Monotherapy Research Articles

Recent efficacy and long-term survival of Astragalus polysaccharide combined with gemcitabine and S-1 in pancreatic cancer

BACKGROUND Pancreatic cancer is a highly malignant tumor with a rapid progression rate and a high susceptibility to infiltration and metastasis. Astragalus polysaccharide (APS), a pure Chinese medicine preparation primarily made from the traditional Chinese herb Astragalus , plays a positive role in the treatment of many malignant tumors. AIM To explore the recent efficacy of APS combined with gemcitabine plus tegafur gimeracil oteracil potassium capsule (S-1) (GS) regimen in the treatment of pancreatic cancer and assess its effect on the immune function and long-term survival of patients. METHODS A total of 97 patients who were diagnosed with pancreatic cancer and received GS chemotherapy at The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine) from March 2021 to December 2021 were included in the retrospective analysis. Among them, 41 patients received APS combined with GS chemotherapy, and 56 patients received GS chemotherapy only. The recent efficacy, immune function, adverse reactions, and long-term survival were compared among these patients. RESULTS After 4 cycles of treatment, the objective response rate of patients receiving the combined therapy of APS and GS was 51.22%, and the disease control rate (DCR) was 56.10%, higher than those of patients receiving the monotherapy with GS alone (30.36% and 35.71%, respectively). Besides, the percentages of CD3+ T cells (50.18% ± 9.57%) and CD4+ T cells (31.52% ± 5.33%) in the peripheral blood of patients receiving the combined therapy of APS and GS were higher compared with those treated with GS regimen alone [(44.06% ± 8.55%) and (26.01% ± 7.83%), respectively]. Additionally, the incidences of leukopenia, thrombocytopenia, and fatigue in patients receiving the combined therapy of APS and GS were significantly lower than those in patients receiving the monotherapy of GS alone (17.07%, 9.76%, 31.71% vs 37.50%, 28.57%, 60.71%). Moreover, the median survival time of patients receiving the combined therapy of APS and GS was 394 days, significantly longer than that of patients receiving the monotherapy of GS alone (339 days) (hazard ratio (HR): 0.66; 95%CI: 0.45-0.99; P = 0.036). All these differences were statistically significant (P < 0.05). CONCLUSION The combined therapy of APS and GS improved the recent efficacy and long-term survival of patients with pancreatic cancer and alleviated chemotherapy-induced immune suppression and adverse reactions.

Pityriasis Rubra Pilaris, Refractory to IL-17A Inhibition, with Rapid Improvement Following IL-17A/IL-17F Blockade by Bimekizumab

Introduction: Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disorder which can severely affect patient quality of life. While there are no FDA-approved therapies for PRP, methotrexate and acitretin are often used as first line treatments. Recent analyses have implicated dysregulation of the IL23/IL17 axis in PRP pathogenesis and the use of biologics for severe cases have been reported in the literature. Case Report: We report the case of a male in his thirties who presented with PRP refractory to a second course of secukinumab. Physical exam revealed diffuse salmon-colored hyperkeratotic patches coalescing to cover his entire body (BSA >95%). The patient was started on combination therapy with acitretin and bimekizumab. The patient recovered rapidly, with near total resolution of his skin findings four weeks after beginning treatment. Discussion: Unlike earlier biologics targeting IL-17, bimekizumab has activity on IL-17F in addition to IL-17AF and IL-17A. The efficacy of bimekizumab in this case may signify an important role for IL-17F in PRP pathogenesis. Bimekizumab may offer improved efficacy for the treatment of pityriasis rubra pilaris (PRP) in patients who do not respond to other therapies.

