Publications by authors named "Thomas Martin"

743 Publications

Evaluation of subcutaneous daratumumab injections in the ambulatory care setting.

J Oncol Pharm Pract 2021 Oct 14:10781552211046911. Epub 2021 Oct 14.

Department of Pharmaceutical Services, 43166San Francisco Medical Center, University of California, San Francisco, CA, USA.

Introduction: Subcutaneous daratumumab is non-inferior to intravenous daratumumab for the treatment of multiple myeloma and significantly reduced incidence of systemic reactions. However, manufacturer for subcutaneous daratumumab has not provided guidance regarding optimal methods for monitoring for hypersensitivity reactions following subcutaneous daratumumab administration.

Methods: A retrospective analysis was performed in two cohorts of patients who received at least two doses of subcutaneous daratumumab for the treatment of plasma cell disorders: patients with previous exposure to intravenous daratumumab (dara-exposed) and patients without history of intravenous daratumumab (dara-naïve). The primary outcome was incidence of systemic and injection-site reactions following first dose of subcutaneous daratumumab. Secondary analysis included time to systemic and injection-site reactions, grading of adverse reaction, and incidence of second systemic reaction.

Results: Thirty-one patients were dara-naïve and 49 patients were dara-exposed. Differences in incidence of systemic (dara-naïve: 9.7% vs dara-exposed: 6.1%, = 0.67) and injection-site reactions (dara-naïve: 12.9% vs dara-exposed: 14.3%, = 0.99) did not reach statistical significance. Difference in median time to systemic reaction (dara-naïve: 3 h vs dara-exposed: 12 h, = 0.18) was clinically important but did not reach statistical significance. Median time to injection-site reactions (dara-naïve: 6 h vs dara-exposed: 24 h,  = 0.03) was shorter in the dara-naïve cohort. No clinically meaningful difference was observed for incidence of second systemic reaction.

Conclusion: Most reactions were mild and did not require medical intervention. Following first subcutaneous daratumumab dose, monitoring for 3 h for dara-naïve patients and no monitoring time for dara-exposed patients for hypersensitivity reactions may be a safe and reasonable practice.
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http://dx.doi.org/10.1177/10781552211046911DOI Listing
October 2021

Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in relapsed multiple myeloma patients with renal impairment: IKEMA subgroup analysis.

Haematologica 2021 Oct 14. Epub 2021 Oct 14.

Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens.

Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The Phase 3 IKEMA study (NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) vs Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate.
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http://dx.doi.org/10.3324/haematol.2021.279229DOI Listing
October 2021

The Intraoperative Use of a Portable Cone-Beam Computed Tomography System for the Diagnosis of Intraperitoneal Bladder Perforation.

Case Rep Urol 2021 23;2021:2060572. Epub 2021 Sep 23.

Department of Urology, Yale University School of Medicine, New Haven, CT, USA.

Background: Intraoperative imaging for endourologic procedures is generally limited to single-plane fluoroscopic X-ray. The O-arm™ is a mobile cone-bean CT scanner that may have applications in urologic surgeries. . We present a case of an 85-year-old male with radiation cystitis and recurrent gross hematuria who was identified to have a bladder perforation on cystoscopy during emergent clot evacuation. Single-view fluoroscopic evaluation was inconclusive as to whether an intraperitoneal bladder perforation occurred. A portable cone-beam CT scan was used to acquire a 3-D CT cystogram, which demonstrated intraperitoneal contrast extravasation, confirming the diagnosis of an intraperitoneal bladder perforation.

Conclusion: We report the first use of a portable cone-beam CT scanner to perform an intraoperative CT cystogram to diagnose an intraperitoneal bladder perforation and guide surgical management.
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http://dx.doi.org/10.1155/2021/2060572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486555PMC
September 2021

Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans.

Biomedicines 2021 Sep 10;9(9). Epub 2021 Sep 10.

Laboratory of Immunogenetics, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.

