Standard Treatment Regimen Research Articles

Cancers of Unknown Primary Origin: Real-World Clinical Outcomes and Genomic Analysis at the European Institute of Oncology.

Cancer of unknown primary origin (CUP) poses a significant challenge due to poor clinical outcomes and limited treatment options. As such, further definition of clinicopathological factors and genomic profile to better adapt treatment strategies is required. Medical records were interrogated to retrospectively include CUP with available clinical and genomics data at the European Institute of Oncology. Next-generation sequencing (NGS) included targeted panels. Statistical analyses were conducted with R Software 4.2.2. A total of 44 patients were included. With a median follow-up of 39.46 months (interquartile range [IQR] 35.98-47.41 months), median PFS (mPFS) to first-line regimen was 3.98 months (95% CI 3.22-5.98), with a clinical benefit rate of 26% (95% CI 14%-49%), and disease control rate (DCR) limited to 48.28%. Most patients (26 of 31, 83.87%) received platinum-doublet chemotherapy, with no statistically significant difference between first-line treatment regimens. Median OS (mOS) was 18.8 months (95% CI 12.3-39.9), with a 12-month OS rate of 66% (95% CI 50%-85%). All patients received comprehensive genomic profiling (CGP). For 11 patients, NGS was unsuccessful due to low sample quantity and/or quality. For the remaining, TP53 (n = 16, 48%) and KRAS (n = 10, 30%) represented the most altered (alt) genes. No microsatellite instability was observed (0 of 28), while 6 of 28 (21.43%) tumors carried high TMB (≥10 mutation per megabase). Eight of 33 tumors (24.2%) displayed at least one actionable alteration with potential clinical benefit according to ESCAT. Only 2 of them received targeted therapy matched to genomic alterations, with a combined mPFS of 2.63 months (95% CI 1.84-not evaluable) as third-line regimens. Six patients received anti-PD1/PD-L1 therapy, showing a meaningful mPFS of 13 months (95% CI 2.04-not evaluable). CUP exhibits poor prognosis with limited benefits from standard treatment regimens. A significant proportion of CUPs carry actionable alterations, underscoring the importance of genomic profiling to gather additional treatment opportunities. In addition, immunotherapy might represent a valuable treatment option for a subset of CUP. Finally, accurate definition of sequencing methods and platforms is crucial to overcome NGS failures.

Abstract 2907: Therapeutic targeting miR-146a and miR-21 induce malignant cell death and regulate CD8+ T-cell function in mycosis fungoides with large-cell transformation

Abstract Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20-50% of advanced MF and is associated with an aggressive clinical course and poor survival not to overcome by any standard treatment regimen. We have previously identified a distinct miRNA expression profile in LCT-MF from that of non-transformed MF with significant upregulation of miR-21 and miR-146a. Our analyses demonstrated the involvement of genes for immune checkpoint pathways such as ICOS-ICOSL and PD1-PDL1 signaling (Di Raimondo C et al. Cancers 2021). Here, we aimed to investigate the efficacy of antagomiR-146a and -21 (amiR-146a, and -21) on the tumor growth and CD8+ tumor infiltrating lymphocyte exhaustion in LCT-MF. The amiR-146a, and -21 were synthesized in our DNA/RNA Synthesis Core by linking CpG-D19. In vitro, CTCL cell lines (Myla and HH) were treated with amiR-146a and -21, the cell viability was assessed by the 2,5-diphenyl-2H-tetrazolium bromide assay and cell apoptosis was evaluated using apoptosis assay. We found that amiR-146a, and -21 synergistically inhibited the proliferation of MyLa and HH cells due to the activation of apoptosis through Caspase3/7 pathways and inducing cell cycle arrest by blocking STAT3/CDK1/Cyclin B1 pathway. Our RNA-seq data indicated that the exhausted CD8+ T cells express elevated amounts of STAT3, IRF4, and BATF in LCT-MF compared with non-LCT MF. To evaluate the functional importance of amiR-146a, and -21 on CD8+ T cell exhaustion, we induced an exhausted state of CD8+ T cells with high level of immune checkpoints and dysfunctional cytokine production by continues anti-CD3/DC28 beads and culture supernatant (MyLa or HH cell) exposure. Our data revealed that amiR-146a and -21 attenuated the CD8+ T cell exhaustion by blockade of immune checkpoints and STAT3/IRF4/BATF pathway to trigger the cytotoxic immune response. Collectively, the findings of our study suggest that targeting miR-146a and -21 is a promising and novel therapeutic strategy for LCT-MF. Citation Format: Zhen Han, Piotr Swiderski, Xiwei Wu, Yate-Ching Yuan, Jun Wu, Chingyu Su, Hanjun Qin, Steven Rosen, Christiane Querfeld. Therapeutic targeting miR-146a and miR-21 induce malignant cell death and regulate CD8+ T-cell function in mycosis fungoides with large-cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2907.