The challenges of difficult-to-treat Acinetobacter infections

SUMMARY Infections due to Acinetobacter spp. are among the most difficult to treat. Most are resistant to standard antibiotics, and there is difficulty in distinguishing colonizers from pathogens. This mini-review examines the available antibiotics that exhibit activity against these organisms and provides guidance as to which cultures are relevant and how to treat active infections. Antibiograms describing resistance mechanisms and the minimum inhibitory concentration (MIC) are essential to determine which agent or combination of agents should be used after confirmation of infection, utilizing clinical parameters and biomarkers such as procalcitonin. Directed therapy should be prompt as despite its reputation as a colonizer, the attributable mortality is high. However, although combination therapy is advised, no specific combination has definite evidence of superiority.

Alternative lengthening of telomere-based immortalization renders H3G34R -mutant diffuse hemispheric glioma hypersensitive to PARP inhibitor combination regimens

Abstract Background Diffuse hemispheric glioma, H3G34R/V-mutant (DHG-H3G34) is characterized by poor prognosis and lack of effective treatment options. DHG-H3G34R further harbor deactivation of Alpha-Thalassemia/Mental Retardation Syndrome X-linked protein (ATRX; DHG-H3G34R_ATRX) suggesting a unique interaction of these two oncogenic alterations. In this study, we dissect their cell biological interplay, investigate the impact on telomere stabilization and, consequently, validate a targeted therapy approach. Methods We characterized patient-derived primary pediatric high-grade glioma (pHGG) models for telomere-maintenance mechanisms, DNA damage stress (including protein expression, pH2AX/Rad51 foci, cell-cycle arrest) and their sensitivity towards poly-ADP polymerase inhibitor (PARPi) combinations. Human induced pluripotent stem cells (iPSCs) were used for modelling the disease. The anticancer activity of PARPi combinations in vivo was studied in Chorioallantoic Membrane (CAM) and orthotopic in vivo experiments. Finally, we treated a DHG-H3G34R_ATRX patient with a PARPi combination therapy. Results We elaborate that alternative lengthening of telomeres (ALT) is a key characteristic of DHG-H3G34R_ATRX. A dominant cooperative effect between H3G34R and ATRX loss in ALT activation also became apparent in iPSCs, which endogenously exert telomerase activity. In both, patient-derived DHG-H3G34R_ATRX models and H3G34R+/ATRX- iPSCs, the ALT phenotype was associated with increased basal DNA damage stress, mediating synergistic susceptibility towards PARPi (talazoparib, niraparib) combinations with topoisomerase-I inhibitors (topotecan, irinotecan). In a first-of-its-kind case, treatment of a DHG-H3G34R_ATRX patient with the brain-penetrant PARP inhibitor niraparib and topotecan resulted in a significant tumor reduction. Conclusion Our preclinical and clinical data strongly support the further development of PARPis together with DNA damage stress-inducing treatment regimens for DHG-H3G34R_ATRX.

Belumosudil combination therapy for chronic graft-versus-host-disease in real-world clinical practice

Belumosudil combination therapy for chronic graft-versus-host-disease in real-world clinical practice

Malleatin A and B: New Premyrsine-Type Diterpenes from Euphorbia malleata with Cytotoxic Effects Against A2780 Wild and A2780 R-CIS Ovarian Cancer Cell Lines in Mono or Combination Treatment with Cisplatin

Background: This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from Euphorbia malleata and explore their cytotoxic properties. Methods: Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin. Results: Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC50 range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.

Does acupuncture combined with MOTOmed movement therapy have a better rehabilitation effect on post-stroke hemiplegia patients? A systematic review and meta-analysis

