Treatment strategies and outcome in relapsed peripheral T-cell lymphoma: results from the Netherlands Cancer Registry.

Optimal treatment in patients with refractory or relapsed peripheral T-cell lymphomas (R/R T-NHL) is unknown. In this population-based study, outcome in R/R PTCL not otherwise specified (PTCL NOS), angioimmunoblastic T-cell lymphoma (AITL) and ALK+ and ALK- anaplastic large cell lymphoma (ALCL) was evaluated. Patients with PTCL NOS, AITL, ALK+ ALCL and ALK- ALCL (≥18 years) diagnosed in 2014-2019 were identified using the Netherlands Cancer Registry. Endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). The 2-year PFS of 821 patients was 57%. Among 311 patients with a relapse, 243 received second-line treatment: 44% salvage chemotherapy, 20% brentuximab vedotin (BV) and 36% other treatment. In third-line, BV was most commonly used (38%). ORR following second-line treatment was 47%. Two-year PFS and OS after relapse were 25% and 34%, respectively. Risk of second relapse was negatively affected by early relapse (<12 months post-diagnosis), while BV reduced this risk compared to salvage chemotherapy (HR 0.55; 0.35-0.87; p=0.01). Reduced risk of relapse was independent of histological subtype. The best outcomes were observed for patients treated with salvage chemotherapy receiving consolidative autologous and allogeneic stem cell transplantation (SCT) (2-year OS 68%), patients treated with BV achieving a second complete remission (2-year OS 74%) and patients with allogeneic SCT (2-year OS 60%). The risk of second relapse was significantly lower for R/R T-NHL patients treated with BV compared to patients treated with salvage chemotherapy, and this was irrespective of subtype. Therefore, the use of salvage chemotherapy for R/R T-NHL patients is challenged.

Subgrouping of facilitatory or inhibitory conditioned pain modulation responses in patients with chronic knee pain. Explorative analysis from a multicentre trial.

BACKGROUND: Facilitatory and inhibitory conditioned pain modulation (CPM) responses are observed in healthy volunteers and chronic pain patients, but the clinical implications for phenotyping are unknown. This study aimed to subgroup and compare chronic knee pain patients according to their CPM responses. METHODS: This explorative, cross-sectional study included 127 patients with chronic knee pain (osteoarthritis or following total knee arthroplasty). Individual CPM responses were categorized as facilitatory (test stimuli pain intensity increased when conditioning stimuli were applied), as inhibitory (test stimuli pain intensity decreased) or as no change (defined as less than 5.3% change in pain intensity). Outcomes were clinical pain intensities, temporal summation, widespread pain, self-reported physical function, PainDETECT questionnaire and Pain Quality Assessment Scale. Data were analysed as comparisons between the inhibitory and the facilitatory groups and using multivariate linear regression models. RESULTS: Fifty-four patients had facilitatory CPM responses, 49 had inhibitory CPM responses, and 24 showed no change in CPM response. A between-group difference was observed for self-reported physical function, with the facilitatory CPM group reporting better function (54.4 vs. 46.0, p = 0.028) and the facilitatory CPM group reported more deep pain sensations (3.2 vs. 2.0, p = 0.021). The remaining outcomes showed no between-group differences. Higher clinical pain intensity and facilitated temporal summation were associated in the facilitated CPM group but not in the inhibitory CPM group. CONCLUSION: These explorative findings indicated that quantitative clinical and experimental differences exist between facilitatory or inhibitory CPM responses in a chronic knee pain patient population. Differences in patients' CPM responses should be further investigated to unravel possible clinical importance. SIGNIFICANCE: Our findings confirm that conditioned pain modulation consist of inhibitory and facilitatory responders among a patient population with chronic knee pain. This explorative study indicates that patients with either facilitatory or inhibitory conditioned pain modulation could exhibit differences in pain outcomes. Subgrouping of chronic pain patients depending on individual conditioned pain modulation responses could be considered in phenotyping patients prior to inclusion in clinical trials or used for personalizing the management regime.

Mesenchyme governs hair follicle induction.