Abstract 6172: Accurate PD-L1 IHC assessment in urothelial carcinoma by an AI algorithm robust across multiple sites, antibody clones, and scanners

Abstract Background: Immunotherapy against PD-L1 is used for treatment of several indications of Urothelial Carcinoma (UC). Recent results indicate that it is likely to become part of the standard first-line treatment regimen for advanced UC in the near future. Accurate readout of Immunohistochemical (IHC) PD-L1 expression is therefore essential to inform UC treatment decisions. However, manual PD-L1-scoring is prone to high inter- and intra-observer variability. Artificial intelligence (AI) may help to improve standardization, accuracy and efficiency of PD-L1 IHC scoring. Yet, previous AI-based approaches struggled to show consistency across images that are diverse with regards to the source institutions, antibody clones, and scanning hardware used. Methods: We developed an AI software for PD-L1 tumor proportion scoring (TPS/TC) on whole-slide images (WSIs) of UC without human supervision. PD-L1 analysis by the software is fully-automated, does not require any adaptation steps, and is concordant with current clinical guidelines. The performance of the software was evaluated on two cohorts of PD-L1 stained UC samples against ground-truth (GT) TPS/TC scores given by human pathologists in clinical routine. The first cohort (n = 53) consisted of samples stained with the 22C3 antibody clone (Agilent) derived from four institutions and three scanner models. It contained both tissue microarray samples and scans of UC resectates. A second validation cohort consisted of n = 83 WSIs stained with the SP263 clone (Ventana), collected from two institutions. Results: For the threshold of TPS≥1% (cut-off established for adjuvant therapy with Nivolumab), agreement rates of AI scores with human GT scores were 92.5% for cohort 1 (22C3) and 96.4% for cohort 2 (SP263). Sensitivity/specificity values were 92.3%/92.9% for cohort 1 and 100%/93.6% for cohort 2. Across both cohorts (n = 136) the agreement rate between AI and human was 94.9%. Conclusions: Across 136 UC samples stained with two PD-L1 antibody clones, and derived from a total of four institutions and three scanner models, the fully automatic AI system showed excellent agreement with human pathologist scores. These results on challenging validation data show the potential of AI applications to standardize and optimize PD-L1 scoring and demonstrate consistency and safety of suitable AI-based systems for application in clinical routine. Citation Format: Niklas Abele, Diego Calvopiña, David Mulder, Patrick Frey, Emre Karakok, Fadime G. Salman, Murat Oktay, Markus Eckstein, Sebastian Springenberg, Arndt Hartmann, Tobias Lang. Accurate PD-L1 IHC assessment in urothelial carcinoma by an AI algorithm robust across multiple sites, antibody clones, and scanners [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6172.

Abstract 145: Unraveling SMARCB1 depletion in hiPSC-derived neural crest cells: Implications for ATRT cell of origin

Abstract Atypical teratoid rhabdoid tumors (ATRTs) are highly aggressive pediatric brain cancers that lack standardized treatment regimens and are associated with poor prognoses. Despite being driven by biallelic inactivation of a single gene, SMARCB1, ATRTs exhibit three epigenetic subgroups (SHH, TYR, and MYC), each with different clinical outcomes. Like many pediatric brain tumors, ATRTs share the fundamental underlying mechanism of stalled differentiation, suggesting that it may arise from neural progenitor cells that fail to terminally differentiate. However, unlike other brain tumors, ATRTs share molecular similarities with malignancies found outside of the CNS, especially in the kidney and soft tissues. This unique feature implies a putative cell of origin that is not restricted to the CNS: neural crest cells, a transient embryonic cell population that emerges from the neuroectoderm but then migrates throughout the embryo during development. To study SMARCB1 loss in a genetically defined neural progenitor cellular context with isogenic controls, the Furnari lab engineered a doxycycline inducible SMARCB1 knockdown system into human induced pluripotent stem cells (hiPSCs). After simultaneous SMARCB1 knockdown with directed neural differentiation, the resulting SMARCB1-depleted neural progenitor cells exhibited transcriptomic profiles that were similar to ATRTs, particularly to the SHH subgroup. Building upon these findings, the engineered hiPSCs were differentiated into neural crest cells using a modified version of a published protocol. Via RT-qPCR, these hiPSC-derived neural crest cells were confirmed to express typical neural crest marker genes and lose expression of SMARCB1 in the presence of doxycycline. Remarkably, ATP assays demonstrated that neural crest cells that were differentiated without SMARCB1 acquired enhanced proliferation in comparison to those differentiated with SMARCB1 intact. Further work aims to tease apart this proliferative phenotype in the neural crest cellular context via RNAseq, evaluate the impact of cell identity upon subgroup status, and to determine whether SMARCB1 depletion post-differentiation also enhances proliferation. Together, these findings feature the utility of hiPSC-derived models for investigating mechanisms underlying ATRTs to hopefully identify novel subgroup-specific targets. Citation Format: Clark Wang, Frank Furnari. Unraveling SMARCB1 depletion in hiPSC-derived neural crest cells: Implications for ATRT cell of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 145.