ABSTRACT Background Combinations of rehabilitation therapies are widely used in patients with post-stroke hemiplegia. A combination of acupuncture and MOTOmed had been shown to promote the recovery of post-stroke hemiplegia patients. We conducted a systematic review of evidence from studies that investigated the use of acupuncture combined with MOTOmed for rehabilitation of patients with post-stroke hemiplegia. Objective To estimate the rehabilitation effect of acupuncture combined with MOTOmed movement therapy in patients with post-stroke hemiplegia. Methods Randomized controlled trials (RCTs) of acupuncture combined with MOTOmed movement therapy in patients with post-stroke hemiplegia were retrieved from nine databases. Risk-of-bias assessments were conducted using the Cochrane Risk-of-bias Tool. Meta-analysis of outcome measures was performed using RevMan 5.4 software. And we followed the PRISMA 2020 guidelines. Results Eighteen studies involving 1637 participants were included. Compared with conventional rehabilitation, acupuncture, or MOTOmed movement therapy alone, acupuncture combined with MOTOmed movement therapy increased the scores of Fugl-Meyer Assessment Scale-lower extremity (FMA-LE), Berg Balance Scale (BBS), Functional Ambulation Categories scale (FAC), Maximal Walking Speed test (MWS), gait parameters of 3D gait analysis, Barthel Index (BI), Modified Barthel Index (MBI), total effective rate, and the levels of neurotrophic factors (NGF, BDNF and NT-3) in serum, while reduced the scores of Clinic Spasticity Index (CSI) and National Institutes of Health Stroke Scale-Lower Extremity (NIHSS-LE) (p < 0.05 for all). Conclusion Acupuncture combined with MOTOmed movement therapy has better efficacy than conventional rehabilitation, acupuncture, or MOTOmed alone in patients with post-stroke hemiplegia. This combination therapy can promote the rehabilitation of these patients.

Abstract C034: Investigating residual disease in its spatial context in BRCA1 p53-deficient mammary tumors

Abstract Although various effective anti-cancer treatments have become available over the last decades, resistance to all available therapies remains the major cause of death of cancer patients with disseminated tumors. Striking examples are patients with triple-negative breast cancer (TNBC), which are frequently defective in the repair of DNA double strand breaks, e.g. due to loss of BRCA1 function. Because of this defect, the patients initially respond very well to DNA damage-inducing chemotherapy. Unfortunately, disseminated tumors are usually not eradicated and resistant tumor cells are eventually selected from residual primary or metastatic tumor sites. It is therefore crucial to understand the molecular mechanisms underlying the drug tolerance of the residual tumor cells. To study residual disease, we used the K14cre;Brca1 F/F ;p53 F/F (KB1P) mouse model for hereditary breast cancer, which provides the unique opportunity to explore and target those mechanisms in a fully immunocompetent model. The mammary tumors that spontaneously develop highly resemble their human counterparts, both morphologically and in their therapy response. For example, tumors shrink in response to poly(ADP-ribose) polymerase inhibition, platinum-based treatment or the commonly used doxorubicin, docetaxel and cyclophosphamide (TAC) combination therapy. But despite repeated drug sensitivity, the KB1P mammary tumors are not eradicated, not even by a frequent dosing schedule. By combining single-cell RNA sequencing, spatial transcriptomics and imaging mass cytometry, we dissected the intratumoral heterogeneity and alterations in the tumor microenvironment of residual disease. We identified specific subpopulations of tumor cells that have a survival benefit after treatment, and these occurred together with an altered microenvironment characterized by a highly reactive stroma infiltrated with both anti-inflammatory and pro-tumoral immune cells. Interestingly, those structural and transcriptional changes are reversed in the relapsed tumors, highlighting the plasticity of drug tolerance. To investigate the mechanisms of the altered tumor-stroma interactions that are relevant for drug tolerance, we have designed a custom-made CRISPR/Cas9 library based on differential gene expression of the residual tumor cells. This library enables us to functionally test relevant mechanisms of drug tolerance in vivo and we expect that these analyses will provide useful insights into the tumor-stroma interactions that contribute to residual disease. Taken together, our detailed analyses demonstrate the substantial remodeling of tumor cells in their microenvironment upon treatment. To develop new therapeutic approaches to eradicate drug-tolerant tumor cells and thereby circumvent tumor relapse, it is essential to better understand the heterogeneous cellular composition of residual tumors in its spatial context. With this project, we hope to provide comprehensive data to develop better therapeutic strategies that target the tumor-stroma interaction and eradicate residual tumors. Citation Format: Morgane Decollogny, Demeter Túrós, Astrid Chanfon, Myriam Siffert, Ismar Klebic, Sven Rottenberg. Investigating residual disease in its spatial context in BRCA1 p53-deficient mammary tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C034.