Tissue interactions are essential for guiding organ development and regeneration. Hair follicle formation relies on inductive signalling between two tissues, the embryonic surface epithelium and the adjacent mesenchyme. Although previous research has highlighted the hair-inducing potential of the mesenchymal component of the hair follicle - the dermal papilla and its precursor, the dermal condensate - the source and nature of the primary inductive signal before dermal condensate formation have remained elusive. Here, we performed epithelial-mesenchymal tissue recombination experiments using hair-forming back skin and glabrous plantar skin from mouse embryos to unveil that the back skin mesenchyme is inductive even before dermal condensate formation. Moreover, the naïve, unpatterned mesenchyme was sufficient to trigger hair follicle formation even in the oral epithelium. Building on previous knowledge, we explored the hair-inductive ability of the Wnt agonist R-spondin 1 and a Bmp receptor inhibitor in embryonic skin explants. Although R-spondin 1 instigated precocious placode-specific transcriptional responses, it was insufficient for hair follicle induction, either alone or in combination with Bmp receptor inhibition. Our findings pave the way for identifying the hair follicle-inducing cue.

Patient outcomes before and after implementation of a selective pre-hospital spinal immobilization protocol: A comparative cohort pilot study in a level 2 trauma center.

BACKGROUND: A new selective preventive spinal immobilization (PSI) protocol was introduced in the Netherlands. This may have led to an increase in non-immobilized spinal fractures (NISFs) and consequently adverse patient outcomes. AIM: A pilot study was conducted to describe the adverse patient outcomes in NISF of the PSI protocol change and assess the feasibility of a larger effect study. METHODS: Retrospective comparative cohort pilot study including records of trauma patients with a presumed spinal injury who were presented at the emergency department of a level 2 trauma center by the emergency medical service (EMS). The pre-period 2013-2014 (strict PSI protocol), was compared to the post-period 2017-2018 (selective PSI protocol). Primary outcomes were the percentage of records with a NISF who had an adverse patient outcome such as neurological injuries and mortality before and after the protocol change. Secondary outcomes were the sample size calculation for a larger study and the feasibility of data collection. RESULTS: 1,147 records were included; 442 pre-period, and 705 post-period. The NISF-prevalence was 10% (95% CI 7-16, n = 19) and 8% (95% CI 6-11, n = 33), respectively. In both periods, no neurological injuries or mortality due to NISF were found, by which calculating a sample size is impossible. Data collection showed to be feasible. CONCLUSIONS: No neurological injuries or mortality due to NISF were found in a strict and a selective PSI protocol. Therefore, a larger study is discouraged. Future studies should focus on which patients really profit from PSI and which patients do not.

ATG versus PTCy in matched unrelated donor haematopoietic stem cell transplantations with non-myeloablative conditioning.

Graft-versus-host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are used as lymphocyte-depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non-myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II-IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3-year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non-relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy-based regimens resulted in a significantly lower rate of acute GvHD than ATG-containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies.

Connexin 43 and cell culture substrate differentially regulate OCY454 osteocytic differentiation and signaling to primary bone cells.

Connexin 43 (Cx43), the predominate gap junction protein in bone, is essential for intercellular communication and skeletal homeostasis. Previous work suggests that osteocyte-specific deletion of Cx43 leads to increased bone formation and resorption; however, the cell-autonomous role of osteocytic Cx43 in promoting increased bone remodeling is unknown. Recent studies using three-dimensional (3D) culture substrates in OCY454 cells suggest that 3D cultures may offer increased bone remodeling factor expression and secretion, such as sclerostin and receptor activator of nuclear factor-κB ligand (RANKL). In this study, we compared culturing OCY454 osteocytes on 3D Alvetex scaffolds with traditional 2D tissue culture, both with [wild-type (WT)] and without Cx43 (Cx43 KO). Conditioned media from OCY454 cell cultures were used to determine soluble signaling to differentiate primary bone marrow cells into osteoblasts and osteoclasts. OCY454 cells cultured on 3D portrayed a mature osteocytic phenotype, relative to cells on 2D, shown by increased osteocytic gene expression and reduced cell proliferation. In contrast, OCY454 differentiation based on these same markers was not affected by Cx43 deficiency in 3D. Interestingly, increased sclerostin secretion was found in 3D cultured WT cells compared with that of Cx43 KO cells. Conditioned media from Cx43 KO cells promoted increased osteoblastogenesis and osteoclastogenesis, with maximal effects from 3D cultured Cx43 KO cells. These results suggest that Cx43 deficiency promotes increased bone remodeling in a cell-autonomous manner with minimal changes in osteocyte differentiation. Finally, 3D cultures appear better suited to study mechanisms from Cx43-deficient OCY454 osteocytes in vitro due to their ability to promote osteocyte differentiation, limit proliferation, and increase bone remodeling factor secretion.NEW & NOTEWORTHY 3D cell culture of OCY454 cells promoted increased differentiation compared with traditional 2D culture. Although Cx43 deficiency did not affect OCY454 differentiation, it resulted in increased signaling, promoting osteoblastogenesis and osteoclastogenesis. Our results suggest that Cx43 deficiency promotes increased bone remodeling in a cell-autonomous manner with minimal changes in osteocyte differentiation. Also, 3D cultures appear better suited to study mechanisms in Cx43-deficient OCY454 osteocytes.

