mild CTS with symptoms for at least 8 weeks were enrolled and randomly allocated into two groups: KT group, according to the technique proposed by Kase plus specific exercises; control group, undergoing a sham taping plus specific exercise. All patients performed 2 sessions/week for 5 weeks of exercises of mobilization of fingers and carpal joint. At the baseline, after 5 weeks (T1), and after 6 months (T2), a physician unaware of patients' allocation assessed the Boston Carpal Tunnel Questionnaire (BCTQ) symptom (BCTQ-S) and functional (BCTQ-F) subscales. RESULTS: Forty-two patients (mean age:54.3 ± 15.0 y) were randomly allocated into KT (n = 21) and control group (n = 21). At T1, in both groups we found a significant improvement in hand function and symptoms, as showed by BCTQ-F (KT:4.2 ± 0.7 vs 3.0 ± 0.6, P < .001; sham: 2.2 ± 0.3 vs 1.7 ± 0.3, P = .012) and by BCTQ-S (KT: 2.2 ± 0.3 vs 1.7 ± 0.3, P < .001; sham: 2.3 ± 0.4 vs 1.9 ± 0.5, P = .007). At T2, only in the KT group there was a significant difference in both sub-items of primary outcome. There were significantly better results in the KT group at T1 and T2. DISCUSSION: The present study showed that KT compared to a sham taping might be more effective in reducing perceived symptoms in mild CTS patients, reporting a clinically significant difference. CONCLUSION: KT might be considered as an effective technique combined to rehabilitative treatment in terms of hand function and symptoms in patients affected by mild CTS.

Information Survey on the Use of Complementary and Alternative Medicine.

Background and Objectives: Complementary and alternative medicines (CAMs) are generally considered non-scientific and poor effective therapies. Nevertheless, CAMs are extensively used in common clinical practice in Western countries. We decided to promote a Delphi consensus to intercept the opinion of Italian physicians on CAM use in clinical practice. Materials and Methods: We run a Delphi-based consensus, interviewing anonymously 97 physicians. Of these, only 78 participate to the questionnaire. Results: Consensus about agreement and disagreement have been reached in several topics, including indication, as well as safety issues concerning CAMs. Conclusions: The use of CAMs in clinical practice still lacks evidence. Experts agree about the possibility to safely use CAMs in combination with conventional medicines to treat non-critical medical conditions.

Surgical Treatment and Rehabilitation Strategies for Upper and Lower Extremity Lymphedema: A Comprehensive Review.

Lymphedema is a chronic disabling condition affecting a growing number of patients worldwide. Although lymphedema is not life-threatening, several reports underlined detrimental consequences in terms of distress, pain, functional impairment, and infections with a relevant decrease in quality of life. Currently, there is no cure, and the therapeutic management of this condition aims at slowing down the disease progression and preventing secondary complications. Early diagnosis is paramount to enhance the effects of rehabilitation or surgical treatments. On the other hand, a multidisciplinary treatment should be truly integrated, the combination of microsurgical and reductive procedures should be considered a valid strategy to manage extremity lymphedema, and rehabilitation should be considered the cornerstone of the multidisciplinary treatment not only for patients not suitable for surgical interventions but also before and after surgical procedures. Therefore, a specialized management of Plastic Reconstructive Surgeons and Physical and Rehabilitative Medicine physicians should be mandatory to address patients' needs and optimize the treatment of this disabling and detrimental condition. Therefore, the aim of this review was to characterize the comprehensive management of lymphedema, providing a broad overview of the potential therapy available in the current literature to optimize the comprehensive management of lymphedema and minimize complications.

Mismatch repair-deficient hormone receptor-positive breast cancers: Biology and pathological characterization.

The clinical outcome of patients with a diagnosis of hormone receptor (HR)+ breast cancer has improved remarkably since the arrival of endocrine therapy. Yet, resistance to standard treatments is a major clinical challenge for breast cancer specialists and a life-threatening condition for the patients. In breast cancer, mismatch repair (MMR) status assessment has been demonstrated to be clinically relevant not only in terms of screening for inherited conditions such as Lynch syndrome, but also for prognostication, selection for immunotherapy, and early identification of therapy resistance. Peculiar traits characterize the MMR biology in HR+ breast cancers compared to other cancer types. In these tumors, MMR genetic alterations are relatively rare, occurring in ~3 % of cases. On the other hand, modifications at the protein level can be observed also in the absence of gene alterations and vice versa. In HR+ breast cancers, the prognostic role of MMR deficiency has been confirmed by several studies, but its predictive value remains a matter of controversy. The characterization of MMR status in these patients is troubled by the lack of tumor-specific guidelines and/or companion diagnostic tests. For this reason, precise identification of MMR-deficient breast cancers can be problematic. A deeper understanding of the MMR biology and clinical actionability in HR+ breast cancer may light the path to effective tumor-specific diagnostic tools. For a precise MMR status profiling, the specific strengths and limitations of the available technologies should be taken into consideration. This article aims at providing a comprehensive overview of the current state of knowledge of MMR alterations in HR+ breast cancer. The available armamentarium for MMR testing in these tumors is also examined along with possible strategies for a tailored pathological characterization.