Abstract C046: PARP inhibitors as immune modulators in metastatic ovarian cancer treatment

Abstract Epithelial ovarian carcinoma (EOC) is one of the top five causes of cancer-related death in women. Most patients with EOC achieve initial remission after primary or interval cytoreductive surgery combined with platinum-taxane chemotherapy. However, mutations in BRCA1 or BRCA2 genes, which lead to homologous recombination (HR) defects, play a crucial role in platinum sensitivity and justify the use of poly (ADP-ribose) polymerase (PARP) inhibitors as maintenance therapy, commonly linked to extended progression-free survival (PFS). Besides their direct cytotoxic and cytostatic effects, PARP inhibitors (PARPi) have shown significant immunostimulatory properties by disrupting DNA repair in cancer cells, and opening possibilities for synergy with immune checkpoint inhibitors (ICIs). In this study, we investigate the immunomodulatory effects of PARPi using multiparametric flow cytometry, multiplexed immunolabeling, single-cell transcriptomics, and functional assays in an experimental BR5Brca1-/- syngeneic mouse model and human EOC tumor samples. We examine the molecular and cellular mechanisms that can be exploited to develop more effective combination therapies. PARPi may increase the mutational burden in EOCs due to unresolved DNA damage and the release of damage-associated molecular patterns (DAMPs), thereby increasing T-cell infiltration. In addition, PARPi appear to promote potent type I interferon (IFN) secretion through the activation of cGAMP synthase and the stimulator of the interferon genes (STING) pathway. In combination with ICIs, PARPi showed a beneficial effect on the balance between adaptive anti-tumor immunity and innate myeloid components, leading to an improved cytotoxic T-cell response, as observed in mouse models and HGSOC tumor samples. These observations emphasize the role of strategically designed combinations of PARPi and immunotherapeutic agents, which could be the key to overcoming immunosuppression in the EOC microenvironment, thereby improving clinical outcomes. Citation Format: Sarka Vosahlikova, Peter Holicek, Irena Moserova, Michal Hensler, Romana Mikyskova, Lenka Kasikova, Josef Pasuvka, Jana Drozenova, Katerina Mojzisova, Marek Kovar, Iain McNiesh, Michael Halaska, Lukas Rob, Sandra Orsulic, Milan Reinis, Lorenzo Galluzzi, Radek Spisek, Jitka Palich Fucikova. PARP inhibitors as immune modulators in metastatic ovarian cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C046.

Abstract C014: Degradation of extracellular trap DNA sustains anti-tumor immune responses in breast cancer