Abstract 6549: Mechanistic models of tumor and patient heterogeneity explain and predict clinical outcomes of large B-cell lymphoma (LBCL) treatment

Abstract Introduction: Heterogeneity between patients and within tumors poses challenges to effective cancer treatment. Drug combinations can overcome heterogeneity by increasing the probability that a patient will have response to one or more drugs. This approach is successful in numerous disease settings, but technological advances have led to new approach to addressing heterogeneity: precision approaches to stratify patients into subpopulations with more uniform, stronger responses to specific drugs. These strategies can be implemented together to improve patient outcomes. We have developed computational mechanistic models of cancer treatment in the context of both sources of heterogeneity which explain and predict clinical outcomes of treatment of LBCL with combination therapy and CAR T-cell therapy. Combination therapy: Our novel population tumor kinetics (pop-TK) model simulates clinical combination therapy outcomes by implementing multidrug dose response functions in heterogeneous populations of tumor cells, within heterogeneous cohorts of patients. Informed by the outcomes of novel drugs in phase 2 trials in relapsed/refractory (r/r) patients, the pop-TK model accurately predicted of outcomes of seven first-line phase 3 trials of novel combinations. Most notably, informed by treatment of r/r LBCL with polatuzumab-vedotin (pola), the pop-TK predicted the success of modifying the standard treatment regimen (RCHOP) with pola before the clinical trial results were published. The pola combination improves overall survival (OS) and PFS in Activated B-Cell (ABC) LBCL (hazard ratio (HR): OS 0.3, PFS 0.4), but reduces OS (HR: 1.6) and does not improve PFS (HR: 1.0) in Germinal Center B-Cell (GCB) LBCL. The subtype specific difference in PFS was also predictable based on subtype results of r/r trials (predicted HR: ABC 0.3, GCB 0.9). CAR T-cell therapy: We used a population pharmacokinetic/pharmacodynamic (pop-PK/PD) model of CAR T-cell therapy to reproduce the PFS distribution and the distribution CAR T-cell abundance for CAR T therapy in r/r LBCL patients. The impact of tumor size on patient outcome in our model and in clinical studies led us to computationally explore the impact treating smaller tumors with CAR T-cell therapy on treatment outcomes. We found that using detectable circulating tumor DNA (ctDNA) as a biomarker for administering CAR T-cell therapy immediately after RCHOP increased the proportion of simulated patients without a second disease progression event by 30% (HR: 0.43 [0.34, 0.55]). Conclusions: The pop-TK model supports LBCL subtype biomarker for pola performance, and the pop-PK/PD model demonstrates that detectable ctDNA is a potential biomarker for early CAR T-cell administration. These examples of model-driven precision trial design have the potential to improve outcomes using readily-available biomarkers and existing therapies. Citation Format: Amy E. Pomeroy, Adam C. Palmer. Mechanistic models of tumor and patient heterogeneity explain and predict clinical outcomes of large B-cell lymphoma (LBCL) treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6549.

Treatment Strategies for Glioblastoma in the Elderly: What Should We Focus on Compared to Younger Patients.

(1) Background: Although the incidence of glioblastoma (GB) has a peak in patients aged 75-84 years, no standard treatment regimen for elderly patients has been established so far. The goal of this study was to analyze the outcome of GB patients ≥ 65 years to detect predictors with relevant impacts on overall survival (OS) and progression-free survival (PFS). (2) Methods: Medical records referred to our institution from 2006 to 2020 were analyzed. Adult GB patients with clinical data, postoperative MRI data, and ≥1 follow-up investigation after surgical resection were included. The complete cohort was divided into a younger (<65) and an elderly group (≥65 years). Multiple factors regarding OS and PFS were scanned using univariate and multivariable regression with p < 0.05. (3) Results: 1004 patients were included with 322 (61.0%) male individuals in the younger and 267 (56.1%) males in the older cohort. The most common tumor localization was frontal in both groups. Gross total resection (GTR) was the most common surgical procedure in both groups, followed by subtotal resection (STR) (145; 27.5%) in the younger group, and biopsy (156; 32.8%) in the elderly group. Multivariate analyses detected that in the younger cohort, MGMT promoter methylation and GTR were predictors for a longer OS, while MGMT methylation, GTR, and hypofractionated radiation were significantly associated with a longer OS in the elderly group. (4) Conclusions: Elderly patients benefit from surgical resection of GB when they show MGMT promoter methylation, undergo GTR, and receive hypofractionated radiation. Furthermore, MGMT methylation seems to be associated with a longer PFS in elderly patients. Further investigations are required to confirm these findings, especially within prospective radiation therapy studies and molecular examinations.

