Multiple Therapies Research Articles

Clinical profile of Brazilian patients with temporomandibular joint disorder and orofacial pain: A 20-year retrospective study

ObjectiveTemporomandibular joint disorder (TMD) comprises several musculoskeletal conditions in the orofacial region, with chronic pain and/or dysfunction involving the temporomandibular joint (TMJ) and masticatory muscles. This study assessed the clinical characteristics of patients with TMD treated at a public tertiary care facility in Brazil. MethodsIn this retrospective study, we assessed data from adult patients attending the Center for Occlusion, TMD, and Orofacial Pain at a Brazilian school of dentistry, from 2000 to 2020. Data from eligible charts were collected: demographic variables, clinical complaints, location of pain, pain intensity (10-point VAS), duration of treatment, and therapeutic procedures. Data were analyzed using descriptive and inferential statistics at the 0.05 significance level. ResultsThe sample consisted of 2324 patients (79.4 % females) with a median age of 38 years and median duration of treatment of 35 days. Major clinical complaints were craniofacial pain (including in the TMJ region) (82.9 %), self-reported bruxism (clenching/grinding) (44.6 %), and clicking/crepitation (39.1 %). Craniofacial pain was associated with female gender and age of 39 years and older, but not with bruxism. The most frequent procedures were counseling (96.5 %), exercises (47.5 %), occlusal splints (18.5 %), and physiotherapy (13.8 %). Reduction in pain intensity was moderately associated with multiple (3 or more) therapies and longer duration of treatment. ConclusionIt can be concluded that the patients presented a diversity of clinical characteristics requiring individualized treatment. A multimodal, interdisciplinary therapeutic approach, including counseling, appears to benefit most patients with TMD-related pain.

Personalized insulin dosing using reinforcement learning for high-fat meals and aerobic exercises in type 1 diabetes: a proof-of-concept trial

In type 1 diabetes, high-fat meals require more insulin to prevent hyperglycemia while meals followed by aerobic exercises require less insulin to prevent hypoglycemia, but the adjustments needed vary between individuals. We propose a decision support system with reinforcement learning to personalize insulin doses for high-fat meals and postprandial aerobic exercises. We test this system in a single-arm 16-week study in 15 adults on multiple daily injections therapy (NCT05041621). The primary objective of this study is to assess the feasibility of the novel learning algorithm. This study looks at glucose outcomes and patient reported outcomes. The postprandial incremental area under the glucose curve is improved from the baseline to the evaluation period for high-fat meals (378 ± 222 vs 38 ± 223 mmol/L/min, p = 0.03) and meals followed by exercises (−395 ± 192 vs 132 ± 181 mmol/L/min, p = 0.007). The postprandial time spent below 3.9 mmol/L is reduced after high-fat meals (5.3 ± 1.6 vs 1.8 ± 1.5%, p = 0.003) and meals followed by exercises (5.3 ± 1.2 vs 1.4 ± 1.1%, p = 0.003). Our study shows the feasibility of automatically personalizing insulin doses for high-fat meals and postprandial exercises. Randomized controlled trials are warranted.

Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.

KCNT1-related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep-related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug-resistant seizures and global developmental delays. In addition to conventional anti-seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD-including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients. We performed a literature review on PubMed and EMBase with the keyword "KCNT1" and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype. A total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%-25% of patients). Ketogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug-resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1-related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors. We performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti-seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion.

Diaphragm Tracking System That Superimposes Planned Diaphragm Contours on Kilovolt Cine Images During Multiple Breath-Hold Volumetric Modulated Arc Therapy for Abdominal Tumors.