Abstract Increased extracellular DNA (exDNA) levels in the blood are a hallmark of metastatic cancer, arising from tumor lysis, apoptosis, necrosis, and neutrophil extracellular traps (NETs) released by tumor-expanded neutrophils. NETs, web-like chromatin structures extruded by neutrophils to trap pathogens, are highly immunogenic due to their DNA and histone content and their persistent interaction with dendritic cells. Tumor cells can also release extracellular traps. In myeloid leukemia, blasts release nuclear content via traps to activate coagulation or sustain myeloproliferation. Extracellular traps have been found in NPM1 mutant AML patients, with mutant NPM co-localizing with histones along exDNA traps. Forcing trap extrusion in NPM mutant leukemia cells has been used to create dendritic cell-based vaccines that break tolerance against NPMc antigens. This suggests that NETs in the tumor microenvironment (TME) may promote tolerance, with breaking tolerance requiring consistent NET formation and dendritic cell interaction. NETs are also seen in solid tumors, such as triple-negative breast cancer (TNBC), where they aid in cancer cell migration, invasion, and awakening of circulating tumor cells. However, the capacity of tumor cells to directly extrude DNA traps is not fully understood. To investigate this, various human and murine breast cancer cell lines were seeded on poly-D-lysine coated slides, stained with DAPI and Sytoxgreen, and observed via confocal microscopy. Tumor cells extruded DNA traps within 4 hours without stimuli. Notably, trap extrusion correlated with cell line aggressiveness and was abolished by DNase, indicating dsDNA composition. The absence of traps in 24-hour cultures suggests DNA extrusion may help rare tumor cells survive and proliferate. In line, DNase treatment reduced tumor proliferation and increased apoptosis. To assess the significance of DNA traps in vivo, BALB/c mice were injected with the highly metastatic 4T1 clone 5 breast cancer model, with or without DNase treatment, and monitored starting 5 days post-injection and weekly until day 28. Histological analysis at the injection site 5 days post-injection showed that DNase treatment reduced both local trap formation and tumor cell proliferation, as indicated by BrdU incorporation. Moreover, immunohistochemistry revealed that in DNase-treated mice, initial tumor growth was followed by complete tumor regression, accompanied by local and systemic CD8 T cell activation. Correspondingly, although a few metastases were detectable at day 14 in DNase-treated mice, no metastases were observed by day 28. Although it remains unclear whether tumor-derived or immune cell-derived traps are most relevant in our model, the results demonstrate that their presence in the TME promotes tolerance despite the inherent immune adjuvant properties of the traps. This suggests that DNase treatment could be particularly effective in combating early tumor development or relapse when used as part of a combination therapy designed to sustain anti-tumor immune responses. Citation Format: Sabina Sangaletti, Paola Portararo, Laura Botti, Valeria Cancila, Claudio Tripodo, Mario P. Colombo, Claudia Chiodoni. Degradation of extracellular trap DNA sustains anti-tumor immune responses in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C014.

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer

AbstractTargeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase–positive non-small cell lung cancer (ALK + NSCLC) patient–derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth. We confirmed knockdown of both TNKS1/2 in DTP cells recovered the sensitivity to alectinib. Further, our study suggested knockdown of TNKS1/2 increased stability of Axin1/2, which induced β-catenin degradation and decreased its nuclear translocation, thereby suppressing transcription of antiapoptotic and proliferation-related genes (survivin, c-MYC). Targeting both pathways with alectinib+pan-HER inhibitor and alectinib+TNKS1/2 inhibitor suppressed alectinib-induced DTP cells, and the triple combination almost completely prevented the appearance of DTP cells. In conclusion, combination with ALK-TKI, pan-HER and TNKS1/2 inhibitors has the potential to prevent the emergence of DTP in ALK + NSCLC.

Abstract C051: Epigenetic reprogramming of brain-infiltrating myeloid cells deters brain metastasis outgrowth

Abstract The unique brain immune microenvironment (BrIME) co-evolves with brain metastasis (BrM) and is marked by immune suppression, posing a significant therapeutic challenge. BrIME is dominated by myeloid cells, with monocyte-derived macrophages (MDMs) comprising nearly half of the tumor-infiltrating leukocytes. Targeting MDMs remains challenging due to their inherent heterogeneity and high plasticity, which are regulated by epigenetic modifiers, including histone deacetylases (HDACs). Yet, the impact of HDAC inhibition in BrIME and its implications for BrM immunotherapy remains unclear. Here, we establish BrM syngenetic model by intracarotid artery (ICA) injection. Immune profiling by mass cytometry (CyTOF) analysis shows that selective class I HDAC inhibitor (HDACi) Entinostat (ENT) significantly enriches inflammatory MDMs in E0771 murine mammary tumor BrM model. Additionally, functional assay with bone marrow-derived macrophages (BMDMs) shows that ENT significantly enhances tumor cell phagocytosis and antigen presentation, increasing the proliferation of antigen-specific T cells in vitro. To test whether HDAC inhibition enhances antitumoral response in the BrIME, we designed a novel sequential treatment: with (1) ENT pre-conditioning the BrIME, (2) low- dose whole brain radiotherapy (LD-WBRT) to release tumor antigen followed by (3) anti-PD1 immune checkpoint therapy (ICT) to reinvigorate tumor-infiltrating. Our result shows that sequential triple treatment demonstrates significant BrM deterrence and induce a specific interferon-responsive MDM subset with robust type I interferon response in single-cell RNA sequencing, correlating with improved ICT clinical outcomes. Our data show that selective HDACi treatment reprograms the suppressive BrIME by steering the BrM-infiltrating MDMs toward immuno-stimulatory status. Sequential triple combinatorial therapy impedes BrM by activating innate and adaptive immunity simultaneously and is well tolerated in the animal model. Our findings highlight the potential of HDACi-mediated epigenetic reprogramming of the BrIME to enhance therapeutic efficacy in treating BrM. Citation Format: Shao-Ping Yang, Yimin Duan, Xiangliang Yuan, Lin Zhang, Wendao Liu, Jun Yao, Patrick Zhang, Jason T Huse, Zhongming Zhao, Dihua Yu. Epigenetic reprogramming of brain-infiltrating myeloid cells deters brain metastasis outgrowth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C051.