Obesity, insulin resistance, and type 2 diabetes contribute to increased morbidity and mortality in humans. The mouse is an important mouse model that displays many key features of the human disease. Herein, we used the drug pioglitazone, a thiazolidinedione with insulin-sensitizing properties, to investigate blood glucose levels, indicators of islet β-cell health and maturity, and gene expression in adipose tissue. Oral administration of pioglitazone lowered blood glucose levels in mice with a corresponding increase in respiratory quotient, which indicates improved whole-body carbohydrate utilization. In addition, white adipose tissue from mice and from humans treated with pioglitazone showed increased expression of glycerol kinase. Both mice and humans given pioglitazone displayed increased expression of , a marker typically associated with brown adipose tissue. Moreover, pancreatic β-cells from mice treated with pioglitazone had greater expression of insulin and Nkx6.1 as well as reduced abundance of the de-differentiation marker Aldh1a3. Collectively, these findings indicate that four weeks of pioglitazone therapy improved overall metabolic health in mice. Our data are consistent with published reports of human subjects administered pioglitazone and with analysis of human adipose tissue taken from subjects treated with pioglitazone. In conclusion, the current study provides evidence that pioglitazone restores key markers of metabolic health and also showcases the utility of the mouse to understand mechanisms associated with human metabolic disease and interventions that provide therapeutic benefit.
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http://dx.doi.org/10.3390/biomedicines9091189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470788PMC
September 2021

Isatuximab, carfilzomib and dexamethasone (Isa-Kd) for the management of relapsed multiple myeloma.

Future Oncol 2021 Sep 23. Epub 2021 Sep 23.

Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA 94143, USA.

The treatment of relapsed multiple myeloma remains challenging. Based on interim data from the randomized Phase III IKEMA study demonstrating a progression-free survival benefit with a combination of isatuximab (Isa, a CD38-targeted monoclonal antibody) and carfilzomib/dexamethasone (Kd) versus Kd alone, Isa-Kd recently received regulatory approval in the USA and Europe for patients with multiple myeloma who have received at least one prior line of therapy (in the USA, up to three prior lines). In this review we discuss the rationale and clinical trial experience to date with Isa-Kd. Although final IKEMA results are pending, Isa-Kd has emerged as an effective and tolerable therapy for patients with relapsed multiple myeloma. Given the growing number of antibody-containing triplet regimens in this setting, potential niches and limitations for Isa-Kd are also discussed.
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http://dx.doi.org/10.2217/fon-2021-0778DOI Listing
September 2021

Hypophosphatasia: An Underappreciated Cause of Atraumatic Stress Fractures.

Am J Med 2021 Sep 17. Epub 2021 Sep 17.

Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Poland. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2021.08.018DOI Listing
September 2021

Infectious complications in relapsed refractory multiple myeloma patients after BCMA Car t-cell therapy.

Blood Adv 2021 Sep 20. Epub 2021 Sep 20.

University of California, San Francisco (UCSF), San Francisco, California, United States.

B-cell maturation antigen-targeted chimeric antigen receptor T cell therapy (BCMA CAR-T) is an effective treatment for relapsed refractory multiple myeloma (RRMM). However the pattern of infectious complications is not well-elucidated. We performed a single-center retrospective analysis of infection outcomes up to 1-year post BCMA CAR-T for MM from 2018-2020. Fifty-five MM patients were treated with BCMA CAR-T. Prior to lymphodepletion (LD), 35% of patients had severe hypogammaglobulinemia and 18% had severe lymphopenia. Most patients (68%) received bridging chemotherapy (BC) prior to LD. In the first month post CAR-T, 98% patients had grade 3-4 neutropenia. At 1-year post infusion, 76% patients had hypogammaglobulinemia. With a median follow-up of 6.0 months (95% CI: 4.7 to 7.4), there were a total of 47 infection events in 29 (53%) patients, 40% bacterial, 53% viral and 6% fungal. Most (92%) were mild-moderate and of the lower/upper respiratory tract system (68%). Half of infections (53%) occurred in the first 100 days post CAR-T infusion. Though no statistically significant risk factors for infection were identified, prior lines of therapy, use of BC, recent infections, and post CAR-T lymphopenia were identified as possible risk factors that need to be further explored. This is the largest study to date to assess the infectious complications post BCMA CAR-T. Despite multiple risk factors for severe immunosuppression in this cohort, relatively few life-threatening or severe infections occurred. Further larger studies are needed to better characterize the risk factors for and occurrence of infections post BCMA CAR-T.
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http://dx.doi.org/10.1182/bloodadvances.2020004079DOI Listing
September 2021

Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis.

Blood Cancer Discov 2021 Sep 16;2(5):434-449. Epub 2021 Jul 16.

Department of Medicine, University of California, San Francisco, CA 94158, USA.

Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single cell RNA sequencing using prospectively acquired patient specimens identified interferon response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well-tolerated with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.
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http://dx.doi.org/10.1158/2643-3230.bcd-21-0055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425277PMC
September 2021

Pharmacological inhibition of BAG3-HSP70 with the proposed cancer therapeutic JG-98 is toxic for cardiomyocytes.

J Cell Biochem 2021 Sep 6. Epub 2021 Sep 6.

Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, Illinois, USA.

The co-chaperone Bcl2-associated athanogene-3 (BAG3) maintains cellular protein quality control through the regulation of heat shock protein 70 (HSP70). Cancer cells manipulate BAG3-HSP70-regulated pathways for tumor initiation and proliferation, which has led to the development of promising small molecule therapies, such as JG-98, which inhibit the BAG3-HSP70 interaction and mitigate tumor growth. However, it is not known how these broad therapies impact cardiomyocytes, where the BAG3-HSP70 complex is a key regulator of protein turnover and contractility. Here, we show that JG-98 exposure is toxic in neonatal rat ventricular myocytes (NRVMs). Using immunofluorescence microscopy to assess cell death, we found that apoptosis increased in NRVMs treated with JG-98 doses as low as 10 nM. JG-98 treatment also reduced autophagy flux and altered expression of BAG3 and several binding partners involved in BAG3-dependent autophagy, including SYNPO2 and HSPB8. We next assessed protein half-life with disruption of the BAG3-HSP70 complex by treating with JG-98 in the presence of cycloheximide and found BAG3, HSPB5, and HSPB8 half-lives were reduced, indicating that complex formation with HSP70 is important for their stability. Next, we assessed sarcomere structure using super-resolution microscopy and found that disrupting the interaction with HSP70 leads to sarcomere structural disintegration. To determine whether the effects of JG-98 could be mitigated by pharmacological autophagy induction, we cotreated NRVMs with rapamycin, which partially reduced the extent of apoptosis and sarcomere disarray. Finally, we investigated whether the effects of JG-98 extended to skeletal myocytes using C2C12 myotubes and found again increased apoptosis and reduced autophagic flux. Together, our data suggest that nonspecific targeting of the BAG3-HSP70 complex to treat cancer may be detrimental for cardiac and skeletal myocytes.
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http://dx.doi.org/10.1002/jcb.30140DOI Listing
September 2021

Thanks to Song et al.

Trends Ecol Evol 2021 Nov 1;36(11):978. Epub 2021 Sep 1.

Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA.

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http://dx.doi.org/10.1016/j.tree.2021.08.001DOI Listing
November 2021

Case Report: Can Inhaled Adenosine Attenuate COVID-19?

Front Pharmacol 2021 9;12:676577. Epub 2021 Aug 9.

Department of Community Health and Family Medicine, University of Florida, College of Medicine, Gainesville, FL, United States.

This case report demonstrates a small repetition of the case series carried out in Italy wherein inhaled adenosine was administered to patients experiencing severe and worsening coronavirus disease-2019 (COVID-19). The two cases are important not only because they were the first of their type in the United States, but also because both patients were DNR/DNI and were therefore expected to die. Study repetition is vitally important in medicine. New work in pharmacology hypothesizes that adenosine-regulator proteins may play a role in the pathogenesis of COVID-19 infection. Furthermore, adenosine, by interacting with cell receptor sites, has pluripotent effects upon inflammatory cells, is anti-inflammatory, and is important in tissue hypoxia signaling. Inhaled adenosine is potentially safe; thousands have received it for asthmatic challenge testing. The effects of adenosine in these two cases were rapid, positive, and fit the pharmacologic hypotheses (as seen in prior work in this journal) and support its role as a therapeutic nucleoside.
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http://dx.doi.org/10.3389/fphar.2021.676577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381598PMC
August 2021

Application of pie-crusting technique to facilitate closure of open abdomen after decompressive laparotomy.

BMJ Case Rep 2021 Aug 17;14(8). Epub 2021 Aug 17.

