Progression-free survival is a weakly predictive surrogate end-point for overall survival in follicular lymphoma: A systematic review and meta-analysis.

Although progression-free survival (PFS) is a commonly used surrogate end-point for clinical trials of follicular lymphoma (FL), no analyses have evaluated the strength of surrogacy for PFS with overall survival (OS). A systematic review was performed and 20 studies (total participants, 10 724) met final inclusion criteria. PFS was weakly associated with OS (correlation coefficient; 0.383, p < 0.001). The coefficient of determination was 0.15 (95% CI: 0.002-0.35) suggesting 15% of OS variance could be explained by changes in PFS. This challenges the role for PFS as a surrogate end-point for clinical trials and drug approvals.

Effect of bio-polyol molecular weight on the structure and properties of polyurethane-polyisocyanurate (PUR-PIR) foams.

The increasing interest in polyurethane materials has raised the question of the environmental impact of these materials. For this reason, the scientists aim to find an extremely difficult balance between new material technologies and sustainable development. This work attempts to validate the possibility of replacing petrochemical polyols with previously synthesized bio-polyols and their impact on the structure and properties of rigid polyurethane-polyisocyanurate (PUR-PIR). To date, biobased polyols were frequently used in the manufacturing of PU, but application of bio-polyols synthesized via solvothermal liquefaction using different chains of polyethylene glycol has not been comprehensively discussed. In this work, ten sets of rigid polyurethane foams were synthesized. The influence of bio-polyols addition on foam properties was investigated by mechanical testing, thermogravimetric analysis (TGA), and cone calorimetry. The structure was determined by scanning electron microscopy (SEM) and a gas pycnometer. The tests revealed a significant extension of foam growth time, which can be explained by possible steric hindrances and the presence of less reactive secondary hydroxyl groups. Moreover, an increase average size of pores and aspect ratio was noticed. This can be interpreted by the modification of the cell growth process by the introduction of a less reactive bio-polyol with different viscosity. The analysis of foams mechanical properties showed that the normalized compressive strength increased up to 40% due to incorporation of more cross-linked structures. The thermogravimetric analysis demonstrated that the addition of bio-based polyols increased temperature of 2% (T2%) and 5% (T5%) mass degradation. On the other hand, evaluation of flammability of manufactured foams showed increase of total heat release (HRR) and smoke release (TSR) what may be caused by reduction of char layer stability. These findings add substantially to our understanding of the incorporation of bio-polyols into industrial polyurethane systems and suggest the necessity of conducting further research on these materials.

Overlapping Surgery in Orthopaedics: A Review of Efficacy, Surgical Costs, Surgical Outcomes, and Patient Safety.

INTRODUCTION: Overlapping surgery (OS) refers to when an attending surgeon supervises two surgeries at the same time with noncritical portions of both surgeries occurring simultaneously. Limited literature reviewing OS exists in orthopaedics. Our goal is to provide insight into this practice across orthopaedic subspecialities to inform its future utilization. METHODS: A review of the literature was conducted after Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review guidelines. All articles (630 total) were independently reviewed by two authors with a third to resolve discrepancies. Inclusion criteria encompassed any journal publication that included data on a series of orthopaedic OS. Data points sought included the type of surgery, quantity of cases, case duration, overlap time, perioperative complications, and cost. RESULTS: Eleven articles met the inclusion criteria, encompassing a total of 34,494 overlapping surgeries. The studies varied regarding setting and subspecialties included. Six studies demonstrated increased surgical times for overlap cases. Two studies found that although OS increased cost per case, it improved the overall efficiency. Ten studies tracked short-term outcomes (<90 days) and reported no increase in complications with OS. Only one study examined long-term outcomes (1 year) and found a markedly increased risk for surgical complications with OS, with higher complication rates among nonelective compared with elective cases. DISCUSSION: Current literature suggests that OS may increase surgical time, but from the 11 articles reviewed, only one demonstrates an increase in perioperative complications across orthopaedic subspecialities. OS also seems to increase costs per case; however, this is offset by the ability to perform more cases in the same period, resulting in an overall increase in the net profit. These data are consistent with studies from other surgical specialties. CONCLUSION: Although OS seems to be both safe and effective, future investigations are needed to understand the impact it has on patients and healthcare systems.

Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial.

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody-drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8-69.0) and 45.9% (45/98; 95% CI: 35.8-56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5-not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2-18.7). Median overall survival was 23.3 months (95% CI: 14.8-NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018 .