Effectiveness of autologous fat graft and methylprednisolone as single and combination therapy in the prevention of epidural fibrosis

Objectives: Epidural fibrosis is a common complication following laminectomy, contributing to failed back surgery syndrome characterized by back pain and radiculopathy. Despite ongoing research, no consensus exists on the best method to prevent epidural fibrosis. This animal study aimed to compare the effectiveness of autologous fat grafts and methylprednisolone as single and combination therapies in preventing epidural fibrosis. Methods: Four groups of rats, each containing 7, underwent different treatments post-lumbar laminectomy: A control group, a group receiving methylprednisolone in the epidural space, a group receiving an autologous fat graft, and a group receiving both methylprednisolone and an autologous fat graft. After 6 weeks, the formation of epidural fibrosis was evaluated through histopathological examination based on the classification. The degree of epidural fibrosis was analyzed. Results: The autologous fat graft group exhibited the lowest degree of fibrosis (Grade 1). Comparisons between this group and the others showed a significant difference (P &lt; 0.05). No significant difference was observed between the control, methylprednisolone, and combination groups (P &gt; 0.05). Conclusion: The study demonstrated a significant reduction in histological epidural fibrosis using autologous fat grafts compared to methylprednisolone and their combination in animal models. Histological analysis indicated that autologous fat grafts resulted in a lower degree of fibrosis following laminectomy.

Efficacy of intravitreal faricimab therapy for polypoidal choroidal vasculopathy: A systematic review and meta-analysis.

Polypoidal choroidal vasculopathy (PCV) is an aneurismal type of macular neovascularization that show similarities with age-related macular degeneration and diseases that are part of the pachychoroid disease spectrum. Exudative changes in PCV can be treated with intravitreal anti-vascular endothelial growth factor monotherapy; however, a combination therapy with photodynamic therapy may be required. In this systematic review and meta-analysis, we evaluated the efficacy of faricimab for PCV. We searched 12 literature databases for eligible studies. All study evaluation and data extraction were made by two authors in duplicate. Studies eligible for analysis were included for a qualitative and quantitative review. We identified seven studies with data from 150 eyes with PCV, five studies were of treatment-naïve eyes who were commenced in faricimab monotherapy, and two studies were of switch-over to faricimab from other anti-VEGF drugs. After faricimab loading dose in treatment-naïve eyes, the best-corrected visual acuity (BCVA) remained stable at -0.09 (95% CI: -0.20-0.03) logMAR, central retinal thickness (CRT) decreased -169 (95% CI: -311--27) μm, and 48.7 (95% CI: 32.5-65.0) % of eyes obtained polyp closure. In switch-over eyes, 57%-67% experienced fluid reduction and 21% were able to extend their treatment interval. In conclusion, faricimab monotherapy for PCV leads to acceptable clinical outcomes in terms of stable BCVA, reduction of CRT, and high incidence of polyp closure. Some cases may benefit from a switch to faricimab. However, long-term efficacy studies and controlled comparative studies are warranted.

