Clinical Response Patterns Research Articles

Clinicopathological features, response patterns, outcomes and BRAF status in patients with advanced acral melanoma: a preliminary Peruvian study.

Globally, acral melanoma (AM) is underrepresented in most clinical trials, being predominant in Caucasian populations. Latin America is a niche that needs to be explored. Therefore, this study aimed to determine the clinical features, response patterns, outcomes and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) status in Peruvian patients with advanced AM. We retrospectively reviewed the medical records of 19 patients with advanced AM who received immunotherapy (IO) in first- or subsequent-line therapy. The samples were analysed, and their mutational state was performed by deoxyribonucleic acid sequencing, focusing primarily on the most frequently mutated gene, BRAF. Descriptive statistics were used to assess the baseline characteristics. Overall survival was estimated using the Kaplan-Meier method. The median age was 64 years and 63.2% were men. Plantar was the site most frequently affected (84.2%). The most frequent stage was stage III (68.4%), with 26.4% receiving adjuvant therapy. The majority of cases exhibited a Breslow thickness of >4 mm (52%), a Clark level of IV/V (89.4%), and all patients presented ulceration and a high range of mitosis. During follow-up, all patients experienced recurrent advanced disease, with 52.6% developing visceral metastasis. Patients who received IO as first or subsequent line had an overall response rate (ORR) of 33.3%, and those who received it as first-line therapy had an ORR of 40%. Twenty-one percent of the patients harbored BRAF V6000E mutation and, showing an ORR of 50% compared to wild-type individuals (44.4%) after the first line of treatment. Our preliminary study reported that AM has poor clinico-pathological features and response rates to IO in Peruvian patients. However, those who received IO as a first-line treatment or harbored the BRAF mutation appeared to have a slightly better response than wild-type patients.

Introducing Neoadjuvant Immunotherapy for Colorectal Cancer: Advancing the Frontier.

To give surgeons a review of the current and future use of neoadjuvant immunotherapy in patients with localized colorectal cancer. Immunotherapy has revolutionized the standard of care in oncology and improved survival outcomes in several cancers. However, the applicability of immunotherapy is still an ongoing challenge. Some cancer types are less responsive to immunotherapy, and the heterogeneity in responses within cancer types is poorly understood. Clinical characteristics of the patient, the timing of immunotherapy in relation to surgery, diversities in the immune responses, clonal heterogeneity, different features of the tumor microenvironment, and genetic alterations are some factors among many that may influence the efficacy of immunotherapy. In this narrative review, we describe the major types of immunotherapy used to treat localized colorectal cancer. Furthermore, we discuss the prediction of response to immunotherapy in relation to biomarkers and radiological assessment. Finally, we consider the future perspectives of clinical implications and response patterns, as well as the potential and challenges of neoadjuvant immunotherapy in localized colorectal cancer. Establishing mismatch repair status at the time of diagnosis is central to the potential use of neoadjuvant immunotherapy, in particular immune checkpoint inhibitors, in localized colorectal cancer. To date, efficacy is primarily seen in patients with deficient mismatch repair status and POLE mutations, although a small group of patients with proficient mismatch repair does respond. In conclusion, neoadjuvant immunotherapy shows promising complete response rates, which may open a future avenue of an organ-sparing watch-and-wait approach for a group of patients.

Revisiting glioblastoma classification through an immunological lens: A narrative review

Glioblastoma (GBM) is characterized by a high recurrence rate, significant heterogeneity, and poor prognosis. While there has been a shift in recent years to focus on molecular phenotyping, there are limited data regarding the relationship between the immune milieu and heterogeneous molecular signatures in GBM. Given the success of immunotherapies in other cancers such as non-small-cell lung cancer and melanoma, there has been a concerted effort to correlate the immune compartment of the GBM tumor microenvironment to clinical outcomes. The aim of this narrative review is to establish the role of immunophenotyping in GBM classification. Major immune cell groups in GBM involve myeloid cells (e.g. myeloid-derived suppressor cells, tumor-associated macrophages and microglia, neutrophils, and dendritic cells), lymphocytes (e.g., T, natural killer, and B-cells), and stromal cells (e.g., fibroblasts, pericytes, and endothelial cells). Understanding the relationships between these different immune cell populations and correlating their roles with the current molecular classification scheme as described in the 2021 World Health Organization criteria may further elucidate patterns of clinical response, especially in light of recent advances in new immunotherapies.