We recently published a phantom validation of our diaphragm tracking system, DiaTrak, on an Elekta linear accelerator with an integrated cone-beam computed tomography (CBCT) unit for multiple breath-hold volumetric modulated arc therapy of abdominal tumors, where the diaphragm position was compared between digitally reconstructed radiography (DRR) and kilovolt (kV) projection streaming images by template matching. In the present report, the visual feedback of the diaphragm position was added to the reported system. DICOM-RT diaphragm contour data were additionally exported from a treatment planning system to the DiaTrak PC. Following phantom localization by registering the CBCT to the planning CT images, a projected diaphragm contour was overlaid on each DRR image, whereas another two projected diaphragm contours were superimposed on each kV projection cine image every 180 ms after shifting ±5 mm (set as breath-hold tolerance) in the craniocaudal direction during gantry rotation. It was visually confirmed that the projected diaphragm surface was observed within the two contour lines on the kV cine window. The diaphragm registration errors of the localized phantom were also calculated based on image cross-correlation between the DRR and the projection cine images every 180 ms. It was found that the mean diaphragm registration error was -0.29 mm with a standard deviation of 0.32 mm during the gantry rotation. In conclusion, a new interface for the 5 mm tolerance check was proposed to provide direct visual feedback, thereby giving a sense of assurance to the attending radiotherapy technologists. The calculated diaphragm registration errors were relatively small compared to the tolerance of 5 mm, and therefore it is considered clinically acceptable.

Use of Bedinvetmab (Librela®) for Canine Osteoarthritis in France, Germany, Italy, Spain, and the UK: Quantitative Analysis of Veterinarian Satisfaction and Real-World Treatment Patterns.

Bedinvetmab (Librela®) represents a new class of canine osteoarthritis pain therapy. The aim of this study was to understand patient selection, usage behaviours, and satisfaction amongst veterinarians using bedinvetmab. Overall, 1932 patient record forms (PRF) were collected from 375 veterinarians across five countries in Europe. Veterinarians were asked to provide 5-7 PRF representing an average patient prescribed bedinvetmab. Veterinarian satisfaction with bedinvetmab usage averaged 8.0 out of 10.0 across all countries. Dissatisfaction as a reason for discontinuation was less than 1% for veterinarians. Veterinarians prescribed bedinvetmab broadly, across patient severity stages, weights, and ages. Adherence to monthly dosing per the product label was over 99%, and compliance with bedinvetmab treatment regimens was 85%. Following initiation of bedinvetmab, the proportion of patients requiring multiple pharmacological therapies for osteoarthritis pain fell from 47% to 31% (p < 0.05). After initiation of bedinvetmab, the mean total number of pharmacological therapies per patient across the population was 1.3, a reduction from 1.9 pre-treatment (p < 0.05). This investigation provides evidence on the benefit of bedinvetmab use post-launch in a broad population of dogs across the five most populous countries in western Europe. Compliance and satisfaction appear high and the use of other analgesic therapies to treat osteoarthritis pain is reduced in most cases following administration of bedinvetmab.

Laser Therapy in Heavily Treated Oncological Patients Improves Vaginal Health Parameters.

This study aimed to investigate the efficacy and duration of multiple non-ablative intravaginal CO2 laser (V-lase®) cycles in breast cancer patients, gynecological and other pelvic cancers previously subjected to multiple oncological treatments. This prospective study enrolled women under the age of 65 years who reported vaginal symptoms. Data on the Vaginal Health Index (VHI), vaginal length (VL), vaginal pain measured using a Visual Analog Scale (VAS), and the Female Sexual Function Index (FSFI) were collected at baseline and before each laser application, and at subsequent follow-up visits. A total of 170 laser applications were performed on 113 women with various types of cancer. Most patients (57.5%) had received radiotherapy-based treatments before receiving laser treatment. Vaginal health parameters and sexual function improved significantly with each laser application. However, a temporary decline in these improvements occurred during the intervals between cycles. Such worsening was reversed with the subsequent cycle in all groups of patients, irrespective of the type of oncological treatments they had undergone. Multiple course vaginal laser therapy showed promising results as a potential treatment for vaginal atrophy in heavily treated gynecological and breast cancer patients, necessitating further research to determine the optimal time interval between cycles to ensure sustained positive effects.

Local Therapy and Reconstruction in Penile Cancer: A Review.

Local therapy for penile cancer provides robust survival and can preserve the penis functionally and cosmetically. Interventions must target the appropriate clinical stage. We reviewed studies regarding the primary therapy in penile cancer, from topical therapy to radical penectomy, and reconstructive techniques. Topical therapy (5-FU or Imiquimod) provides a robust oncologic response in patients with Ta or Tis disease. Multiple laser therapies are available for localized patients and those with low-grade T1 disease. There is a non-trivial risk of progression and nodal metastases in poorly selected patients. Wide local excision provides an oncologically sound option in patient with up to T1 disease; less evidence exists for Mohs microsurgery in the setting of penile cancer. Increasingly aggressive approaches include glansectomy and partial/radical penectomy, which provide 5- and 10-year cancer-specific survival rates of over 80%. Meticulous reconstruction is necessary for the durable function of the remaining penis. Preservation of voiding and sexual function occurs via penile skin grafting, glans resurfacing, creation of a functional penile stump, and phalloplasty with a penile implant. Perineal urethrostomy provides an alternative in pathology demanding extensive partial or radical penectomy, and a durable option for seated voiding. Clinical suspicion and timely diagnosis are paramount in terms of management as less-invasive options for earlier-stage disease develop.