Connexin 43 and Cell Culture Substrate Differentially Regulate OCY454 Osteocytic Differentiation and Signaling to Primary Bone Cells.

Connexin 43 (Cx43), the predominate gap junction protein in bone, is essential for intercellular communication and skeletal homeostasis. Previous work suggests osteocyte-specific deletion of Cx43 leads to increased bone formation and resorption, however the cell-autonomous role of osteocytic Cx43 in promoting increased bone remodeling is unknown. Recent studies using 3D culture substrates in OCY454 cells suggest 3D cultures may offer increased bone remodeling factor expression and secretion, such as sclerostin and RANKL. In this study, we compared culturing OCY454 osteocytes on 3D Alvetex scaffolds to traditional 2D tissue culture, both with (WT) and without Cx43 (Cx43 KO). Conditioned media from OCY454 cell cultures was used to determine soluble signaling to differentiate primary bone marrow stromal cells into osteoblasts and osteoclasts. OCY454 cells cultured on 3D portrayed a mature osteocytic phenotype, relative to cells on 2D, shown by increased osteocytic gene expression and reduced cell proliferation. In contrast, OCY454 differentiation based on these same markers was not affected by Cx43 deficiency in 3D. Interestingly, increased sclerostin secretion was found in 3D cultured WT cells compared to Cx43 KO cells. Conditioned media from Cx43 KO cells promoted increased osteoblastogenesis and increased osteoclastogenesis, with maximal effects from 3D cultured Cx43 KO cells. These results suggest Cx43 deficiency promotes increased bone remodeling in a cell autonomous manner with minimal changes in osteocyte differentiation. Finally, 3D cultures appear better suited to study mechanisms from Cx43-deficient OCY454 osteocytes in vitro due to their ability to promote osteocyte differentiation, limit proliferation, and increase bone remodeling factor secretion. New and Noteworthy: 3D cell culture of OCY454 cells promoted increased differentiation compared to traditional 2D culture. While Cx43 deficiency did not affect OCY454 differentiation, it resulted in increased signaling, promoting osteoblastogenesis and osteoclastogenesis. Our results suggest Cx43 deficiency promotes increased bone remodeling in a cell autonomous manner with minimal changes in osteocyte differentiation. Also, 3D cultures appear better suited to study mechanisms in Cx43-deficient OCY454 osteocytes.

Genital Self-Image and Esthetic Genital Surgery.

Genital self-image describes the perception of one's genital appearance as being "normal" or "abnormal," and a disharmonious image leads to an increasing number of women seeking esthetic genital surgery each year. The concept of what constitutes "normal" is strongly influenced by the media, cultural norms, and sexual relations. In reality, the extent of normalcy is highly variable and overall patient education regarding extremes of size and shape should be provided to all patients considering surgery. When performed with appropriate training, expertise, and attention to detail in a properly selected patient, esthetic genital surgery is associated with minimal complications or sequelae.

Impact of radiotherapy schedule on survival of patients treated with immune-checkpoint inhibitors for advanced melanoma and non-small cell lung cancer.