Modeling hypoxia-induced radiation resistance and the impact of radiation sources

Hypoxia contributes significantly to resistance in radiotherapy. Our research rigorously examines the influence of microvascular morphology on radiotherapy outcome, specifically focusing on how microvasculature shapes hypoxia within the microenvironment and affects resistance to a standard treatment regimen (30×2GyRBE). Our computational modeling extends to the effects of different radiation sources. For photons and protons, our analysis establishes a clear correlation between hypoxic volume distribution and treatment effectiveness, with vascular density and regularity playing a crucial role in treatment success. On the contrary, carbon ions exhibit distinct effectiveness, even in areas of intense hypoxia and poor vascularization. This finding points to the potential of carbon-based hadron therapy in overcoming hypoxia-induced resistance to RT. Considering that the spatial scale analyzed in this study is closely aligned with that of imaging data voxels, we also address the implications of these findings in a clinical context envisioning the possibility of detecting subvoxel hypoxia.

Impact of Resistance on Therapeutic Design: A Moran Model of Cancer Growth

Resistance of cancers to treatments, such as chemotherapy, largely arise due to cell mutations. These mutations allow cells to resist apoptosis and inevitably lead to recurrence and often progression to more aggressive cancer forms. Sustained-low dose therapies are being considered as an alternative over maximum tolerated dose treatments, whereby a smaller drug dosage is given over a longer period of time. However, understanding the impact that the presence of treatment-resistant clones may have on these new treatment modalities is crucial to validating them as a therapeutic avenue. In this study, a Moran process is used to capture stochastic mutations arising in cancer cells, inferring treatment resistance. The model is used to predict the probability of cancer recurrence given varying treatment modalities. The simulations predict that sustained-low dose therapies would be virtually ineffective for a cancer with a non-negligible probability of developing a sub-clone with resistance tendencies. Furthermore, calibrating the model to in vivo measurements for breast cancer treatment with Herceptin, the model suggests that standard treatment regimens are ineffective in this mouse model. Using a simple Moran model, it is possible to explore the likelihood of treatment success given a non-negligible probability of treatment resistant mutations and suggest more robust therapeutic schedules.

Bigger problems from smaller colonies: emergence of antibiotic-tolerant small colony variants of Mycobacterium avium complex in MAC-pulmonary disease patients.

Mycobacterium avium complex (MAC) is a group of slow-growing mycobacteria that includes Mycobacterium avium and Mycobacterium intracellulare. MAC pulmonary disease (MAC-PD) poses a threat to immunocompromised individuals and those with structural pulmonary diseases worldwide. The standard treatment regimen for MAC-PD includes a macrolide in combination with rifampicin and ethambutol. However, the treatment failure and disease recurrence rates after successful treatment remain high. In the present study, we investigated the unique characteristics of small colony variants (SCVs) isolated from patients with MAC-PD. Furthermore, revertant (RVT) phenotype, emerged from the SCVs after prolonged incubation on 7H10 agar. We observed that SCVs exhibited slower growth rates than wild-type (WT) strains but had higher minimum inhibitory concentrations (MICs) against multiple antibiotics. However, some antibiotics showed low MICs for the WT, SCVs, and RVT phenotypes. Additionally, the genotypes were identical among SCVs, WT, and RVT. Based on the MIC data, we conducted time-kill kinetic experiments using various antibiotic combinations. The response to antibiotics varied among the phenotypes, with RVT being the most susceptible, WT showing intermediate susceptibility, and SCVs displaying the lowest susceptibility. In conclusion, the emergence of the SCVs phenotype represents a survival strategy adopted by MAC to adapt to hostile environments and persist during infection within the host. Additionally, combining the current drugs in the treatment regimen with additional drugs that promote the conversion of SCVs to RVT may offer a promising strategy to improve the clinical outcomes of patients with refractory MAC-PD.

Metastatic melanoma to small bowel: metastasectomy is supported in the era of immunotherapy and checkpoint inhibitors

BackgroundMetastatic melanoma to the small bowel is an aggressive disease often accompanied by obstruction, abdominal pain, and gastrointestinal bleeding. With advancements in melanoma treatment, the role for metastasectomy continues to evolve. Inclusion of novel immunotherapeutic agents, such as checkpoint inhibitors, into standard treatment regimens presents potential survival benefits for patients receiving metastasectomy.Case PresentationWe report an institutional experience of 15 patients (12 male, 3 female) between 2014-2022 that underwent small bowel metastasectomy for metastatic melanoma and received perioperative systemic treatment. Median age of patients was 64 years (range: 35-83 years). No patients died within 30 days of their surgery, and the median hospital length of stay was 5 days. Median overall survival in these patients was 30.1 months (range: 2-115 months). Five patients died from disease (67 days, 252 days, 426 days, 572 days, 692 days postoperatively), one patient died of non-disease related causes (1312 days postoperatively), six patients are alive with disease, and three remain disease free.ConclusionsThis case series presents an updated perspective of the utility of metastasectomy for small bowel metastasis in the age of novel immunotherapeutic agents as standard systemic treatment. Small bowel metastasectomy for advanced melanoma performed in conjunction with perioperative systemic therapy is safe and appears to promote long-term survival and enhanced quality of life.

