Impact of individualized treatment on recovery from fatigue and return to work in survivors of advanced-stage Hodgkin's lymphoma: results from the randomized international GHSG HD18 trial.

BACKGROUND: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W). PATIENTS AND METHODS: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables. RESULTS: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL. CONCLUSIONS: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL.

Active and passive microrheology with large tracers in hard colloids.

The dynamics of a tracer particle in a bath of quasi-hard colloidal spheres is studied by Langevin dynamics simulations and mode coupling theory (MCT); the tracer radius is varied from equal to up to seven times larger than the bath particles radius. In the simulations, two cases are considered: freely diffusing tracer (passive microrheology) and tracer pulled with a constant force (active microrheology). Both cases are connected by linear response theory for all tracer sizes. It links both the stationary and transient regimes of the pulled tracer (for low forces) with the equilibrium correlation functions; the velocity of the pulled tracer and its displacement are obtained from the velocity auto-correlation function and the mean squared displacement, respectively. The MCT calculations give insight into the physical mechanisms: At short times, the tracer rattles in its cage of neighbours, with the frequency increasing linearly with the tracer radius asymptotically. The long-time tracer diffusion coefficient from passive microrheology, which agrees with the inverse friction coefficient from the active case, arises from the transport of transverse momentum around the tracer. It can be described with the Brinkman equation for the transverse flow field obtained in extension of MCT, but cannot be recovered from the MCT kernel coupling to densities only. The dynamics of the bath particles is also studied; for the unforced tracer the dynamics is unaffected. When the tracer is pulled, the velocity field in the bath follows the prediction of the Brinkman model, but different from the case of a Newtonian fluid.

Advances in rectal cancer: Real-world evidence suggests limited gains in prognosis for elderly patients.

BACKGROUND: Rectal cancer treatment has improved considerably due to the introduction of total meso-rectal excision, radio-chemotherapy, and high-resolution imaging. The aim of this observational cohort study was to quantify the effectiveness of these advances using high-quality data from a representative cohort of patients. METHODS: 20 281 non-metastasized cases retrieved from the Munich Cancer Registry database were divided into three time periods corresponding to before (1988-1997), partial (1998-2007), and full implementation (2008-2019) of clinical advances. Early-onset (<50 yrs.), middle-aged, elderly patient subgroups (> 70 yrs.) were compared. The overall effectiveness of evidence-based guideline adherence was also examined. RESULTS: Median survival improved by 1.5 yrs. from the first to the last time period. Relative survival increased from 74.9% (5-yr 95%CI[73.3 - 76.6]) to 79.2% (95%CI[77.8 - 80.5]). The incidence of locoregional recurrences was reduced dramatically by more than half (5-yr 17.7% (95%CI[16.5 - 18.8]); 6.7% (95%CI[6.1 - 7.3])). Gains in 5-yr relative survival were limited to early-onset and middle-aged patients with no significant improvement seen in elderly patients (Female 68.6% [63.9 - 73.3] to 67.6% [64.0 - 71.2]; Male 71.7% [65.9 - 77.4] to 74.0% [70.8 - 77.2]). CONCLUSIONS: Real-world evidence suggests that recent treatment advances have lead to an increase in prognosis for rectal cancer patients. However, more effort should be made to improve the implementation of new developments in elderly patients. Especially considering, that these cases represent a growing majority of diagnosed patients.

D-lactate is a promising biomarker for the diagnosis of periprosthetic joint infection.

Introduction: Reliable biomarkers for the diagnosis of periprosthetic joint infection (PJI) are of paramount clinical value. To date, synovial fluid leukocyte count is the standard surrogate parameter indicating PJI. As D-lactate is almost solely produced by bacteria, it represents a promising molecule in the diagnostic workflow of PJI evaluation. Therefore, the purpose of this study was to assess the performance of synovial fluid D-lactate for diagnosing PJI of the hip and knee. Materials and Methods: These are preliminary results of a prospective multicenter study from one academic center. Seventy-two consecutive patients after total hip arthroplasty (THA) or total knee arthroplasty (TKA) were prospectively included. All patients received a joint aspiration in order to rule out or confirm PJI, which was diagnosed according to previously published institutional criteria. Synovial fluid D-lactate was determined spectrophotometrically at 450 nm. Receiver operating characteristic (ROC) analysis was performed to assess the diagnostic performance. Results: Eighteen patients (25%) were diagnosed with PJI and 54 patients (75%) were classified as aseptic. Synovial fluid D-lactate showed a sensitivity of 90.7% (95% CI: 79.7%-96.9%) and specificity of 83.3% (95% CI: 58.6%-96.4%) at a cut-off of 0.04 mmol/L. The median concentration of D-lactate was significantly higher in patients with PJI than in those with aseptic conditions (0.048 mmol/L, range, 0.026-0.076 mmol/L vs. 0.024 mmol/L, range, 0.003-0.058 mmol/L, p < 0.0001). The predominat microogranisms were staphylococci, followed by streptococci and gram-negative bacteria. Conclusion: D-lactate bears a strong potential to act as a valuable biomarker for diagnosing PJI of the hip and knee. In our study, a cutoff of 0.04 mmol/L showed a comparable sensitivity to synovial fluid leukocyte count. However, its specificity was higher compared to conventional diagnostic tools. The additional advantages of D-lactate testing are requirement of low synovial fluid volume, short turnaround time and low cost.

