How Should we Use Multicolumn Spinal Cord Stimulation to Optimize Back Pain Spatial Neural Targeting? A Prospective, Multicenter, Randomized, Double-Blind, Controlled Trial (ESTIMET Study).

BACKGROUND: Recent studies have highlighted multicolumn spinal cord stimulation (SCS) efficacy, hypothesizing that optimized spatial neural targeting provided by new-generation SCS lead design or its multicolumn programming abilities could represent an opportunity to better address chronic back pain (BP). OBJECTIVE: To compare multicolumn vs. monocolumn programming on clinical outcomes of refractory postoperative chronic BP patients implanted with SCS using multicolumn surgical lead. MATERIALS AND METHODS: Twelve centers included 115 patients in a multicenter, randomized, double-blind, controlled trial. After randomization, leads were programmed using only one or several columns. The primary outcome was change in BP visual analogic scale (VAS) at six months. All patients were then programmed using the full potential of the lead up until 12-months follow-up. RESULTS: At six months, there was no significant difference in clinical outcomes whether the SCS was programmed using a mono or a multicolumn program. At 12 months, in all patients having been receiving multicolumn SCS for at least six months (n = 97), VAS decreases were significant for global pain (45.1%), leg pain (55.8%), and BP (41.5%) compared with baseline (p < 0.0001). CONCLUSION: The ESTIMET study confirms the significant benefit experienced on chronic BP by patients implanted with multicolumn SCS, independently from multicolumn lead programming. These good clinical outcomes might result from the specific architecture of the multicolumn lead, giving the opportunity to select initially the best column on a multicolumn grid and to optimize neural targeting with low-energy requirements. However, involving more columns than one does not appear necessary, once initial spatial targeting of the "sweet spot" has been achieved. Our findings suggest that this spatial concept could also be transposed to cylindrical leads, which have drastically improved their capability to shape the electrical field, and might be combined with temporal resolution using SCS new modalities.

Cx43 Present at the Leading Edge Membrane Governs Promigratory Effects of Osteoblast-Conditioned Medium on Human Prostate Cancer Cells in the Context of Bone Metastasis.

Among the different interacting molecules implicated in bone metastases, connexin43 (Cx43) may increase sensitivity of prostate cancer (PCa) cells to bone microenvironment, as suggested by our in silico and human tissue samples analyses that revealed increased level of Cx43 expression with PCa progression and a Cx43 specific expression in bone secondary sites. The goal of the present study was to understand how Cx43 influences PCa cells sensitivity and aggressiveness to bone microenvironment. By means of Cx43-overexpressing PCa cell lines, we revealed a Cx43-dependent promigratory effect of osteoblastic conditioned media (ObCM). This effect on directional migration relied on the presence of Cx43 at the plasma membrane and not on gap junctional intercellular communication and hemichannel functions. ObCM stimulation induced Rac1 activation and Cx43 interaction with cortactin in protrusions of migrating PCa cells. Finally, by transfecting two different truncated forms of Cx43 in LNCaP cells, we determined that the carboxy terminal (CT) part of Cx43 is crucial for the responsiveness of PCa cells to ObCM. Our study demonstrates that Cx43 level and its membrane localization modulate the phenotypic response of PCa cells to osteoblastic microenvironment and that its CT domain plays a pivotal role.

Adapting palliative radiation therapy for bone metastases during the Covid-19 pandemic: GEMO position paper.

The current health crisis caused by COVID-19 is a challenge for oncology treatment, especially when it comes to radiotherapy. Cancer patients are already known to be very fragile and COVID-19 brings about the risk of severe respiratory complications. In order to treat patients safely while protecting medical teams, the entire health care system must optimize the way it approaches prevention and treatment at a time when social distancing is key to stemming this pandemic. All indications and treatment modalities must be re-discussed. This is particularly the case for radiotherapy of bone metastases for which it is possible to reduce the number of sessions, the frequency of transport and the complexity of treatments. These changes will have to be discussed according to the organization of each radiotherapy department and the health situation, while medical teams must remain vigilant about the risks of complications of bone metastases, particularly spinal metastases. In this short piece, the members of the GEMO (the European Study Group of Bone Metastases) offer a number of recommendations to achieve the above objectives, both in general and in relation to five of the most common situations on radiation therapy for bone metastases.