Efficacy and Safety of Combination Treatment of Oral Terbinafine and Itraconazole in Patients with Extensive Superficial Dermatophytes

Background: Dermatophytosis, a prevalent fungal infection, is instigated by species like Trichophyton, Epidermophytonand Microsporum. The current approach for treating dermatophytosis involves a blend of systemic and topical antifungal therapies, applicable to all patients except those with localized, untreated Tinea. Notably, there is a growing incidence of inadequate response to the standard treatment regimen in recent times. Objective: To evaluate the efficacy andsafety of combination treatment of oralterbinafine anditraconazole in patients with extensive superficial dermatophytes. Materials and Methods: This research comprised a randomized clinical trial involving 50 individuals diagnosed with extensive superficial dermatophytosis. Study conducted at the Department of Dermatology and Venereology, Combined Military HospitalCumilla, the study spanned from July 2022 to June 2023. During the six-week duration, patients underwent treatment with terbinafine and itraconazole, with follow-up examinations every two weeks, including relevant investigations. Evaluation of treatment outcomes occurred at both four and six weeks. Statistical analysis was performed using version 25 of the Statistical Package for the Social Sciences (SPSS). Results: This study shows the majority of the participants within the age range of 16-30 years (56.0%) and the average age of the participants is 31.74±11.77 years. In terms of gender, the majority are male (78.0%). The most prevalent diagnosis is Tinea corporis (68.0%), followed by Tinea cruris (36.0%), Tinea faciei (28.0%), and Tinea incognito (12.0%). The majority of participants (85.0%) have had the disease for 12 months or less. The most common sites are the trunk (35.0%), whole body (26.0%), and crural area (24.0%). The majority of participants experience severe itching (56.0%), followed by moderate itching (34.0%), and a smaller percentage report mild itching (10.0%). The majority of participants showed improvement, with percentages increasing from 66.0% after 2 weeks to 84.0% after 4 weeks.The percentage of cured individuals also increased over time, reaching a substantial 90.0% after 6 weeks. Conclusion: The amalgamation of terbinafine and itraconazole demonstrates a superior clinical cure rate compared to use of single systemic antifungals. However, the observed clinical cure rate percentage is lower when juxtaposed with findings from previous studies. Notably, neither combination of systemic antifungals has exhibited efficacy against tinea infections previously treated with formulations containing topical steroids

A systematic efficacy analysis of tuberculosis treatment with BPaL-containing regimens using a multiscale modeling approach.

Tuberculosis (TB) is a life-threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. This harsh treatment process causes adherence issues for patients because of the long treatment times and a myriad of adverse effects. Therefore, the World Health Organization has focused goals of shortening standard treatment regimens for TB in their End TB Strategy efforts, which aim to reduce TB-related deaths by 95% by 2035. For this purpose, many novel and promising combination antibiotics are being explored that have recently been discovered, such as the bedaquiline, pretomanid, and linezolid (BPaL) regimen. As a result, testing the number of possible combinations with all possible novel regimens is beyond the limit of experimental resources. In this study, we present a unique framework that uses a primate granuloma modeling approach to screen many combination regimens that are currently under clinical and experimental exploration and assesses their efficacies to inform future studies. We tested well-studied regimens such as HRZE and BPaL to evaluate the validity and accuracy of our framework. We also simulated additional promising combination regimens that have not been sufficiently studied clinically or experimentally, and we provide a pipeline for regimen ranking based on their efficacies in granulomas. Furthermore, we showed a correlation between simulation rankings and new marmoset data rankings, providing evidence for the credibility of our framework. This framework can be adapted to any TB regimen and can rank any number of single or combination regimens.

Perioperative immunotherapy for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the main prevalent histological subtype and accounts for 85% of esophageal cancer cases worldwide. Traditional treatment for ESCC involves chemotherapy, radiotherapy, and surgery. However, the overall prognosis remains unfavorable. Recently, immune checkpoint blockade (ICB) therapy using anti-programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) antibodies have not only achieved remarkable benefits in the clinical management of ESCC but have also completely changed the treatment approach for this cancer. In just a few years, ICB therapy has rapidly advanced and been added to standard first-line treatment regimen in patients with ESCC. However, preoperative immunotherapy is yet to be approved. In this review, we summarize the ICB antibodies commonly used in clinical immunotherapy of ESCC, and discuss the advances of immunotherapy combined with chemotherapy and radiotherapy in the perioperative treatment of ESCC, aiming to provide reference for clinical management of ESCC patients across the whole course of treatment.

Exploring Esketamine's Therapeutic Outcomes as an FDA-Designated Breakthrough for Treatment-Resistant Depression and Major Depressive Disorder With Suicidal Intent: A Narrative Review.