Therapy of chronic extensor mechanism deficiency after total knee arthroplasty using a monofilament polypropylene mesh.

Introduction: Lesions of the quadriceps or patellar tendon after total knee arthroplasty (TKA) are a rare but serious complication which, if left untreated, can lead to loss of function of the knee joint. While acute and subacute extensor mechanism disruptions may have several causes, chronic deficiencies are often related to multiple prior revision surgeries for joint infection or aseptic TKA failure. Up to date, biological allograft reconstruction showed unsatisfying results. The use of a monofilament polypropylene mesh is a promising approach for this pathological condition. The aim of the present study was to evaluate clinical, functional and patient reported outcomes of this procedure in patients with chronic extensor mechanism deficiency. Materials and Methods: Twenty-eight patients with chronic extensor mechanism deficiency (quadriceps tendon rupture n = 9, patellar tendon rupture n = 19) after TKA were included in this retrospective study. None of the patients were lost to follow-up. Surgical reconstruction was performed at one institution between 2014 and 2020 with a monofilament polypropylene mesh (Marlex Mesh, Bard, Murray Hill, USA). The mean age at the time of surgery was 69 years. Patients presented with a mean BMI of 33 kg/m2. The mean follow-up period was 23 months. Results: The 2-year survivorship free of mesh revision was 89% [95% confidence interval (CI): 75% to 100%]. Three patients (11%) had to undergo revision because of mechanical mesh failure and received another polypropylene mesh. No further revisions were performed thereafter. Flexion was 87° (range, 30-120°) on average. The majority of patients (75%, 21/28) had a full active extension. The mean active extension lag after surgery was 4 degrees (range, 0-30°). Discussion: We observed a substantial improvement of extensor mechanism function. The majority of patients had full extension and showed good clinical results. A failure rate of over 50% has been published for alternative procedures. Thus, the use of the described augmentation technique represents a reasonable treatment option for chronic extensor mechanism disruptions of the patellar tendon as well as the quadriceps tendon after total knee arthroplasty. However, there might be a potentially higher risk for infection persistence in periprosthetic joint infection cases due to the presence of a foreign material.

Prognostic and predictive value of CA 19-9 in locally advanced pancreatic cancer treated with multiagent induction chemotherapy: results from a prospective, multicenter phase II trial (NEOLAP-AIO-PAK-0113).

BACKGROUND: The prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs). PATIENTS AND METHODS: A total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate. RESULTS: From the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: -82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection. CONCLUSIONS: CA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery. CLINICAL TRIAL NUMBER: ClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results.

Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer.

BACKGROUND: Initial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches. METHODS: FIRE-8 ( NCT05007132 ) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1-5 and 8-12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled. DISCUSSION: To the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy. TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT) 2019-004223-20 . Registered October 22, 2019, ClinicalTrials.gov NCT05007132 . Registered on August 12, 2021.

[Singing Voice Handicap Index-12 : Development and validation of a German version]. / Der Singing Voice Handicap Index-12 : Entwicklung und Validierung einer deutschen Fassung.

BACKGROUND: The aim of this study was to develop a shortened German version of the Singing Voice Handicap Index (SVHI). The SVHI is a one-dimensional instrument for self-assessment of a voice disorder in singers. The questionnaire developed in the USA comprises 36 items and has been available in a validated German version since 2013. METHODS: Bicentric data from a total of 200 patients formed the basis for item analysis and selection. Using corrected item-total correlations, 12 items were selected for the abridged version. The internal consistency was calculated. The SVHI-12 was subsequently validated in 97 vocal patients and 105 vocally healthy singers (control group) using the test-retest procedure. RESULTS: The SVHI-12 achieved a good internal consistency (Cronbach's alpha = 0.93) and a good test-retest reliability (intra-class correlation r = 0.88 ; p < 0.001). The patients had significantly higher overall scores (18 ± 13 vs. 7 ± 6) compared to the healthy control group. The SVHI-12 overall score correlated significantly positively with the severity of the voice disorder as reported by the patient (r = 0.68; p < 0.001). As a threshold value above which a voice can be described as disturbed, a total score > 7 points was calculated using receiver operating curve analysis. As an indication of a voice disorder, a sensitivity of 81% and a specificity of 71% is thus achieved (Youden index 0.523, area under the curve 0.827, 95% confidence interval 0.769-0.885). CONCLUSION: The shortened SVHI has similarly good psychometric characteristics to the original SVHI. With the SVHI-12, a valid and effective instrument for the detection of singing voice disorders is available for German-speaking countries.