Fetal Lower Urinary Tract Obstruction: Current Diagnostic and Therapeutic Strategies and Future Directions.

Fetal lower urinary tract obstruction (LUTO) is a rare congenital anomaly in which the bladder cannot empty properly. The clinical presentation is variable. On the severe end of the spectrum, the amniotic fluid index can be sufficiently low, resulting in fetal lung development that is incompatible with life outside the womb. The pressure in the urinary tract system can also result in severe damage to the kidney, resulting in renal failure in utero or in the first couple years of life. Therefore, much work has been done to determine which fetuses need intervention in utero to allow for survival outside of the womb and avoidance of end-stage renal disease. Multiple therapies have been developed to relieve the obstruction in utero with the mainstay being vesicoamniotic shunting and posterior urethral valve ablation. While much has been investigated to determine which fetuses would benefit from fetal intervention, the current indications are not without their flaws. This review describes the current indications and their shortcomings, as well as new experimental methods of determining need for intervention. Additionally, this review describes the milestone animal studies that established the challenges of current fetal interventions and the utility of an experimental valved shunt in sheep over the last 20 years. Our understanding of LUTO and which fetuses benefit from in utero intervention has grown over the last 20 years. However, traditional markers have proven to be less predictive than previously thought, opening the door to exciting new advances. Vesicoamniotic shunting, while lifesaving, does not preserve bladder function and frequently dislodges. Animal studies over the last 20 years have established the utility of a valved shunt to maintain bladder function. Current advances are working to create such a shunt that can be percutaneously deployed and have greater adherence to the bladder wall to avoid dislodgement.

Synthesis of scaberol C amino acid ester derivatives with anti-cancer activity

A series of amino acid ester trifluoroacetate derivatives was synthesized from scaberol C. They were screened for their inhibitory activity against Non-Small Cell Lung Cancer (NSCLC) cells. Among them, compound 2 l showed significant cytotoxicity against A549 and H460 cells (IC50), and was more active than cisplatin (DDP). The epidermal growth factor receptor (EGFR) was overexpressed in NSCLC, which was the target of multiple cancer therapies and a strong prognostic indicator. Our previous studies reported that the target of scaberol C derivatives against NSCLC cells was EGFR. And then molecular docking analysis and molecular dynamics (MD) simulations indicated that 2 l can stably and covalently bind to the EGFR target protein.

Pityriasis Rubra Pilaris Following Administration of the Pfizer-BioNTech COVID-19 Vaccine Successfully Treated with Acitretin and Dupilumab

Introduction: Pityriasis rubra pilaris (PRP) is an inflammatory eruption of unknown origin; rare cases of COVID-19 vaccine-induced PRP have been reported. Here, we present a case of COVID-19 vaccine-induced pityriasis rubra pilaris inadequately managed with acitretin, successfully treated with the IL-4/IL-13 inhibitor dupilumab. Case Report: A 76-year-old male presented to an outpatient dermatology clinic with a 2-month history of a profoundly pruritic worsening rash characterized by large, orange-salmon-colored follicular papules with scale coalescing into plaques covering approximately 80% of the body surface area. The plaques had well-defined borders and multiple islands of sparing characteristic of PRP. Multiple therapies were trialed with no improvement, including oral prednisone, mycophenolate, topical corticosteroids, antiparasitics, antifungals, doxepin, and UVB treatments. A trial of oral acitretin resulted in improvement of the skin plaques and keratoderma, but the patient remained uncontrollably pruritic. Dupilumab was initiated which provided rapid relief, and the patient has remained clear for several months. Conclusion: Clinicians should be aware of dupilumab’s potential for effective treatment of PRP with recalcitrant pruritus.