French recommendations on strategies for preventing and treating osteoporosis induced by adjuvant breast cancer therapies.

Standard adjuvant therapies for breast cancer such as chemotherapy or aromatase inhibitor and LH-RH agonist hormone therapy are associated with significant survival gains but also induce bone loss by aggravating the estrogen deprivation. The bone loss may be substantial, notably during early treatment, and occurs regardless of the baseline bone mineral density values. The objective of developing these recommendations was to achieve a practical consensus among various scientific societies, based on literature review, about osteoporosis prevention and treatment in these patients. The following scientific societies contributed to the work: Société Française de Rhumatologie (SFR), Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO), Groupe Européen d'Etudes des Métastases Osseuses (GEMO), Association Francophone pour les Soins Oncologiques de Support (AFSOS), Société Française de Sénologie et de Pathologie Mammaire (SFSPM), Société Française de Radiothérapie Oncologique (SFRO). Drug prescription and reimbursement modalities in France were taken into account. These recommendations apply to postmenopausal women taking systemic chemotherapy and/or aromatase inhibitor therapy, non-postmenopausal women taking LH-RH agonist therapy, and non-postmenopausal women with persistent amenorrhea 1 year after chemotherapy completion. All women in these three categories should undergo an evaluation of bone health and receive interventions to combat risk factors for bone loss. Patients with a history of severe osteoporotic fracture and/or a T-score value <-2.5 should receive osteoporosis drug therapy. The FRAX® score should be used to guide treatment decisions in patients whose T-score is between -1 and -2.5. General osteoporosis prevention measures should be applied in patients without criteria for osteoporosis drug therapy, who should undergo bone mineral density measurements 18-24 months later if the baseline T-score is<-1 and 3-5 years later if the baseline T-score is>-1. The anti-tumor effect of bisphosphonates and denosumab was not considered when establishing these recommendations.

French recommendations for osteoporosis prevention and treatment in patients with prostate cancer treated by androgen deprivation.

Androgen-deprivation therapy (ADT) in patients with prostate cancer can be achieved surgically or chemically, notably by prescribing LHRH analogs. Major bone loss occurs rapidly in both cases, due to the decrease in testosterone levels, and can increase the fracture risk. The objective of developing these recommendations was to achieve a practical consensus among various scientific societies, based on a literature review, about osteoporosis prevention and treatment in patients on ADT. The following scientific societies contributed to the work: Société française de rhumatologie (SFR), Groupe de recherche et d'information sur les ostéoporoses (GRIO), Groupe européen d'études des métastases osseuses (GEMO), Association francophone pour les soins de support (AFSOS), Association française d'urologie (AFU), Société française de radiothérapie oncologique (SFRO). Medication prescription and reimbursement modalities in France were taken into account. The recommendations state that a fracture-risk evaluation and interventions targeting risk factors for fractures should be provided to all patients on ADT. Those patients with a history of severe osteoporotic fracture and/or a T-score < -2.5 should receive osteoporosis therapy. Patients whose T-score is between -1.5 and -2.5 should be treated if they exhibit at least two other risk factors among the following: age ≥ 75 years, history of non-severe fracture after 50 years of age, body mass index < 19 kg/m2, at least three comorbidities (e.g., cardiovascular disease, depression, Parkinson's disease, and dementia), current glucocorticoid therapy, and repeated falls. When the decision is difficult, FRAX® score determination and an assessment by a bone disease specialist may be helpful. When osteoporosis therapy is not indicated, general measures should be applied, and bone mineral density measured again after 12-24 months. The anti-tumor effects of bisphosphonates and denosumab fall outside the scope of these recommendations.

High bone mass in adults.