PURPOSE: Preclinical and clinical data suggest a potential benefit in the addition of radiotherapy (RT) to immune-checkpoint inhibitors (ICI) during the treatment of advanced cancers. Nevertheless, the ideal patients for this approach and the optimal RT regimen is still debated. MATERIAL AND METHODS: The aim of this study was to determine the effect RT schedule has on survival for advanced non-small cell lung cancer and melanoma patients (pts) treated with ICI (anti-PD1 or anti-CTLA4) and concomitant RT. RESULTS: A total of 58 pts were identified, of which 26 received RT concomitantly with ICI while the remaining 32 pts were treated with RT at the time of progression under ICI. The RT parameters associated with outcome include dose per fraction, biological effective dose, RT to all targets and lung irradiation. Independent predictors of improved progression-free survival were lung irradiation, melanoma histology, oligometastatic status (<6 metastasis), presence of liver metastasis, PNN<7000/mm3 and normal LDH. Independent predictors of improved overall survival were melanoma histology and normal LDH. Among pts who were irradiated at progression, 68.7% had an overall clinical benefit and had a median extension of ICI use by 2.3 months (range: 0-29.1), among which 2 presented with an abscopal effect. CONCLUSIONS: The irradiation of lung metastases may increase survival in patients under ICI. RT at progression could prolong the use of ICI, and neutrophilia and LDH should be considered during patient selection of this combined RT/ICI approach.

Utility of a Test-to-Return Strategy to Identify Individuals With Coronavirus Disease 2019 (COVID-19) in the Prekindergarten Through Grade 12 School Setting-District of Columbia, January 2022.

The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant led to increased hospitalizations, staffing shortages, and increased school closures. To reduce spread in school-aged children during the Omicron peak, the District of Columbia implemented a test-to-return strategy in public and public charter schools after a 2-week break from in-person learning.

Back-translating GWAS findings to animal models reveals a role for Hgfac and Slc39a8 in alcohol and nicotine consumption.

Alcohol and tobacco are the most commonly used addictive substances, with high comorbidity rates between alcohol use disorder and tobacco use disorder. Risk for alcohol and nicotine addiction is highly heritable, and they share common genetic factors. A GWAS in over 1 million individuals has revealed 566 genetic variants in 406 loci associated with multiple stages of alcohol and tobacco use. Three novel genes-SLC39A8, GRK4 and HGFAC-within loci associated with altered alcoholic drinks per week (ADW) or cigarettes per day (CPD) were selected to further study their role in alcohol and tobacco use disorder. The role of these genes was assessed using the two-bottle choice addiction paradigm in transgenic mice for each of the genes. We found significant decreases in chronic alcohol consumption and preference in female Hgfac knockout (KO) mice, and decreased nicotine preference in male Hgfac KO compared with wild-type (WT) mice. Additionally, male Slc39a8 hypomorph mice showed greater overall nicotine preference compared with WT mice, while no differences were detected for Grk4 KO mice in alcohol or nicotine consumption and preference in either sex. Thus, this study implicates Hgfac and Slc39a8 in alcohol and tobacco use in a sex-specific manner.

Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study.

INTRODUCTION: ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) is a rare lung cancer with limited treatment options. Phase I-II studies with ROS1-tyrosine kinase inhibitors (TKIs) included small numbers of patients and real-world data are lacking. We investigate the efficacy and safety of lorlatinib, a third-generation TKI targeting ALK and ROS1, in patients with ROS1+ NSCLC treated through an expanded access program. METHODS: Consecutive patients with advanced ROS1+ NSCLC treated with lorlatinib between October 2015 and June 2019 were included. Data were collected from medical records. The primary endpoint was progression-free survival. RESULTS: Out of the 80 patients included, 47(59%) were female, 49(62%) never smokers (less than 100 cigarettes over the lifetime), and 68(85%) had stage IV NSCLC at diagnosis. Most frequent histology was adenocarcinoma (95%) and median age was 58.2 years. At the time of lorlatinib initiation, 51(64%) patients had brain metastases and 55(81%) were PS 0-1. Lorlatinib was administered as second/third/fourth/fifth+ line in 29%/28%/18%/26% of patients. All patients previously received at least one ROS1 TKI, and 55(69%) previously received chemotherapy. Median follow-up from lorlatinib initiation was 22.2 months. Median progression-free survival and overall survival from lorlatinib initiation were 7.1 months [95% confidence interval (CI) 5.0-9.9 months] and 19.6 months (95% CI 12.3-27.5 months). Median duration of treatment with lorlatinib was 7.4 months (95% CI 6.5-13.1 months). Overall response and disease control rates were 45% and 82%, respectively. The central nervous system response rate was 72%. Treatment was stopped due to toxicity in 10 patients (13%). The safety profile was consistent with previously published data. CONCLUSIONS: Lorlatinib is a major treatment option for advanced refractory ROS1+ NSCLC in treatment strategy.