Mites Living in the Nests of the White Stork and Black Stork in Microhabitats of the Forest Environment and Agrocenoses.

The White Stork (Ciconia ciconia) and the Black Stork (Ciconia nigra) are well-known model organisms for the study of bird migration, as well as the selectivity of nesting sites and the choice of living environment. The former breeds mainly in open areas, while the latter inhabits forest areas. The acarofauna, and in particular Oribatida, inhabiting the nests of these species, has not been thoroughly explored so far. Therefore, we analyzed the material collected from 70 White Stork nests and 34 Black Stork nests in Poland, between Poznan and Rawicz, and in Kampinos National Park. Our research has increased the faunal and ecological knowledge of the mite fauna inhabiting the nests of large migratory bird species. Oribatida constituted 5-12% of the total mites identified in the nests of White and Black Storks. Their average number was several times higher in the Black Stork nests (80.2 individuals in 500 cm3). Also, the species diversity of moss mites was greater in the Black Stork nests (47 species). In total, the nests of the two stork species were inhabited by 62 moss mite species, with only 22 recorded in both the White and the Black Storks' nests. The most numerous species included Ramusella clavipectinata, R. fasciata, Oppiella subpectinata, Acrogalumna longipluma, and Scheloribates laevigatus. In addition, we found that juvenile oribatid mites accounted for 0.6% of all the mites in the White Stork nests, with tritonymphs having the largest share, while juveniles in the Black Stork nests comprised 1.4%, of which larvae and protonymphs had the largest share. Our research shows that the nests of large migratory birds provide living space for many mite species. In addition, we noted the potential importance of White and Black Stork nests for mite dispersion and the evolution of interspecies interactions.

Advances in Immunotherapy for the Treatment of Cutaneous T-Cell Lymphoma.

Cutaneous T-Cell Lymphoma (CTCL) is a heterogenous disease that consists of distinct clinicopathologic entities and presentations requiring a unique and expert approach to management. The most common subtype is mycosis fungoides, in which local disease has an excellent prognosis and is often managed with topical therapy alone. More extensive cutaneous involvement as well as involvement of lymph nodes and the peripheral blood (Sezary syndrome) require systemic therapies. Recent years have brought an expansion of therapeutic options, specifically with immune-based approaches that were developed using the knowledge gained regarding the biology and molecular pathology of CTCL. Previous systemic therapies such as retinoids, histone deacetylase inhibitors, and chemotherapeutic agents come with significant toxicity and only short-term response. Newer agents such as mogamulizumab and brentuximab vedotin use a targeted immune-based approach leading to longer periods of response with less systemic toxicity. While still in its infancy, the use of immune checkpoint inhibitors such as nivolumab and pembrolizumab appears promising, and while their current clinical application is limited, early data suggest possible future areas for research of immune manipulation to treat CTCL. Herein, we review these novel immune-based treatment strategies, their superiority over prior systemic options, and the ongoing need for further research and clinical trial enrollment.

Tandem cranial and spinal cerebrospinal fluid leaks presenting with otogenic tension pneumocephalus: illustrative case.

BACKGROUND: Cranial and spinal cerebrospinal fluid (CSF) leaks are associated with opposite CSF fluid dynamics. The differing pathophysiology between spontaneous cranial and spinal CSF leaks are, therefore, mutually exclusive in theory. OBSERVATIONS: A 66-year-old female presented with tension pneumocephalus. The patient underwent computed tomography (CT) scanning, which demonstrated left-sided tension pneumocephalus, with an expanding volume of air directly above a bony defect of the tegmen tympani and mastoideum. The patient underwent a left middle fossa craniotomy for repair of the tegmen CSF leak. In the week after discharge, she developed a recurrence of positional headaches and underwent head CT. Further magnetic resonance imaging of the brain and thoracic spine showed bilateral subdural hematomas and multiple meningeal diverticula. LESSONS: Cranial CSF leaks are caused by intracranial hypertension and are not associated with subdural hematomas. Clinicians should maintain a high index of suspicion for intracranial hypotension due to spinal CSF leak whenever "otogenic" pneumocephalus is found. Close postoperative follow-up and clinical monitoring for symptoms of intracranial hypotension in any patients who undergo repair of a tegmen defect for otogenic pneumocephalus is recommended.