A finding of high bone mineral density (BMD) from routine dual-energy X-ray absorptiometry (DXA) screening is not uncommon. No consensus exists about the definition of high BMD, and T-score and/or Z-score cutoffs of ≥+2.5 or ≥+4 have been suggested. The many disorders that can result in high BMD are usually classified based on whether the BMD changes are focal vs. generalized or acquired vs. constitutional. In over half the cases, careful interpretation of the DXA report and images identifies the cause as an artefact (e.g., degenerative spinal disease, vascular calcifications, or syndesmophytes) or focal lesion (e.g., sclerotic bone metastasis or Paget's disease). Generalized acquired high BMD may be secondary to a diverse range of disorders such as fluorosis, diffuse bone sclerosis related to renal osteodystrophy, hematological diseases, and hepatitis C. Identification of the cause may require additional investigations such as imaging studies, serum tryptase assay, or serological tests for the hepatitis C virus. Finally, high BMD is a feature of many genetic diseases, most notably osteopetrosis and the disorders caused by mutations in the sclerostin gene SOST (sclerosing bone dysplasia and van Buchem disease) or in the LRP5 gene encoding the low-density lipoprotein receptor-related protein 5 (which is the Wnt co-receptor).

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

Connexins, important players in the dissemination of prostate cancer cells.

Over the past 50years, increasing experimental evidences have established that connexins (Cxs) and gap junctional intercellular communication (GJIC) ensure an important role in both the onset and development of cancerous processes. In the present review, we focus on the impact of Cxs and GJIC during the development of prostate cancer (PCa), from the primary growth mainly localized in acinar glands and ducts to the distant metastasis mainly concentrated in bone. As observed in several other types of solid tumours, Cxs and especially Cx43 exhibit an ambivalent role with a tumour suppressor effect in the early stages and, conversely, a rather pro-tumoural profile for most of invasion and dissemination steps to secondary sites. We report here the current knowledge on the function of Cxs during PCa cells migration, cytoskeletal dynamics, proteinases activities and the cross talk with the surrounding stromal cells in the microenvironment of the tumour and the bones. In addition, we discuss the role of Cxs in the bone tropism even if the prostate model is rarely used to study the complete sequence of cancer dissemination compared to breast cancer or melanoma. Even if not yet fully understood, these recent findings on Cxs provide new insights into their molecular mechanisms associated with progression and bone targeted behaviour of PCa. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing.

Hypophosphatasia (HPP) is a rare inherited skeletal dysplasia due to loss of function mutations in the ALPL gene. The disease is subject to an extremely high clinical heterogeneity ranging from a perinatal lethal form to odontohypophosphatasia affecting only teeth. Up to now genetic diagnosis of HPP is performed by sequencing the ALPL gene by Sanger methodology. Osteogenesis imperfecta (OI) and campomelic dysplasia (CD) are the main differential diagnoses of severe HPP, so that in case of negative result for ALPL mutations, OI and CD genes had often to be analyzed, lengthening the time before diagnosis. We report here our 18-month experience in testing 46 patients for HPP and differential diagnosis by targeted NGS and show that this strategy is efficient and useful. We used an array including ALPL gene, genes of differential diagnosis COL1A1 and COL1A2 that represent 90% of OI cases, SOX9, responsible for CD, and 8 potentially modifier genes of HPP. Seventeen patients were found to carry a mutation in one of these genes. Among them, only 10 out of 15 cases referred for HPP carried a mutation in ALPL and 5 carried a mutation in COL1A1 or COL1A2. Interestingly, three of these patients were adults with fractures and/or low BMD. Our results indicate that HPP and OI may be easily misdiagnosed in the prenatal stage but also in adults with mild symptoms for these diseases.

[Biomarkers of bone remodelling]. / Marqueurs biochimiques du remodelage osseux.

Bone is a frequent site for metastases patients with advanced solid tumors. Metastatic bone disease alters bone homeostasis and biochemical markers of bone turnover are studied in patients with cancer. These markers include bone matrix synthesis and degradation products, or enzymes expressed by osteoblasts or osteoclasts. Thus, the use of these biochemical markers of bone metabolism is being evaluated in screening for development of bone metastases, in predicting risk of skeletal-related events and survival in patients with bone metastases, and in monitoring response to antiresorptive therapy. Bone markers have potential to provide information, but their routine use in the clinic cannot be recommended yet.

[Bone targeting agents: bisphosphonates]. / Agents ciblant le remodelage osseux : les bisphosphonates.