Inhibition of focal adhesion turnover prevents osteoblastic differentiation through ß-catenin mediated transduction of pro-osteogenic substrate.

The mechanism by which substrate surface characteristics are transduced by osteoblastic cells and their progenitors is not fully known. Data from previous studies by our group suggest the involvement of ß-catenin in the mechanism by which substrate surface characteristics are transduced. This focal adhesion and ß-catenin mediated mechanism functions through the liberation of ß-catenin from focal adhesion complexes in response to pro-osteogenic substrate (POS) characteristics. After liberation, ß-catenin translocates and facilitates upregulation of genes associated with osteogenesis. It is not known whether the observed correlation between focal adhesion turnover and ß-catenin translocation directly results from focal adhesion turnover. In this study we inhibited focal adhesion turnover using a focal adhesion kinase inhibitor PF-573228. We found that inhibition of focal adhesion turnover resulted in an abrogation of the more rapid translocation and increased transcriptional activity of ß-catenin induced by POS. In addition, inhibition of focal adhesion turnover mitigated the increase in osteoblastic differentiation induced by a POS as measured by alkaline phosphatase enzymatic activity and osteogenic gene and protein expression. Together, these data, coupled with previous findings, suggest that the observed ß-catenin translocation is a result of focal adhesion turnover, providing evidence for a focal adhesion initiated, ß-catenin mediated mechanism of substrate surface signal transduction.

Life-prolonging treatment restrictions and outcomes in patients with cancer and COVID-19: an update from the Dutch Oncology COVID-19 Consortium.

AIM OF THE STUDY: The coronavirus disease 2019 (COVID-19) pandemic significantly impacted cancer care. In this study, clinical patient characteristics related to COVID-19 outcomes and advanced care planning, in terms of non-oncological treatment restrictions (e.g. do-not-resuscitate codes), were studied in patients with cancer and COVID-19. METHODS: The Dutch Oncology COVID-19 Consortium registry was launched in March 2020 in 45 hospitals in the Netherlands, primarily to identify risk factors of a severe COVID-19 outcome in patients with cancer. Here, an updated analysis of the registry was performed, and treatment restrictions (e.g. do-not-intubate codes) were studied in relation to COVID-19 outcomes in patients with cancer. Oncological treatment restrictions were not taken into account. RESULTS: Between 27th March 2020 and 4th February 2021, 1360 patients with cancer and COVID-19 were registered. Follow-up data of 830 patients could be validated for this analysis. Overall, 230 of 830 (27.7%) patients died of COVID-19, and 60% of the remaining 600 patients with resolved COVID-19 were admitted to the hospital. Patients with haematological malignancies or lung cancer had a higher risk of a fatal outcome than other solid tumours. No correlation between anticancer therapies and the risk of a fatal COVID-19 outcome was found. In terms of end-of-life communication, 50% of all patients had restrictions regarding life-prolonging treatment (e.g. do-not-intubate codes). Most identified patients with treatment restrictions had risk factors associated with fatal COVID-19 outcome. CONCLUSION: There was no evidence of a negative impact of anticancer therapies on COVID-19 outcomes. Timely end-of-life communication as part of advanced care planning could save patients from prolonged suffering and decrease burden in intensive care units. Early discussion of treatment restrictions should therefore be part of routine oncological care, especially during the COVID-19 pandemic.