Oesophageal cancer.

Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last decade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treatment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and radiotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening, diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particular focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based therapies.

Evidence Supporting Conservative Scar Management Interventions Following Burn Injury: a review article.

Conservative management for hypertrophic scars (HSc) and scar contractures is of utmost importance to optimally reintegrate burn survivors into society. Many conservative treatment interventions have been described in the literature for the management of HSc. Recent advancements in the literature pertaining to post-burn scarring and HSc formation, have advanced our understanding of the mechanisms that support or refute the use of common rehabilitation treatment modalities after burn injury. This is particularly relevant for recent advancements in the fields of mechanotransduction and neurogenic inflammation resulting in the need for rehabilitation clinicians to reflect upon commonly employed treatment interventions. The aim of this review article is to summarize and clinically apply the evidence that supports or refutes the use of common conservative treatment interventions for scar management employed after burn injury. The following treatments are discussed and mechanotransduction and neurogenic inflammation concepts are highlighted: 1) edema management (compression, positioning/elevation, pumping exercises, retrograde massage, manual edema mobilization), 2) pressure therapy (including custom fabricated pressure garments, inserts, face masks, and other low-load long duration orthotic devices), 3) gels or gel sheets, 4) combined pressure therapy and gels, 5) serial casting, 6) scar massage, and 7) passive stretching. This review supports the following statements: 1) Compression for edema reduction should be initiated 48-72 hrs post-injury and continued for wounds that require longer than 21 days to heal until scar maturation; 2) Elevation, pumping exercises and retrograde massage/MEM should be used in combination with other edema management techniques; 3) Custom fabricated pressure garments should be applied once the edema is stabilized and adequate healing has occurred. Garments should be monitored on a regular basis to ensure that optional pressure, >15mm Hg, is maintained, adding inserts when necessary. The wearing time should be >16 hrs/day; 4) Gels for post-burn scar management should extend beyond the scar; 5) Serial casting should be applied when contractures interfere with function; 6) Forceful scar massage should be avoided early in the wound healing process or when the scar is inflamed or breaks down; 7) Other treatment modalities should be prioritized over passive stretching for scar management.

Is there a place for surgery in oligometastatic ductal carcinoma of the pancreatic head?

Background: New chemotherapy regimens (gemcitabine / nab-paclitaxel, FOLFIRINOX) have improved overall survival rates in ductal carcinoma, which has renewed the interest in surgical treatment for isolated liver metastases. Aim: To identify the role of surgery in ductal carcinoma of the pancreatic head with liver oligometastases. Methods: We retrospectively analyzed the data from 490 patients with morphologically verified ductal carcinoma of the pancreatic head in two specialized centers, who had undergone pancreatoduodenectomy (PD) from January 2011 to April 2024. In 21 patients, PD was performed simultaneously with liver resection (liver oligometastases were found during the surgery). Results: In the postoperative period after PD with liver resection, compared to that after PD without liver resection, intra-abdominal abscesses were more frequent (4/21 (19.0%) versus 10/469 (2.2%), p = 0.002) and relaparotomy was performed more often by 9.8% [95 confidence interval (CI, Miettinen-Nurminen score method) 0.21–30.3] (3/21 (14.3%) versus 21/469 (4.5%), p = 0.077). The postoperative death rates were comparable (1/21 (4.8%) versus 19/469 (4.1%), p = 0.8). The median overall survival of the patients after PD with liver resection was 11 (95% CI: 6–16) months, and overall 1-, 2-, and 3-year survival rates were 39.2, 16.8 and 7.2%, respectively. In the patients after PD with liver resection without any adjuvant chemotherapy (n = 5), the median overall survival was 6 (95% CI: 5–7) months, and in those with chemotherapy, 13 (95% CI: 6–16) months (p = 0.006). The overall three-year survival of the patients after PD with liver resection and adjuvant chemotherapy was 11.5%. In the patients after PD with liver resection R0, the median overall survival was 13 (95% CI: 6–32) months, with R1 resection 6 (95% CI: 6–7), and with R2 resection 6 (95% CI: 6–7) months (p = 0.021). The median overall survival of patients after PD with liver resection for G1 tumors was 17 (95% CI: 6–32) months. Conclusion: Surgery as a component of combination therapy for oligometastatic pancreatic head cancer can be considered in a certain category of patients with high tumor differentiation grade and mandatory preliminary assessment of the feasibility of R0 surgery and systemic chemotherapy.