Malignant tumor osteolysis is a frequent complication in many cancers. It can cause skeletal-related events with alteration of quality of life and survival. Bisphosphonates play an important role in the management of this malignant osteolysis, via an inhibition of osteoclast-mediated bone resorption, and a potential direct antitumor activity. Their use constitutes an important therapeutic advance in patients with bone metastases so as to reduce or delay the appearance of these skeletal events. They are also useful for the treatment of hypercalcemia, which could arise in these patients. Their interest as adjuvant therapy before the onset of bone metastases is currently being evaluated.

The gap junction protein Cx43 is involved in the bone-targeted metastatic behaviour of human prostate cancer cells.

For decades, cancer was associated with gap-junction defects. However, more recently it appeared that the gap junction proteins (connexins) could be re-expressed and participate to cancer cell dissemination during the late stages of tumor progression. Since primary tumors of prostate cancer (PCa) are known to be connexin deficient, it was interesting to verify whether their bone-targeted metastatic behaviour could be influenced by the re-expression of the connexin type (connexin43) which is originally present in prostate tissue and highly expressed in bone where it participates to the differentiation of osteoblastic cells. Thus, we investigated the effect of the increased Cx43 expression, by retroviral infection, on the metastatic behaviour of two well-characterized cell lines (PC-3 and LNCaP) representing different stages of PCa progression. It appeared that Cx43 differently behaved in those cell lines and induced different phenotypes. In LNCaP, Cx43 was functional, localized at the plasma membrane and its high expression was correlated with a more aggressive phenotype both in vitro and in vivo. In particular, those Cx43-expressing LNCaP cells exhibited a high incidence of osteolytic metastases generated by bone xenografts in mice. Interestingly, LNCaP cells were also able to decrease the proliferation of cocultured osteoblastic cells. In contrast, the increased expression of Cx43 in PC-3 cells led to an unfunctional, cytoplasmic localization of the protein and was correlated with a reduction of proliferation, adhesion and invasion of the cells. In conclusion, the localization and the functionality of Cx43 may govern the ability of PCa cells to metastasize in bones.

New treatments for myeloma.

The management of multiple myeloma has benefited substantially from the introduction of three new drugs, namely, the proteasome inhibitor bortezomib and the immunomodulators thalidomide and lenalidomide. These drugs were initially shown to improve the outcome of advanced myeloma and were subsequently found to transform the treatment of patients with previously untreated myeloma. Melphalan and prednisone combined with thalidomide or bortezomib is the new treatment of reference for patients who are elderly or ineligible for intensification. The introduction of these new drugs into induction regimens, intensified conditioning regimens, and posttransplantation regimens may improve overall survival among young patients by increasing the rate and quality of the treatment responses. Although myeloma remains incurable, prolonged survival is now a reasonable objective.

Safety of infliximab used in combination with leflunomide or azathioprine in daily clinical practice.

OBJECTIVE: To investigate the safety of infliximab (INF) combination therapy with leflunomide (LEF) or azathioprine (AZA) in patients with rheumatoid arthritis (RA). METHOD: A standardized questionnaire on the use of INF in combination with LEF or AZA was mailed to hospital physicians and collected over a 2 month period. Adverse events (AE) and the reasons for withdrawal of combination therapy were analyzed. RESULTS: Data on 225 patients with RA were collected retrospectively. INF was used in combination with LEF in 171 patients and with AZA in 54. The duration of INF exposure was similar in both groups (mean 8.8 mo). AE were reported in 75 patients (33.3%), 60 LEF/INF (35%) and 15 AZA/INF combinations (27.8%) (p=nonsignificant). No unexpected AE were observed. The main AE were infections (6.2%), cytopenia (5.8%), hepatotoxicity (5.8%), reactions to infusion (5.3%), and skin reactions (4%). At the time the questionnaires were sent out, 161 patients were continuing combination therapies. The main reasons for drug withdrawal were AE (53 patients, 23.5%), inefficacy (10 patients, 4%), and one temporary discontinuation for surgery. CONCLUSION: Our study suggests that INF used in combination with LEF or AZA could be an alternative to methotrexate/INF combinations.