Direct Correlation Function of a Crystalline Solid.

Direct correlation functions (DCFs), linked to the second functional derivative of the free energy with respect to the one-particle density, play a fundamental role in a statistical mechanics description of matter. This holds, in particular, for the ordered phases: DCFs contain information about the local structure including defects and encode the thermodynamic properties of crystalline solids; they open a route to the elastic constants beyond low temperature expansions. Via a demanding numerical approach, we have explicitly calculated for the first time the DCF of a solid: based on the fundamental measure concept, we provide results for the DCF of a hard sphere crystal. We demonstrate that this function differs at coexistence significantly from its liquid counterpart-both in shape as well as in its order of magnitude-because it is dominated by vacancies. We provide evidence that the traditional use of liquid DCFs in functional Taylor expansions of the free energy is conceptually wrong and show that the emergent elastic constants are in good agreement with simulation-based results.

Metagenomic analysis of nepoviruses: diversity, evolution and identification of a genome region in members of subgroup A that appears to be important for host range.

Data mining and metagenomic analysis of 277 open reading frame sequences of bipartite RNA viruses of the genus Nepovirus, family Secoviridae, were performed, documenting how challenging it can be to unequivocally assign a virus to a particular species, especially those in subgroups A and C, based on some of the currently adopted taxonomic demarcation criteria. This work suggests a possible need for their amendment to accommodate pangenome information. In addition, we revealed a host-dependent structure of arabis mosaic virus (ArMV) populations at a cladistic level and confirmed a phylogeographic structure of grapevine fanleaf virus (GFLV) populations. We also identified new putative recombination events in members of subgroups A, B and C. The evolutionary specificity of some capsid regions of ArMV and GFLV that were described previously and biologically validated as determinants of nematode transmission was circumscribed in silico. Furthermore, a C-terminal segment of the RNA-dependent RNA polymerase of members of subgroup A was predicted to be a putative host range determinant based on statistically supported higher π (substitutions per site) values for GFLV and ArMV isolates infecting Vitis spp. compared with non-Vitis-infecting ArMV isolates. This study illustrates how sequence information obtained via high-throughput sequencing can increase our understanding of mechanisms that modulate virus diversity and evolution and create new opportunities for advancing studies on the biology of economically important plant viruses.

CD137 (4-1BB) stimulation leads to metabolic and functional reprogramming of human monocytes/macrophages enhancing their tumoricidal activity.

Immunotherapies have heralded a new era in the cancer treatment. In addition to checkpoint inhibitors, agonistic antibodies against co-stimulatory immune receptors hold the potential to invoke efficient antitumor immunity. Targeting CD137 has gained momentum based on its ability to drive NK- and T-cell-based responses. CD137-engaging mAbs have already entered clinical trials for different types of tumors showing promising results. Despite the efforts to translate CD137-mediated immunotherapy into clinical practice, little remains known regarding the role of CD137 in human monocytes/macrophages.We found CD137 being expressed on monocytes of healthy controls and at even higher levels in patients with multiple myeloma or CLL. CD137HI(GH) monocytes displayed a distinct phenotypic, transcriptomic, and metabolic profile. They possessed an increased phagocytic capacity enabling superior antibody-dependent phagocytosis (ADPC) of multiple myeloma and lymphoma cells that were treated with anti-CD38 or anti-CD20 mAbs. Triggering CD137 promoted both metabolic and tumoricidal activity in an extracellular signal-regulated kinase (ERK)-dependent fashion. In addition, we observed a phenotypic, transcriptomic, and functional skewing towards a M1-like phenotype.Overall, we introduce CD137 as a positive immune checkpoint on human monocytes/macrophages, which can have therapeutic implications especially in view of synergistic effects when combining CD137 agonists with tumor-targeting antibodies.

Economic Studies Reinforce Efforts to Safeguard Specialty Crops in the United States.