A Five-Year Review of Newborn Screening for Spinal Muscular Atrophy in the State of Utah: Lessons Learned.

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3-4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.

Refining the optimal CAF cluster marker for predicting TME-dependent survival expectancy and treatment benefits in NSCLC patients

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we have systematically screened multiple databases to identify the most robust marker for distinguishing CAFs in lung cancer, with a particular focus on their potential use in early diagnosis, staging, and treatment response evaluation. Our investigation revealed that COL1A1, COL1A2, FAP, and PDGFRA are effective markers for characterizing CAF subgroups in most lung adenocarcinoma datasets. Through comprehensive analysis of treatment responses, we determined that COL1A1 stands out as the most effective indicator among all CAF markers. COL1A1 not only deciphers the TME signatures related to CAFs but also demonstrates a highly sensitive and specific correlation with treatment responses and multiple survival outcomes. For the first time, we have unveiled the distinct roles played by clusters of CAF markers in differentiating various TME groups. Our findings confirm the sensitive and unique contributions of CAFs to the responses of multiple lung cancer therapies. These insights significantly enhance our understanding of TME functions and drive the translational application of extensive scRNA sequence results. COL1A1 emerges as the most sensitive and specific marker for defining CAF subgroups in scRNA analysis. The CAF ratios represented by COL1A1 can potentially serve as a reliable predictor of treatment responses in clinical practice, thus providing valuable insights into the influential roles of TME components. This research marks a crucial step forward in revolutionizing our approach to cancer diagnosis and treatment.

HER2-CD3-Fc Bispecific Antibody-Encoding mRNA Delivered by Lipid Nanoparticles Suppresses HER2-Positive Tumor Growth.

The human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor and tumor-associated antigen abnormally expressed in various types of cancer, including breast, ovarian, and gastric cancer. HER2 overexpression is highly correlated with increased tumor aggressiveness, poorer prognosis, and shorter overall survival. Consequently, multiple HER2-targeted therapies have been developed and approved; however, only a subset of patients benefit from these treatments, and relapses are common. More potent and durable HER2-targeted therapies are desperately needed for patients with HER2-positive cancers. In this study, we developed a lipid nanoparticle (LNP)-based therapy formulated with mRNA encoding a novel HER2-CD3-Fc bispecific antibody (bsAb) for HER2-positive cancers. The LNPs efficiently transfected various types of cells, such as HEK293S, SKOV-3, and A1847, leading to robust and sustained secretion of the HER2-CD3-Fc bsAb with high binding affinity to both HER2 and CD3. The bsAb induced potent T-cell-directed cytotoxicity, along with secretion of IFN-λ, TNF-α, and granzyme B, against various types of HER2-positive tumor cells in vitro, including A549, NCI-H460, SKOV-3, A1847, SKBR3, and MDA-MB-231. The bsAb-mediated antitumor effect is highly specific and strictly dependent on its binding to HER2, as evidenced by the gained resistance of A549 and A1847 her2 knockout cells and the acquired sensitivity of mouse 4T1 cells overexpressing the human HER2 extracellular domain (ECD) or epitope-containing subdomain IV to the bsAb-induced T cell cytotoxicity. The bsAb also relies on its binding to CD3 for T-cell recruitment, as ablation of CD3 binding abolished the bsAb's ability to elicit antitumor activity. Importantly, intratumoral injection of the HER2-CD3-Fc mRNA-LNPs triggers a strong antitumor response and completely blocks HER2-positive tumor growth in a mouse xenograft model of human ovarian cancer. These results indicate that the novel HER2-CD3-Fc mRNA-LNP-based therapy has the potential to effectively treat HER2-positive cancer.

131I-mIBG Therapy in the Management of High-Risk Neuroblastoma: A Retrospective Study from a Tertiary Level Hospital in South India