A rare case of granulomatous mastitis by Brucella species.

Granulomatous mastitis (GM) is a rare, chronic, benign inflammatory disease of the breast. Here, we present a rare case of GM caused by brucellosis and present the first review to compile the cases in the literature. The diagnosis was confirmed by the patient's serological and histopathological results. The patient was successfully treated with doxycycline+rifampicin combination therapy for six weeks. In conclusion, infectious agents, especially brucellosis, should be considered in the differential diagnosis of GM in endemic regions. Diagnostic methods, such as tissue culture and serological tests, should be used to detect possible infectious agents if necessary.

A multicenter, phase II trial of triplet antiemetic therapy with palonosetron, aprepitant, and olanzapine for highly emetogenic chemotherapy in breast cancer (PATROL-II).

Dexamethasone is an antiemetic drug widely used to prevent nausea and vomiting caused by anticancer drugs. However, dexamethasone can cause several side effects even after short-term administration. Therefore, the development of dexamethasone-free antiemetic therapies has been recognized as an important challenge. The objective of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine. Patients who were chemotherapy-naïve and scheduled to receive highly emetogenic chemotherapy for breast cancer were enrolled and assessed for nausea and vomiting occurring within 120h after the start of chemotherapy. The primary endpoint was the total control (TC) rate of overall phases. Secondary endpoints included the complete response (CR) rate, which was evaluated during the acute, delayed, and overall phases. A total of 88 patients were enrolled from eight centers in Japan, of whom 84 were included in the analysis. The proportion of patients achieving TC throughout the overall period was 17.1%. Similarly, CR and CC rates for the overall period were 43.4% and 39.5%, respectively. Frequently reported adverse events were loss of appetite and constipation, with rates of 52.4% and 50.0%, respectively. The primary endpoint was not achieved. Therefore, antiemetic therapy without dexamethasone shows an inadequate effect on nausea, and it is generally advisable to avoid omitting dexamethasone. However, in the overall period, both CR and CC were comparable to conventional three-drug combination therapy. Thus, in patients unable to use dexamethasone, replacing it with olanzapine could be an option.Trial registration number: UMIN 000038644, November 20, 2019. The date of first trial registration: 13/03/2020.

Drug-resistant BRAF V600E-mutant recurrent pleomorphic xanthoastrocytoma, CNS WHO Grade 3 successfully resolved with incidental discontinuation of combined BRAF and MEK inhibitor therapy

Background: Combination therapy with BRAF and MEK inhibitor holds promise for treating gliomas harboring the BRAF V600E mutation; however, the development of acquired resistance remains a challenge. Case Description: We describe a case of repeated recurrent BRAF-mutant pleomorphic xanthoastrocytoma (central nervous system World Health Organization grade 3) treated with combination therapy with BRAF and MEK inhibitor. The patient received dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor); however, she developed resistance to the combination therapy. Remarkably, incidental drug discontinuation contributed to the disappearance of the resistant tumor. The same phenomenon was repeatedly observed after that. Genetic analysis demonstrated that the resistant tumor had BRAF V600E amplification; the resistant tumor remained BRAF→MEK→ERK pathway dependent, and drug resistance might be due to elevated BRAF V600E expression. We speculated that ERK1/2 signal extremes caused by the discontinuation of the combination therapy affected the resistant tumor survival. Conclusion: This case study provides important insights into novel treatment strategies and their underlying mechanisms for gliomas with BRAF mutations.