Department of Surgery, Brown University Warren Alpert Medical School, Providence, Rhode Island, USA

We present the case of a 23-year-old man who developed abdominal compartment syndrome secondary to severe pancreatitis and required decompressive laparotomy and pancreatic necrosectomy. Despite application of a temporary abdominal closure system (ABThera Open Abdomen Negative Pressure Therapy), extensive retroperitoneal oedema and inflammation continued to contribute to loss of domain and prevented primary closure of the skin and fascia. The usual course of action would have involved reapplication of ABThera system until primary closure could be achieved or sufficient granulation tissue permitted split-thickness skin grafting. Though a safe option for abdominal closure, application of a skin graft would delay return to baseline functional status and require eventual graft excision with abdominal wall reconstruction for this active labourer. Thus, we achieved primary closure of the skin through the novel application of abdominal wall 'pie-crusting', or tension-releasing multiple skin incisions, technique.
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http://dx.doi.org/10.1136/bcr-2021-244219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375765PMC
August 2021

Making clinical decisions based on measurable residual disease improves the outcome in multiple myeloma.

J Hematol Oncol 2021 08 17;14(1):126. Epub 2021 Aug 17.

Department of Medicine, Division of Hematology-Oncology, University of California San Francisco, San Francisco, USA.

The assessment of measurable residual disease (MRD) in bone marrow has proven of prognostic relevance in patients with multiple myeloma (MM). Nevertheless, and unlike other hematologic malignancies, the use of MRD results to make clinical decisions in MM has been underexplored to date. In this retrospective study, we present the results from a multinational and multicenter series of 400 patients with MRD monitoring during front-line therapy with the aim of exploring how clinical decisions made based on those MRD results affected outcomes. As expected, achievement of MRD negativity at any point was associated with improved PFS versus persistent MRD positivity (median PFS 104 vs. 45 months, p < 0.0001). In addition, however, 67 out of 400 patients underwent a clinical decision (treatment discontinuation, intensification or initiation of a new therapy) based on MRD results. Those patients in whom a treatment change was made showed a prolonged PFS in comparison with those 333 patients in which MRD results were not acted upon (respectively, mPFS 104 vs. 62 months, p = 0.005). In patients who achieved MRD negativity during maintenance (n = 186) on at least one occasion, stopping therapy in 24 patients vs. continuing in 162 did not alter PFS (mPFS 120 months vs. 82 months, p = 0.1). Most importantly, however, in patients with a positive MRD during maintenance (n = 214), a clinical decision (either intensification or change of therapy) (n = 43) resulted in better PFS compared to patients in whom no adjustment was made (n = 171) (mPFS NA vs. 39 months, p = 0.02). Interestingly, there were no significant differences when MRD was assessed by flow cytometry or by next-generation sequencing. Herein, we find that MRD is useful in guiding clinical decisions during initial therapy and has a positive impact on PFS in MM patients. This potentially opens a new dimension for the use of MRD in MM, but this role still remains to be confirmed in prospective, randomized clinical trials.
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http://dx.doi.org/10.1186/s13045-021-01135-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369640PMC
August 2021

Advancing precision medicine for acute respiratory distress syndrome.

Lancet Respir Med 2021 Jul 23. Epub 2021 Jul 23.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, and Department of Anesthesia, University of California San Francisco, San Francisco, CA, USA.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.
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http://dx.doi.org/10.1016/S2213-2600(21)00157-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302189PMC
July 2021

Individualized genetic makeup that controls natural killer cell function influences the efficacy of isatuximab immunotherapy in patients with multiple myeloma.

J Immunother Cancer 2021 07;9(7)

Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California, USA

Background: Phase IIb clinical trial with isatuximab (Isa)-lenalidomide (Len)-dexamethasone (Dex) showed an improved progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM), but the efficacy varied by patient. Antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells plays a crucial role in arbitrating antitumor activities of therapeutic-antibodies. We tested if patient-specific genetic makeup known to set NK cell functional threshold influence response to Isa-Len-Dex therapy.

Methods: We characterized 57 patients with RRMM receiving Isa-Len-Dex for polymorphisms of killer-cell immunoglobulin-like receptors (KIR), human leukocyte antigen (HLA) class I, and FCGR3A loci. In vitro ADCC assay, coincubating primary NK cells expressing specific KIR repertoire with multiple myeloma cell lines (MM cells) expressing selected HLA class I ligands, was used to confirm the identified genetic correlatives of clinical response.