Pathogen-tested foundation plant stocks are the cornerstone of sustainable specialty crop production. They provide the propagative units that are used to produce clean planting materials, which are essential as the first-line management option of diseases caused by graft-transmissible pathogens such as viruses, viroids, bacteria, and phytoplasmas. In the United States, efforts to produce, maintain, and distribute pathogen-tested propagative material of specialty crops are spearheaded by centers of the National Clean Plant Network (NCPN). Agricultural economists collaborated with plant pathologists, extension educators, specialty crop growers, and regulators to investigate the impacts of select diseases caused by graft-transmissible pathogens and to estimate the return on investments in NCPN centers. Economic studies have proven valuable to the NCPN in (i) incentivizing the use of clean planting material derived from pathogen-tested foundation plant stocks; (ii) documenting benefits of clean plant centers, which can outweigh operating costs by 10:1 to 150:1; (iii) aiding the development of disease management solutions that are not only ecologically driven but also profit maximizing; and (iv) disseminating integrated disease management recommendations that resonate with growers. Together, economic studies have reinforced efforts to safeguard specialty crops in the United States through the production and use of clean planting material.

G-POEM in patients with gastroparesis - gambling for healing or bigger armamentarium ? A case series and review of the literature.

Approximately 30% of all affected patients suffering from gastroparesis do not respond to any available treatment modality. Gastric peroral endoscopic myotomiy (G-POEM, antropyloromyotomy) represents a new principle of therapy. In this single center study, G-POEM showed a high technical success rate with a very low procedural complication rate. However, the clinical response beyond a short-term post-interventional improvement did not succeed in a single patient. The heterogeneity of the clinical picture, which represents a spectrum of different pathophysiological, etiological and clinical characteristics, still requires a therapy tailored to the individual patient. G-POEM should be considered especially in patients with pylorus-dominant gastroparesis.

Plantar pressure distribution and wearing characteristics of three forefoot offloading shoes in healthy adult subjects.

Forefoot offloading shoes are used to reduce pressure on specific regions of the foot. Aim of the pressure reduction is to aid healing of the soft and bony tissues and prevent complications by treating foot disorders. A great variety of forefoot offloading shoes are available. In a first step to investigate the appropriate use of these footwear in orthopedic settings, we studied plantar pressure distribution and wearing characteristics of three forefoot offloading shoes namely the Mailand, OrthoWedge and Podalux in a healthy population. Twenty subjects walked in a randomized order wearing three forefoot offloading shoes and a reference shoe for six minutes. The Pedar system was used to measure the pressure in 7 regions. Peak pressure and pressure time integral were analyzed as measures of pressure distribution. Furthermore, wearing characteristics were addressed using a Numeric Rating Scale. Pressure distribution and wearing characteristics of the forefoot offloading shoes were compared to a reference shoe. The Mailand and OrthoWedge shoes significantly reduced peak pressure with more than 80% under the hallux and more than 45% under MTH1 (p<.001). The Podalux did not show significant peak pressure reduction under the forefoot compared to the reference shoe. Under the lesser toes, the MTH4-5 region and heel region the Podalux shoe showed even a significant increase in peak pressure (p=.001). Looking at wearing characteristics, the Podalux and reference shoe scored significantly better than the other two forefoot offloading shoes (p<.01). In this study the differences between different forefoot offloading shoes was assessed. The Mailand and OrthoWedge shoes gave the best pressure reduction in the forefoot but are less comfortable in use. The Podalux rocker shoe showed opposite results. Next step is a patient study to compare our results in a patient population.

Dynamics and friction of a large colloidal particle in a bath of hard spheres: Langevin dynamics simulations and hydrodynamic description.

The analysis of the dynamics of tracer particles in a complex bath can provide valuable information about the microscopic behavior of the bath. In this work, we study the dynamics of a forced tracer in a colloidal bath by means of Langevin dynamics simulations and a theory model within continuum mechanics. In the simulations, the bath is comprised of quasihard spheres with a volume fraction of 50% immersed in a featureless quiescent solvent, and the tracer is pulled with a constant small force (within the linear regime). The theoretical analysis is based on the Navier-Stokes equation, where a term proportional to the velocity arises from coarse-graining the friction of the colloidal particles with the solvent. As a result, the final equation is similar to the Brinkman model, although the interpretation is different. A length scale appears in the model, k_{0}^{-1}, where the transverse momentum transport crosses over to friction with the solvent. The effective friction coefficient experienced by the tracer grows with the tracer size faster than the prediction from Stokes's law. Additionally, the velocity profiles in the bath decay faster than in a Newtonian fluid. The comparison between simulations and theory points to a boundary condition of effective partial slip at the tracer surface. We also study the fluctuations in the tracer position, showing that it reaches diffusion at long times, with a subdiffusive regime at intermediate times. The diffusion coefficient, obtained from the long-time slope of the mean-squared displacement, fulfills the Stokes-Einstein relation with the friction coefficient calculated from the steady tracer velocity, confirming the validity of the linear response formalism.