Mosunetuzumab in combination with CHOP in previously untreated DLBCL: safety and efficacy results from a phase 2 study.

Up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) are refractory to or relapse after first-line therapy, highlighting the need for better treatments. Mosunetuzumab is a CD20 × CD3 bispecific antibody that engages and redirects T cells to eliminate malignant B cells. In this phase 2, open-label study (NCT03677141), 40 patients (52.5% with international prognostic index ≥3) with previously untreated DLBCL initiated 6 cycles of IV mosunetuzumab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Mosunetuzumab was administered in cycle 1 as step-up doses to mitigate cytokine release syndrome [CRS], and a dose of 30 mg was given on day 1 of cycles 2-6. Efficacy end points included objective and complete response rates, as determined by the investigator, via positron emission tomography-computed tomography, using Lugano 2014 criteria (87.5% and 85.0%, respectively). At a median follow-up of 32.0 months, the estimated 2-year progression-free survival and event-free survival rates were 65.4% (95% confidence interval [CI], 49.5-81.4) and 60.4% (95% CI, 44.7-76.1), respectively. CRS occurred in 60.0% of patients; all events were grade 1 (45.0%) or grade 2 (15.0%) and occurred primarily in cycle 1. Mosunetuzumab-related grade ≥3 neurologic adverse events (AEs) potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 1 patient (2.5%). Grade 5 AEs were reported in 2 patients. Neutropenia occurred in 70.0% of patients, mostly during cycle 1 and was of short duration. These findings demonstrate promising activity and a manageable safety profile for mosunetuzumab-CHOP and warrant further investigation of mosunetuzumab in first-line combination regimens for DLBCL.

Campylobacter fetus seeding of a cavernous malformation resulting in brain abscess: case report and literature review.

Microbial seeding of a cerebral cavernous malformation is an extremely rare occurrence with only 3 cases reported in the literature thus far. Campylobacter fetus is an opportunistic pathogen that rarely causes neurological infection with only 3 cases of C. fetus cerebral abscesses and 38 cases of C. fetus meningitis reported in the literature. There have been no cases of cerebral cavernous malformation seeding by C. fetus reported to date. We report the first case of cerebral cavernous malformation seeding by C. fetus, a case occurring in a previously healthy 16-year-old female who presented with suspected left cerebellar cavernous malformation with subacute hemorrhage. She underwent a suboccipital craniectomy for the resection of the cavernous malformation with additional intraoperative findings suggestive of cerebral abscess. Following positive blood and CSF cultures and surgical pathology results, the patient was diagnosed with C. fetus meningoencephalitis with co-infected left cerebellar cavernous malformation. This is the fourth reported case of microbial seeding of a cerebral cavernous malformation, and to our knowledge, the first case of a C. fetus-infected cavernous malformation. Compared to previous reports, the clinical events of this case strongly support the presence of a preexisting lesion that was secondarily seeded versus de novo formation as a result of prior infection.

Immunochemotherapy or chemotherapy alone in primary central nervous system lymphoma: a National Cancer Database analysis.

Debate remains over the role of rituximab, a large molecule with reduced central nervous system (CNS) penetration, in therapy for primary CNS lymphoma (PCNSL). Since 2013, the National Cancer Database has distinguished between chemotherapy and immunotherapy for frontline treatment. In this setting, rituximab would be the only standard frontline immunotherapy. We examined factors associated with the receipt of immunotherapy using a multivariate regression model for relative risk, with a random intercept to account for the hospital-specific treatment selection process. Patients were matched using a 1:1 propensity score to limit possible confounders, and overall survival (OS) was compared in the matched cohort. We identified 4691 patients with PCNSL diagnosed between 2013 and 2018. The use of immunotherapy has increased from 45% in 2013 to 76% in 2018. Immunotherapy use was associated with sociodemographic variables and local (hospital level) preference rather than clinical factors. The main factors associated with reduced use of immunotherapy included male sex, Black race or Hispanic ethnicity (compared with White non-Hispanic), HIV+ status, treatment in a lower-volume hospital, and earlier year of diagnosis. We matched 2830 patients for the survival analysis. Receipt of immunotherapy was associated with a significantly better OS (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.67-0.83). There was heterogeneity according to age, because the advantage of immunotherapy was more pronounced for patients aged ≤75 years (HR, 0.71; 95% CI, 0.63-0.80) than for those older than 75 years (HR, 0.87; 95% CI, 0.70-1.08). Overall, our findings support the current trend toward rituximab use, although a nuanced approach should be adopted when treating older patients.