Results: Patients with KIR3DL2+ and its cognate-ligand HLA-A3/11+ had superior PFS than patients missing this combination (HR=0.43; p=0.02), while patients carrying KIR2DL1+ and HLA-C2C2+ compared with to patients missing this pair showed short PFS (HR=3.54; p=0.05). Patients with KIR3DL2+ and HLA-A3/11+ plus high-affinity FCGR3A-158V allele showed the most prolonged PFS (HR=0.35; p=0.007). Consistent with these clinical data, mechanistic experiments demonstrated that NK cells expressing KIR3DL2 trigger greater ADCC when MM cells express HLA-A3/11. Inversely, NK cells expressing KIR2DL1 do not kill if MM cells express the HLA-C2C2 ligand. NK cells expressing high-affinity FCGR3A-158VV-induced greater ADCC compared with those with low-affinity FCGR3A-158FF.

Conclusions: Our results suggest that KIR3DL2+ and HLA-A3/11+ with FCGR3A-158V markers lead to enhanced Isa-dependent NK-mediated cytolysis against MM cells and results in improved PFS in patients with RRMM treated by Isa-Len-Dex. Moreover, the presence of KIR2DL1+ and HLA-C2C2+ identifies patients who may have a lower response to Isa-Len-Dex therapy linked to a reduced NK-mediated ADCC. These biomarkers could potentially identify, via precision medicine, patients more likely to respond to Isa-Len-Dex immunotherapy.

Trial Registration Number: NCT01749969.
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http://dx.doi.org/10.1136/jitc-2021-002958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287616PMC
July 2021

Incidence and Progression of Hallux Valgus: a Prospective Cohort Study.

Arthritis Care Res (Hoboken) 2021 Jul 15. Epub 2021 Jul 15.

Haywood Academic Rheumatology Centre, Midlands Partnership NHS Foundation Trust, Haywood Hospital, Burslem Staffordshire, ST6 7AG, United Kingdom.

Objective: Hallux valgus is a common and disabling condition. The objective of this study was to identify factors associated with hallux valgus incidence and progression.

Methods: Participants were from a population-based prospective cohort study, the Clinical Assessment Study of the Foot. All adults aged ≥50 years registered with four general practices in North Staffordshire, UK were invited to take part in a postal survey at baseline and at 7-year follow-up which included health questionnaires and self-assessment of hallux valgus using line drawings.

Results: Complete baseline and follow-up data were available for 1,482 participants (739 women and 743 men, mean [standard deviation] age 62.9 [8.1] years), of whom 450 (30.4%) had hallux valgus in at least one foot at baseline. Incident hallux valgus was identified in 207 (20.1%) participants (349 [15.4%] feet) and was associated with baseline age, poorer physical health, foot pain and wearing shoes with a very narrow toe-box shape between the age of 20 and 29 years. Hallux valgus progression was identified in 497 (33.6%) participants (719 [24.3%] feet) but was not associated with any baseline factors.

Conclusion: Incident hallux valgus develops in one in five adults aged ≥50 years over a 7-year period and is related to age, poorer physical health, foot pain and previous use of constrictive footwear. Progression occurs in one in three adults. These findings suggest that changes in first metatarsophalangeal joint alignment may still occur beyond the age of 50 years.
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http://dx.doi.org/10.1002/acr.24754DOI Listing
July 2021

Influence of the Gingival Condition on the Performance of Different Gingival Displacement Methods-A Randomized Clinical Study.

J Clin Med 2021 Jun 22;10(13). Epub 2021 Jun 22.

Department of Prosthetic Dentistry, Center of Dentistry, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.

This randomized clinical study examined the influence of the gingival condition-healthy versus mild inflammation-on sulcus representation and possible gingival recession for two gingival displacement procedures prior to conventional impression making. The interventions double cord technique or a kaolin paste containing aluminum chloride were applied to 40 probands. The opposite quadrant served as intrapersonal reference (split-mouth design). Precision impressions were then made. Extraoral digitization of the plaster models resulting from the reference impression prior to gingival displacement, the intervention impression and control impressions were the basis for the computer-aided three-dimensional analysis. After six months, a mild artificial gingivitis was induced, and the contralateral quadrant (cross-over design) was examined for the intervention. The gingivitis deteriorated the sulcus representation for the double cord technique group but did not affect the paste technique group. The gingival condition had no influence on the marginal gingiva height changes. The minor extent of those changes, which were measured up to six months after intervention at the palatal study site, were not considered to be in the clinically relevant range for gingival recession. For healthy gingiva, the cord technique showed superior sulcus representation compared to the paste technique. This advantage was lost to a great extent under the conditions of mild gingivitis.
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http://dx.doi.org/10.3390/jcm10132747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268533PMC
June 2021

Impact of enhanced recovery pathway in 408 gallbladder cancer resections.