The expansive spectrum of major depressive disorder (MDD) continues to pose challenges for psychiatrists to treat effectively. Oral antidepressant (OAD) medications that alter monoamine neurotransmitters,mainly selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), have been the mainstay of therapy for decades. Although these drugs have been largely beneficial, a considerable subset of patients do not respond adequately to multiple conventional therapies administered for an appropriate length of time, leading to a diagnosis of treatment-resistant depression (TRD). Ketamine, a non-monoaminergic drug, has long been known for its beneficial effects on TRD when given intravenously (IV). Between 2019 and 2020, an intranasal formulation of the S (+) enantiomer of racemic ketamine, esketamine (ESK), was granted "breakthrough designation" by the FDA and approved for the indicationsof TRD and MDD patients exhibiting acute suicidal intent. The objective of this narrative review was to review the academic literature and collect clinical evidence that may corroborate intranasal ESK's effectiveness for its approved indications while addressing its safety and tolerability profile, adverse effects, andimpact on cognition. An overview ofthe drug'sorigins,pharmacology, and standard treatment regimen are provided. Theoutcomes from double-blinded randomized control trials (DB-RCTs) of ESK are outlinedto demonstrate the efficacy and safety data leading to its FDA approval, along with its long-term post-market safety outcomes. Comparative trials between ESK and ketamine are then evaluated to highlight ESK's consideration as a more practical alternative toketamine in common clinical practice. The authors further discuss currently approved and developing therapies for TRD,propose future research directions, and identify the inherent limitations of the review and further research. To conduct the research required, three digital databases (PubMed, Medline, and ClinicalTrials.gov) were queried to search for key terms, includingketamine, esketamine, treatment-resistant depression, and biomarkers,using automation toolsalong with selective search engine results.After streamlining the results by title and abstract and removing duplicates, a total of 37 results were chosen, of which 18 are clinical trials. A reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score was the primary efficacy endpoint for most of these clinical trials. In conclusion, intranasal ESK, when used as an adjunct to market OADs, shows greater efficacy in treating TRD and MDD with suicidal intent compared to OADs and placebo alone and provides a more suitable alternative to IV ketamine. It is important to note that further research is required to fully understand the novel mechanism of action of ESK, as well as the establishment of a consensus definition of TRD, which may facilitate better detection and treatment protocols. More focused quantitative and qualitative ESK studies are needed, as well as those pertaining to its use in patients with co-existing mental illnesses.

(328) The Relationship Between Multiple Myeloma and Hypogonadism: A Systematic Review

Abstract Introduction Hypogonadism has been reported with substantial frequency in patients with various types of malignancies. Multiple myeloma (MM) is a cancer that affects plasma cells, a type of white blood cell responsible for producing antibodies. It is the second most common blood cancer, accounting for approximately 10% of hematologic malignancies. However, the prevalence, pathophysiology, and significance of hypogonadism as a sequela of MM or its standardized treatment regimens has not been extensively studied. Objective To characterize the existing literature on hypogonadism in patients with MM, including the prevalence, underlying mechanisms, and link to overall disease prognosis. Furthermore, we will examine the effects of testosterone therapy on MM and its hypogonadal symptomatology. Methods Relevant studies published up to November 2022 were retrieved through a search of PubMed using the keywords ‘hypogonadism’, ‘multiple myeloma’, and ‘testosterone’. Studies that reported on the presentation, management, or outcomes of patients with MM and how they were affected by a hypogonadal state were included. The search yielded 72 studies, of which 11 met the inclusion criteria. Results The most comprehensive assessment of the frequency of hypogonadism in a MM cohort found that 74% of 561 MM patients were classified as hypogonadal compared to 33% of patients in a control population. Further evaluation found that male patients with MM were found to have significantly lower levels of testosterone than control (p&amp;lt;0.0001). Another assessment of hormone level differences between MM patients and controls found that male patients had higher: FSH, LH, estrogen, and E/T ratios than healthy controls. Testosterone supplementation was found to lower interleukin-6 (IL-6) levels, which could potentially contribute to the adverse effects of MM. This effect could arise from the finding that IL-6 concentration was independently associated with severe symptomatology in MM patients on multivariate analysis in a study by Wang et al. (p=0.004). Hypogonadism can occur as an adverse effect of MM treatment with immunotherapy/chemotherapy initiation. A small study by Greenfield et al. found that 65% of patients intensively treated for MM were subsequently hypogonadal. This was further supported by a study by Anderson et al. examining sexual function after autologous hematopoietic stem cell transplant (AHSCT), which saw a significant increase in erectile dysfunction at 1-month follow-up from 68.4% to 100% of all patients. Conclusions There appears to be a relationship between MM and hypogonadism, potentially due to the inflammatory state caused by the disease itself. This may have some association with the inflammatory cytokine IL-6. However, there is a paucity of data fully exploring this relationship, the underlying mechanisms, and the effects of testosterone therapy on MM. The true relationship is likely multifactorial, given the mixture of studies that found hypogonadism in MM at baseline as well as after systemic treatment. Future prospective and randomized studies are necessary to elucidate the true link between MM and/or its treatment and hypogonadism. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Hims &amp; Hers Inc, Coloplast, Clarus Therapeutics, Antares Pharma, Acerus.