Impact of detectable monoclonal protein at diagnosis on outcomes in marginal zone lymphoma: a multicenter cohort study.

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein at diagnosis. After adjusting for factors associated with inferior PFS in univariate models, presence of M-protein remained significantly associated with inferior PFS (hazard ratio, 1.74; 95% confidence interval, 1.20-2.54; P = .004). We observed no significant difference in the PFS based on the type or quantity of M-protein at diagnosis. There were differential outcomes in PFS based on the first-line therapy in patients with M-protein at diagnosis, in that, those receiving immunochemotherapy had better outcomes compared with those receiving rituximab monotherapy. The cumulative incidence of relapse in stage 1 disease among the recipients of local therapy was higher in the presence of M-protein; however, this did not reach statistical significance. We found that M-protein at diagnosis was associated with a higher risk of histologic transformation. Because the PFS difference related to presence of M-protein was not observed in patients receiving bendamustine and rituximab, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further.

The prevalence of anthropogenic nest materials differs between two distinct populations of migratory birds in Europe.

A major impact of human development is the transformation of natural habitats into farming lands and the expansion of built-up areas. Also, plastic pollution is affecting wildlife on a global scale. Discarded plastic is ubiquitous and accessible for birds, which can incorporate them into the nest structure. Here, we describe the differences in type, prevalence, and the amount of anthropogenic nest materials between two populations of terrestrial, mainly farmland bird, the white stork Ciconia ciconia, on a broad geographical scale, from two migratory divides-eastern in Poland and western in Spain (in total 303 nests). In the two populations, we detected significant differences in the incorporation of anthropogenic nest material, as measured by the Human Footprint Index (HFI) and the Impervious Surface Areas (ISA). We found that ISA was positively related to anthropogenic nest material incorporation in the Spanish population, and HFI was positively related to anthropogenic nest material, in contrast to the Polish population, in which the relationships were not significant. Moreover, we showed that the prevalence of nests with anthropogenic nest material was two times higher in Spanish than in the Polish white stork population. This study demonstrates that the behavior of incorporation of the anthropogenic nest material differs between two distinct populations of a single bird species.

Real-world evidence of the safety and survival with CD19 CAR-T cell therapy for relapsed/refractory solid organ transplant-related PTLD.

The use of CD19 chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory solid organ transplantation (SOT)-related post-transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT-associated PTLD. Among 22 relapsed/refractory SOT-PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre-CAR-T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR-T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell-associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR-T. The two-year progression-free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post-CAR-T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR-T therapy in relapsed/refractory SOT-related PTLD appeared similar to pivotal CAR-T data, including approximately one-third of patients achieving sustained remission.

Impact of early relapse within 24 months after first-line systemic therapy (POD24) on outcomes in patients with marginal zone lymphoma: A US multisite study.

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Choice of anticoagulation in patients with low risk antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an acquired hypercoagulable state necessitating long-term anticoagulation for secondary thrombosis prevention. Anticoagulation guidelines are predominantly based on data in high risk, triple positive patients, and favor Vitamin K antagonists over other forms of anticoagulation. The efficacy of alternative anticoagulants for secondary thrombosis prevention in low risk, single and double positive APS remains uncertain. This study aimed to assess the incidence of recurrent thrombosis and major bleeding for patient with low risk APS on long-term anticoagulation. We performed a retrospective cohort study of patients who met revised criteria for thrombotic APS between January, 2001 and April, 2021 and received care through the Lifespan Health System. Primary outcomes included recurrent thrombosis and WHO Grades 3 and 4 major bleeding. A total of 190 patients were followed over a median duration of 3.1 years. At time of APS diagnosis, 89 patients were treated with warfarin and 59 patients with a direct oral anticoagulant (DOAC). There were similar rates of recurrent thrombosis in low risk patients on warfarin versus DOACs (adjusted IRR 6.91; 95% CI 0.90-53.40, p = 0.064). Major bleeding events only occurred in low risk patients on warfarin (n = 8, log-rank p = 0.13). In conclusion, despite the choice of anticoagulation, patients with low risk APS had similar rates of recurrent thrombosis suggesting DOACs may be a potential treatment option for this cohort. There was a non-significant increase in major bleeding rates in low risk patients on warfarin versus DOACs. Study limitations include a retrospective study design and small event numbers.