HPB (Oxford) 2021 Jun 7. Epub 2021 Jun 7.

Department of Anaesthesia, Critical Care and Pain, Tata Memorial Centre, Homi Bhabha National Institute, Dr Ernest Borges Marg, Parel, Mumbai 400012, India. Electronic address:

Background: Gallbladder cancer (GBC) is the sixth most common gastrointestinal malignancy with poor prognosis. Enhanced Recovery Pathway (ERP) is associated with improved outcomes following abdominal surgical procedures. Currently, there is no study evaluating ERP in patients undergoing GBC surgery. The objective was to assess compliance with ERP elements and evaluate its impact on postoperative outcomes.

Methods: Prospective study conducted from February 2014-2019, including elective GBC surgery. Team was educated prior to ERP implementation. Compliance with the protocol, functional gastrointestinal (GI) recovery, mobilisation, and postoperative outcomes were recorded. Impact of degree of compliance (more or less than 80%) with ERP and postoperative outcomes was evaluated.

Results: In 408 patients, compliance with ERP was 84.6% (53.8-100%). Compliance >80% with ERP elements was observed in 245 patients (60%). Patients with >80% compliance had lower rate of minor (18.8% vs. 27%, p = 0.050) and significantly less major (0.8% vs. 6.1%, p = 0.002) and postoperative stay (5.84 ± 4.86 vs. 7.55 ± 6.6 days, p < 0.001) and earlier functional GI recovery. Intraoperative blood loss more than 600 ml, lower compliance (<80%) with ERP and preoperative albumin independently predicted postoperative complications.

Conclusion: This study demonstrates safety and efficacy of enhanced recovery pathway in gallbladder cancer. Higher compliance with the pathway was associated with significantly improved postoperative outcomes following gallbladder cancer surgery.
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http://dx.doi.org/10.1016/j.hpb.2021.05.010DOI Listing
June 2021

Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study.

Lancet 2021 07 24;398(10297):314-324. Epub 2021 Jun 24.

Legend Biotech USA, Piscataway, NJ, USA.

Background: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.

Methods: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.

Findings: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.

Interpretation: A single cilta-cel infusion at the target dose of 0·75 × 10 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions.

Funding: Janssen Research & Development and Legend Biotech.
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http://dx.doi.org/10.1016/S0140-6736(21)00933-8DOI Listing
July 2021

Best-practice clinical management of flares in people with osteoarthritis: A scoping review of behavioral, lifestyle and adjunctive treatments.

Semin Arthritis Rheum 2021 08 5;51(4):749-760. Epub 2021 May 5.

Institute of Bone and Joint Research, Kolling Institute, The University of Sydney, Sydney, Australia; Department of Rheumatology, Royal North Shore Hospital, Sydney, Australia.

Introduction: Transient episodes of increased pain, stiffness or swelling are common in people with osteoarthritis (OA). Yet, evidence-based management strategies for lessening the impact of OA flares are rarely covered in clinical guidelines and have been identified as a gap by clinicians delivering OA care. We aimed to identify evidence on behavioral, lifestyle or other adjunctive flare management strategies that could be used by clinicians or consumers.

Materials And Methods: A literature search between 1990-2020 was performed in three databases using a scoping methodology. We included qualitative or quantitative studies, and reviews that examined OA flare management, or that reported OA flare outcomes at timepoints ≤2 weeks post-intervention. Outcomes included any physical or psychological OA outcome treatable with a therapeutic intervention.

Results: We included 9 studies, all of which examined the relationship between therapeutic exercise/ physical activity and OA flares. All studies reported pain outcomes at the knee. Two also included the hip. Only two studies examined specific management strategies for OA flares. Both favorably reported the benefits of undertaking an exercise program modified accordingly during an episode, but the quality of the evidence was low.

Discussion: This scoping review highlights the paucity of evidence available on non-pharmacological treatments of OA flare management that could influence clinical practice. At present, there is no robust evidence to support or reject any specific therapies for OA flare management in clinical practice. Future work is needed, particularly around outcomes beyond pain, trajectories of symptom improvement, and for joints other than the knee.
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http://dx.doi.org/10.1016/j.semarthrit.2021.04.017DOI Listing
August 2021

Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial.