(081) Fertility Trends in Men with Prior History of Anabolic Steroid Use: Results from a Standardized Treatment Regimen

Abstract Introduction The management of infertility in men who have previously used anabolic steroids poses a complicated clinical challenge. Addressing the infertility issues in this specific population requires a comprehensive approach that considers the underlying physiological alterations caused by anabolic steroid use and tailors treatment interventions accordingly to restore and optimize reproductive function. In this study, we report an analysis of sperm parameter recovery and fertility outcomes in men who had azoospermia or severe oligospermia caused by anabolic steroid use and underwent a standardized treatment regimen for recovery of spermatogenesis. Objective The study aims to assess the longitudinal trends in sperm concentrations, determine the proportion of men achieving normozoospermia, and evaluate subsequent pregnancy rates in this specific population. Additionally, the study seeks to identify potential predictors for improved semen parameters and successful pregnancy outcomes. Methods A retrospective analysis of the period spanning from 2018 to 2022 was conducted on a cohort of men with a prior history of anabolic steroid use who complained of infertility. The standardized treatment approach involved the cessation of testosterone replacement therapy (TRT) and the administration of a combination regimen comprising clomiphene citrate and human chorionic gonadotropin (hCG) for a minimum of 3 to 6 months. Following adequate treatment, men were contacted in March 2023 to determine the most up-to-date pregnancy outcomes. Statistical analysis was performed utilizing SPSS, employing univariate logistic regression analysis to establish a predictive mathematical model. The level of statistical significance was defined as p &amp;lt; 0.05. Results A total of 45 men (median age 37 years, IQR 32-45) met inclusion criteria for this analysis. Median duration of prior T use was 4 years (IQR 1.3-10), with the two most common modalities consisting of injection therapy (43.5%) and oral therapy (34.8%). Median initial sperm concentration was 0 million/cc (IQR 0-1.15), and 23 (51.1%) men initially presented with azoospermia. The median duration of combination hCG/clomid therapy was 5 months (IQR 3-12). In initially azoospermic men (N:23), 5 were lost to follow-up, 6 (33.3%) progressed to severe oligospermia (&amp;lt;5 million/cc), 6 (33.3%) to oligospermia (&amp;lt;15 million/cc), 1 (5.6%) to normozoospermia (&amp;gt;15 million/cc), and 5 (27.8%) remained azoospermic following medical treatment for 6 months. Among the 24 couples who responded to the follow-up call, a total of 9 (37.5%) achieved a successful subsequent pregnancy. Of these, 33.3% (3 couples) used assisted reproductive technology (ART), while 66.7% (6 couples) conceived naturally. On logistic regression analysis, no significant predictors for improved sperm parameters or successful pregnancy were identified. Conclusions Despite the implementation of appropriate treatment regimens, a significant proportion of men with a prior history of anabolic steroid use continue to exhibit severe oligospermia, with more than half failing to demonstrate substantial improvement in their semen parameters even after undergoing a six-month medical treatment protocol. Moreover, only a fraction of men, estimated to be 1 in 6, achieve normozoospermia following medical treatment after anabolic steroid use. Future work should continue to explore predictors for improved sperm parameters on follow-up as well as subsequent successful pregnancy in men with prior history of anabolic steroid use. Disclosure No.

Epidemiology, Characteristics, and Prognostic Factors of Primary Atypical Teratoid/Rhabdoid Tumors in the Spinal Canal: A Systematic Review.

Primary atypical teratoid/rhabdoid tumors (AT/RTs) in the spinal canal are rare central nervous system (CNS) neoplasms that are challenging to diagnose and treat. To date, there has been no standard treatment regimen for these challenging malignant tumors. Thus, we conducted this research to explore potential prognostic factors and feasible treatment modalities for improving the prognosis of these tumors. Articles were retrieved from the PubMed, MEDLINE, and Embase databases, using the keywords "atypical teratoid/rhabdoid tumor," "rhabdoid tumor," "spine," "spinal," "spinal neoplasm", and "spinal cord neoplasm." All eligible cases demonstrated SMARCB1-deficient expression validated by pathological examination. We collected and analyzed data related to clinical presentation, radiological features, pathological characteristics, treatment modalities and prognosis via Kaplan-Meier and Cox regression analyses. Thirty-six articles comprising 58 spinal AT/RT patients were included in the study. The median progression-free survival (PFS) and overall survival (OS) were 18 and 22 months, respectively. Kaplan-Meier analysis demonstrated significant survival improvements for OS in the nonmetastasis, male, radiotherapy and intrathecal chemotherapy groups as well as for PFS in the chemotherapy and radiotherapy groups. Multivariate analysis revealed that chemotherapy and radiotherapy were prognostic factors for improved PFS, and that intrathecal chemotherapy reduced the risk of mortality. Spinal AT/RTs are uncommon malignant entities with a dismal survival rate. Although our review is limited by variability between cases, there is some evidence revealing potential risk factors and the importance of systematic chemotherapy, intrathecal chemotherapy and radiotherapy in spinal AT/RT treatment modalities.