Abstract Introduction Neuroblastoma is the most common extracranial solid tumor in childhood. The data on the treatment experience with 131iodine-meta-iodo-benzyl-guanidine (131I-mIBG) and clinical outcome data are meager from India. Objectives This article studies the efficacy and treatment outcomes in patients treated with 131I-mIBG in high-risk neuroblastoma. Materials and Methods The study group consisted of 201 consecutive patients (aged between 1 and 15 years) with biopsy-proven neuroblastoma who underwent 131I-mIBG scans from 2012 to 2022. The majority of these children had a disease that was inoperable or had poor response to chemotherapy. Patients with positive scintigraphy were considered for therapy with 131I-mIBG. The findings were analyzed and correlated with the final diagnosis and outcomes obtained from survival during follow-up and reviewing patient records. Results Thirty-nine children, 22 males and 17 females, with a median age of 4 years had positive 131I-mIBG scintigraphy. Intra-abdominal primary lesions and osseous lesions were the most common sites of uptake on 131I-mIBG scan. Of these, 13 had upfront chemotherapy and 26 had surgery followed by chemotherapy. All the patients underwent therapy with 131I-mIBG. Fourteen patients had multiple therapies while the remaining 25 had only one therapy. Eight patients had no follow-up, and 13 had disease relapse. The remaining 18 had regression of disease which was confirmed by follow-up 131I-mIBG scintigraphy and with bone scintigraphy in patients with osseous metastases. Conclusion 131I-mIBG scintigraphy should be preferred in intermediate and high-risk neuroblastoma to know the extent of the disease and also for patient selection for early therapy with 131I-mIBG. It holds significant utility in the management of metastatic neuroblastoma, facilitating palliative pain relief and tumor size reduction in inoperable or metastatic disease.

Predictors of response to Radioactive Iodine Therapy in Intermediate and high risk patients with papillary thyroid carcinoma

BackgroundRadioactive iodine (RAI) therapy is the standard treatment approach after total thyroidectomy in patients with papillary thyroid carcinoma (PTC). We aimed to identify predictive factors of response to the treatment in intermediate and high-risk patients with PTC. In addition, the impact of multiple RAI treatments was explored.MethodsIn a 3-year retrospective study, data from intermediate and high-risk patients with PTC who received RAI therapy following total thyroidectomy, were analyzed by the end of year-one and year-three. Demographic data, tumor size, capsular/vascular invasion, extrathyroidal extension, local or distant metastasis, initial dose and cumulative dose of RAI, serum thyroglobulin(Tg), antithyroglobulin antibody(TgAb), and imaging findings were investigated. Patients with an excellent response to a single dose of RAI treatment, after three years of follow-up were classified as the “Responder group”. Excellent response was defined as stimulated serum Tg less than 1 ng/ml, or unstimulated serum Tg less than 0.2 ng/ml in TgAb-negative patients with negative imaging scans.Results333 patient records with a complete data set were analyzed in this study. After three years of initial treatment, 271 patients were non-responders (NR) and 62 were responders (R). At baseline, the median pre-ablation serum Tg level was 5.7 ng/ml in the NR group, and 1.25 ng/ml in the R group (P < 0.001). TSH-Stimulated serum Tg greater than 15.7 ng/ml, was associated with response failure even after multiple RAI therapy, AUC: 0.717(0.660–0.774), sensitivity: 52.5%, specificity: 89.47%, P < 0.001. On the other hand, multiple RAI therapy was associated with excellent response in 16.2% of the patients. The chance of ER was decreased by 74% if initial post-operation ultrasound imaging confirmed the presence of locoregional involvement, OR 0.26, (95% CI: 0.12–0.55), P < 0.001.ConclusionStimulated serum Tg and locoregional involvement after total thyroidectomy are predictive factors of non-response to RAI therapy in intermediate and high-risk patients with PTC. In addition, a minority of patients achieve excellent response after multiple RAI therapy.

Treatment Strategies for Locoregional Recurrence in Esophageal Squamous-Cell Carcinoma: An Updated Review.

Emerging evidence has shown remarkable advances in the multimodal treatment of esophageal squamous-cell carcinoma. Despite these advances, the oncological outcomes for advanced esophageal cancer remain controversial due to the frequent observation of local recurrence in the regional or other lymph nodes and distant metastasis after curative treatment. For cases of locoregional recurrence in the cervical lymph nodes alone, salvage surgery with lymph node dissection generally provides a good prognosis. However, if recurrence occurs in multiple regions, the oncological efficacy of surgery may be limited. Radiotherapy/chemoradiotherapy can be employed for unresectable or recurrent cases, as well as for selected cases in neo- or adjuvant settings. Dose escalation and toxicity are potential issues with conventional three-dimensional conformal radiotherapy; however, more precise therapeutic efficacy can be obtained using technical modifications with improved targeting and conformality, or with the use of proton beam therapy. The introduction of immune checkpoint inhibitors, including pembrolizumab or nivolumab, in addition to chemotherapy, has been shown to improve the overall survival in unresectable, advanced/recurrent cases. For patients with lymph node recurrence in multiple regions, chemotherapy (5-fluorouracil [5-FU] plus cisplatin) and combination therapy with nivolumab and ipilimumab have shown comparable oncological efficacy. Further prospective studies are needed to improve the treatment outcomes in patients with esophageal cancer with locoregional recurrence.