Lancet 2021 Jun 4;397(10292):2361-2371. Epub 2021 Jun 4.

Department of Hematology, University of California San Francisco, San Francisco, CA, USA.

Background: Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma.

Methods: This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285.

Findings: Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients.

Interpretation: The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population.

Funding: Sanofi. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/S0140-6736(21)00592-4DOI Listing
June 2021

A Painful Beginning: Early Life Surgery Produces Long-Term Behavioral Disruption in the Rat.

Front Behav Neurosci 2021 5;15:630889. Epub 2021 May 5.

Pain Mechanisms Lab, Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, United States.

Early life surgery produces peripheral nociceptive activation, inflammation, and stress. Early life nociceptive input and inflammation have been shown to produce long-term processing changes that are not restricted to the dermatome of injury. Additionally stress has shown long-term effects on anxiety, depression, learning, and maladaptive behaviors including substance abuse disorder and we hypothesized that early life surgery would have long-term effects on theses complex behaviors in later life. In this study surgery in the rat hindpaw was performed to determine if there are long-term effects on anxiety, depression, audiovisual attention, and opioid reward behaviors. Male animals received paw incision surgery and anesthesia or anesthesia alone (sham) at postnatal day 6. At 10 weeks after surgery, open field center zone entries were decreased, a measure of anxiety ( = 20) ( = 0.03) (effect size, Cohen's = 0.80). No difference was found in the tail suspension test as a measure of depression. At 16-20 weeks, attentional performance in an operant task was similar between groups at baseline and decreased with audiovisual distraction in both groups ( < 0.001) (effect size, η = 0.25), but distraction revealed a persistent impairment in performance in the surgery group ( = 8) ( = 0.04) (effect size, η = 0.13). Opioid reward was measured using heroin self-administration at 16-24 weeks. Heroin intake increased over time in both groups during 24-h free access ( < 0.001), but was greater in the surgery group ( = 0.045), with a significant interaction between time and treatment ( < 0.001) (effect size, Cohen = 0.36). These results demonstrate long-term disruptions in complex behaviors from surgical incision under anesthesia. Future studies to explore sex differences in early life surgery and the attendant peripheral neuronal input, stress, and inflammation will be valuable to understand emerging learning deficits, anxiety, attentional dysfunction, and opioid reward and their mechanisms. This will be valuable to develop optimal approaches to mitigate the long-term effects of surgery in early life.
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http://dx.doi.org/10.3389/fnbeh.2021.630889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131510PMC
May 2021

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover.

Nat Commun 2021 05 19;12(1):2942. Epub 2021 May 19.

Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, IL, USA.

The association between reduced myofilament force-generating capacity (F) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired F arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with F. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced F and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/F, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued F and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.
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http://dx.doi.org/10.1038/s41467-021-23272-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134551PMC
May 2021

A derived dryolestid mammal indicates possible insular endemism in the Late Jurassic of Germany.

Naturwissenschaften 2021 May 16;108(3):23. Epub 2021 May 16.

Natural Sciences Collections, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.

The Langenberg Quarry near Bad Harzburg has yielded the first Jurassic stem therian mammal of Germany, recovered from Kimmeridgian (Late Jurassic) near shore deposits of a palaeo-island within the Lower Saxony Basin of the European archipelago. The new stem therian is represented by one lower and three upper molars. Hercynodon germanicus gen. et sp. nov. is attributed to the Dryolestidae, a group of pretribosphenic crown mammals that was common in western Laurasia from the Middle Jurassic to the Early Cretaceous. The new taxon is characterised by small size, a reduced cusp pattern in the upper molars lacking a metacone, and enhancement of the shearing crests paracrista and metacrista. Phylogenetic analysis identified Hercynodon gen. nov. as sister taxon of Crusafontia from the Lower Cretaceous (Barremian) of Spain. Both taxa belong to an endemic European clade of dryolestids, including also Achyrodon and Phascolestes from the earliest Cretaceous (Berriasian) of England. Despite its greater geological age, Hercynodon gen. nov. is the most derived representative of that clade, indicated by the complete reduction of the metacone. The discrepancy between derived morphology and geological age may be explained by an increased rate of character evolution in insular isolation. Other insular phenomena have earlier been observed in vertebrates from the Langenberg Quarry, such as dwarfism in the small sauropod Europasaurus, and possible gigantism in the morganucodontan mammaliaform Storchodon and the pinheirodontid multituberculate mammal Teutonodon which grew unusually large.
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http://dx.doi.org/10.1007/s00114-021-01719-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126546PMC
May 2021

BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease.