Gram-Negative Toe Web Infections.

Gram-negative bacterial toe web infection (GNTWI) is a common dermatologic condition affecting the interdigital spaces. The clinical presentation ranges from mild erythema to exudative maceration of the web spaces that may extend to in other areas of the foot and lead to cellulitis in severe cases. Pseudomonas aeruginosa is the most commonly identified etiologic agent. Occlusive and humid environments, pre-existing dermatologic conditions, and fungal infections increase the risk of developing GNTWI. GNTWI has a broad differential diagnosis including erythrasma, tinea pedis, pitted keratolysis, eczematous dermatitis, and malignancies. Diagnosis is performed using bacterial and fungal cultures. There is a lack of a standardized treatment regimen for GNTWI. While GNTWI is fairly common, it may still be under-recognized by dermatologists due to the limited medical literature. This article presents a review of GNTWI, its clinical features, epidemiologic factors, etiologic agents, predisposing factors, diagnostic methods, and therapeutic options.

Radiographic Impact on the Clinical Decision Making of Achilles Tenotomy in Clubfoot: In Search of an Objective Cut-Off Value

Background: We tried to determine whether the indication of Achilles tenotomy (AT) in clubfoot patients based on clinical evaluation could be confirmed radiographically, and to find an objective radiographic cut-off value for its indication. Methods: Eighty-six clubfeet from 60 patients, (26 bilateral and 34 unilateral) were included. A standard Ponseti treatment regimen was applied. Group 1 comprised patients who underwent AT immediately after serial plaster casting (26 feet). Group 2 comprised patients who underwent AT during the follow-up period (48 feet). Group 3 comprised patients who were assumed to have a corrected foot and did not undergo AT (12 feet). Group 4 comprised the healthy sides of the unilateral cases (34 feet). Results: Both Group 1 and Group 2 showed significant improvement after tenotomy (p = 0.002). In order to differentiate between the normal and AT groups according to the pre-tenotomy angle, we obtained an optimal cut-off value of &gt;85° according to the Youden index, a sensitivity of 96%, a specificity of 91.2%, a positive predictive value of 95.9%, a negative predictive value of 91.2%, and an accuracy rate of 94.4% (AUC: 0.983; p &lt; 0.001). Conclusions: Feet with a lateral tibio-calcaneal angle &gt; 85° can be considered pathologic and accepted as candidates for AT.

The prognostic and predictive role of class III β-Tubulin and hENT1 expression in patients with advanced pancreatic ductal adenocarcinoma

BackgroundFOLFIRINOX and gemcitabine-nabpaclitaxel (GnP) are standard first-line treatment regimens for advanced pancreatic ductal adenocarcinoma (PDAC). However, currently, there is a lack of predictive biomarkers to aid in the treatment selection. We aimed to explore the prognostic and predictive value of class III β-Tubulin (TUBB3) and human equilibrative nucleoside transporter 1 (hENT1) expression, which have previously been shown to be associated with taxane and gemcitabine resistance in advanced PDAC. MethodsWe conducted a retrospective analysis of 106 patients with advanced PDAC treated with GnP and/or FOLFIRINOX at our institution. TUBB3 and hENT1 immunohistochemical staining was performed on tumor specimens and subsequently evaluated based on the intensity and percentage of expression. ResultsIn patients who received the GnP regimen, a high combined score (TUBB3low/hENT1high) was associated with a higher DCR and longer PFS compared to those with intermediate (TUBB3high/hENT1high or TUBB3low/hENT1low) and low score (TUBB3high/hENT1low). In the multivariate analysis, a high combined score was an independent predictor of higher DCR (OR:11.96; 95 % CI:2.61–54.82; p = 0.001) and longer PFS (HR:0.33; 95%CI:0.18–0.60; p < 0.001). However, there was no difference in response rates or PFS based on TUBB3 and hENT1 expression among patients receiving the FOLFIRINOX regimen. ConclusionOur findings indicate that tumor TUBB3 and hENT1 expression may predict the efficacy of the GnP regimen, and low TUBB3 and high hENT1 expression (TUBB3low/hENT1high) are associated with a higher DCR and longer PFS in patients treated with GnP. Evaluating TUBB3 and hENT1 jointly can identify the patients most (as well as least) likely to benefit from GnP chemotherapy.