The Treatment of Hepatocellular Carcinoma with Major Vascular Invasion.

Vascular invasion of hepatocellular carcinoma involves tumor plugs in the main trunk of the portal vein, bile ducts, and veins, and it indicates poor prognosis. It is often associated with portal hypertension, which requires evaluation and management. Treatment includes hepatic resection, systemic pharmacotherapy, hepatic arterial infusion chemotherapy, and radiation therapy. Recurrence rates post-hepatic resection are high, and systemic drug therapy often has limited therapeutic potential in patients with a poor hepatic reserve. Single therapies are generally inadequate, necessitating combining multiple therapies with adjuvant and systemic pharmacotherapy before and after hepatectomy. This narrative review will provide an overview of the treatment of hepatocellular carcinoma with vascular invasion.

Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results.

Adoptive cell transfer (ACT) with neoantigen-reactive T lymphocytes can mediate cancer regression. Here we isolated unique, personalized, neoantigen-reactive T cell receptors (TCRs) from tumor-infiltrating lymphocytes of patients with metastatic gastrointestinal cancers and incorporated the TCR α and β chains into gamma retroviral vectors. We transduced autologous peripheral blood lymphocytes and adoptively transferred these cells into patients after lymphodepleting chemotherapy. In a phase 2 single-arm study, we treated seven patients with metastatic, mismatch repair-proficient colorectal cancers who had progressive disease following multiple previous therapies. The primary end point of the study was the objective response rate as measured using RECIST 1.1, and the secondary end points were safety and tolerability. There was no prespecified interim analysis defined in this study. Three patients had objective clinical responses by RECIST criteria including regressions of metastases to the liver, lungs and lymph nodes lasting 4 to 7 months. All patients received T cell populations containing ≥50% TCR-transduced cells, and all T cell populations were polyfunctional in that they secreted IFNγ, GM-CSF, IL-2 and granzyme B specifically in response to mutant peptides compared with wild-type counterparts. TCR-transduced cells were detected in the peripheral blood of five patients, including the three responders, at levels ≥10% of CD3+ cells 1 month post-ACT. In one patient who responded to therapy, ~20% of CD3+ peripheral blood lymphocytes expressed transduced TCRs more than 2 years after treatment. This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and can mediate tumor regression in patients with metastatic colorectal cancers. ClinicalTrials.gov registration: NCT03412877 .

Remote coupling of electrical and mechanical cues by diurnal photothermal irradiation synergistically promotes bone regeneration

Recapitulating the natural extracellular physical microenvironment has emerged as a promising method for tissue regeneration, as multiple physical interventions, including ultrasound, thermal and electrical therapy, have shown great potential. However, simultaneous coupling of multiple physical cues to highly bio-mimick natural characteristics for improved tissue regeneration still remains formidable. Coupling of intrinsic electrical and mechanical cues has been regarded as an effective way to modulate tissue repair. Nevertheless, precise and convenient manipulation on coupling of mechano-electrical signals within extracellular environment to facilitate tissue regeneration remains challengeable. Herein, a photothermal-sensitive piezoelectric membrane was designed for simultaneous integration of electrical and mechanical signals in response to NIR irradiation. The high-performance mechano-electrical coupling under NIR exposure synergistically triggered the promotion of osteogenic differentiation of stem cells and enhances bone defect regeneration by increasing cellular mechanical sensing, attachment, spreading and cytoskeleton remodeling. This study highlights the coupling of mechanical signals and electrical cues for modulation of osteogenesis, and sheds light on alternative bone tissue engineering therapies with multiple integrated physical cues for tissue repair.Graphical

Growth Hormone Receptor Antagonist Markedly Improves Gemcitabine Response in a Mouse Xenograft Model of Human Pancreatic Cancer.

Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.