Am J Physiol Heart Circ Physiol 2021 06 14;320(6):H2339-H2350. Epub 2021 May 14.

Department of Cell and Molecular Physiology, Loyola University Stritch School of Medicine, Maywood, Illinois.

Mutations to the sarcomere-localized cochaperone protein Bcl2-associated athanogene 3 (BAG3) are associated with dilated cardiomyopathy (DCM) and display greater penetrance in male patients. Decreased protein expression of BAG3 is also associated with nongenetic heart failure; however, the factors regulating cardiac BAG3 expression are unknown. Using left ventricular (LV) tissue from nonfailing and DCM human samples, we found that whole LV BAG3 expression was not significantly impacted by DCM or sex; however, myofilament localized BAG3 was significantly decreased in males with DCM. Females with DCM displayed no changes in BAG3 compared with nonfailing. This sex difference appears to be estrogen independent, as estrogen treatment in ovariectomized female rats had no impact on BAG3 expression. BAG3 gene expression in noncardiac cells is primarily regulated by the heat shock transcription factor-1 (HSF-1). We show whole LV HSF-1 expression and nuclear localized/active HSF-1 each displayed a striking positive correlation with whole LV BAG3 expression. We further found that HSF-1 localizes to the sarcomere -disc in cardiomyocytes and that this myofilament-associated HSF-1 pool decreases in heart failure. The decrease of HSF-1 was more pronounced in male patients and tightly correlated with myofilament BAG3 expression. Together our findings indicate that cardiac BAG3 expression and myofilament localization are differentially impacted by sex and disease and are linked to HSF-1. Myofilament BAG3 expression decreases in male patients with nonischemic DCM but is preserved in female patients with DCM. BAG3 expression in the human heart is tightly linked to HSF-1 expression and nuclear translocation. HSF-1 localizes to the sarcomere Z-disc in the human heart. HSF-1 expression in the myofilament fraction decreases in male patients with DCM and positively correlates with myofilament BAG3.
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http://dx.doi.org/10.1152/ajpheart.00419.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289355PMC
June 2021

Partial nephrectomy in frail patients: Benefits of robot-assisted surgery.

Surg Oncol 2021 Sep 22;38:101588. Epub 2021 Apr 22.

Cancer Prognostics and Health Outcomes Unit, Division of Urology, University of Montreal Health Center, Montreal, Quebec, Canada.

Background: To compare the effect of robot-assisted (RAPN) vs. open (OPN) partial nephrectomy on short-term postoperative outcomes and total hospital charges in frail patients with non-metastatic renal cell carcinoma (RCC).

Methods: Within the National Inpatient Sample database we identified 2745 RCC patients treated with either RAPN or OPN between 2008 and 2015, who met the Johns Hopkins Adjusted Clinical Groups frailty-defining indicator criteria. We examined the rates of RAPN vs. OPN over time. Moreover, we compared the effect of RAPN vs. OPN on short-term postoperative outcomes and total hospital charges. Time trends and multivariable logistic, Poisson and linear regression models were applied.

Results: Overall, 1109 (40.4%) frail patients were treated with RAPN. Rates of RAPN increased over time, from 16.3% to 54.7% (p < 0.001). Frail RAPN patients exhibited lower rates (all p < 0.001) of overall complications (35.3 vs. 48.3%), major complications (12.4 vs. 20.4%), blood transfusions (8.0 vs. 13.5%), non-home-based discharge (9.6 vs. 15.2%), shorter length of stay (3 vs. 4 days), but higher total hospital charges ($50,060 vs. $45,699). Moreover, RAPN independently predicted (all p < 0.001) lower risk of overall complications (OR: 0.58), major complications (OR: 0.55), blood transfusions (OR: 0.60) and non-home-based discharge (OR: 0.51), as well as shorter LOS (RR: 0.77) but also higher total hospital charges (RR: +$7682), relative to OPN.

Conclusions: In frail patients, RAPN is associated with lower rates of short-term postoperative complications, blood transfusions and non-home-based discharge, as well as with shorter LOS than OPN. However, RAPN use also results in higher total hospital charges.
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http://dx.doi.org/10.1016/j.suronc.2021.101588DOI Listing
September 2021
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