Abstract 4136: Tracking metastatic dissemination and tumor growth using longitudinal imaging and ctDNA

Abstract Metastatic lung cancer is a heterogeneous disease, characterized by different patterns of clinical progression and therapy response. The scale of this heterogeneity on a lesion specific level has yet to be quantified but is of clinical importance because it may provide an indication of molecular mechanisms underpinning metastasis growth. Currently, whether metastasis growth patterns can be predicted by the primary tumor or governed by metastasis specific characteristics is not known. Furthermore, circulating tumor DNA (ctDNA) has proven useful to predict disease relapse, but how closely it reflects metastatic growth post relapse is unclear. In 104 patients enrolled in the TRACERx study with disease relapse post-surgical resection of the primary tumor, lesion volumetric dynamics were tracked in 460 metastases. Total volume growth rate (TVGR) was calculated using CT imaging performed between disease relapse and death. All patients had whole exome sequencing (WES) of the primary tumor. For 19 patients enrolled in the PEACE autopsy study WES and RNAseq from 60 metastases visible on imaging prior to death and subsequently sampled at autopsy were analyses. In 29 patients, ctDNA was used to track 200 tumor-specific mutations to assess tumor burden and detect metastatic subclones. High TVGR correlated with poor survival (hazard ratio for death 1st vs 2nd tertile was 0.21, p<0.001; 2nd vs 3rd tertile was 0.51, p=0.04). Primary tumor subclonal whole genome doubling was predictive of high TVGR. There was considerable heterogeneity in the growth rate of metastases within patients. The anatomical location of metastases contributed to this, extrathoracic soft tissue and pleura had the highest growth rates, whilst lymph node and adrenal the lowest (p<0.001). Molecular attributes differed between metastases, with fast growing metastases being enriched for proliferation pathway gene expression. It was observed that the most prevalent population of cells, or clone, in the fastest growing metastasis within a patient was exclusive to that metastasis, suggesting that genomic features that characterize the clone might support rapid growth. ctDNA tracked with tumor burden post relapse and patients with extrathoracic relapse had higher levels of ctDNA. In 9 patients, metastasis specific mutations identified at autopsy and in ctDNA, were used to determine the proportion of ctDNA shed by different metastatic sites. ctDNA subclonal fraction was found to track with changes in lesion volumes during disease progression. This work highlights significant heterogeneity in metastatic growth rates which can potentially be attributed to the presence of distinct genomic features which may dictate tumor growth rate. ctDNA accurately reproduces patterns of radiological disease progression and when combined with longitudinal imaging and tumor DNA sequencing, can accurately reconstruct the natural history of cancer evolution. Citation Format: Wing Kin Liu, Boyue Ding, Hessey Sonya, Carlos Martinez-Ruiz, Cristina Naceur-Lombardelli, Corentin Richard, Hyothaek Lee, Catarina Veiga, Kishen Patel, Ariana Huebner, Allan Hackshaw, Christopher Abbosh, Alexander M. Frankell, Gary Royle, Charles Swanton, Mariam Jamal-Hanjani. Tracking metastatic dissemination and tumor growth using longitudinal imaging and ctDNA [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 4136.

67 Patterns of clinical response in patients with alopecia areata (AA) treated with ritlecitinib in the ALLEGRO phase 2b/3 and ongoing, phase 3, ALLEGRO-LT studies

67 Patterns of clinical response in patients with alopecia areata (AA) treated with ritlecitinib in the ALLEGRO phase 2b/3 and ongoing, phase 3, ALLEGRO-LT studies

Efficacy of Immune Checkpoint Inhibition and Cytotoxic Chemotherapy in Mismatch Repair-Deficient and Microsatellite Instability-High Pancreatic Cancer: Mayo Clinic Experience.

Pancreatic cancer (PC) carries a poor prognosis with high rates of unresectable/metastatic disease at diagnosis, recurrence after resection, and few systemic therapy options. Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) PCs demonstrated uncharacteristically poor outcomes in KEYNOTE-158, evaluating pembrolizumab in MSI-H solid tumors. Our study aggregates the Mayo Clinic experience with dMMR/MSI-H PCs, characterizing the clinical, molecular, and treatment response patterns with a focus on response to immune checkpoint inhibitors (ICIs). Retrospective data were collected from the electronic medical record from December 2009 to February 2023. Patients were included if they had a pathologically confirmed pancreatic malignancy and had (1) deficient expression of mismatch repair (MMR) proteins by tumor immunohistochemistry, (2) pathogenic mutation of MMR genes on genomic sequencing, and/or (3) MSI-H by polymerase chain reaction. Thirty-two patients were identified for inclusion, with all stages of disease represented. Sixteen of these patients underwent surgery or chemoradiotherapy. Of these patients, uncharacteristically favorable responses were seen, with a recurrence rate of only 19% (n = 3) despite a median follow-up of 25 months. In the palliative setting, excellent responses to ICI were seen, with overall response rate (ORR) of 75% (20% complete response). Median time to disease progression was not reached. Response rates to cytotoxic chemotherapy in the palliative setting were poor, with 30% ORR and median time to progression of 4 months. We observed a high rate of discrepancy between MMR and MSI testing methods, representing 19% of the entire cohort and 26% of evaluable cases. Our data argue for the preferential use of ICI over cytotoxic chemotherapy in any patient with dMMR/MSI-H PC requiring systemic therapy, including in the metastatic and adjuvant/neoadjuvant settings.

Pattern of grade C molar-incisor pattern periodontitis in families.

The aim of this study was to determine the clinical and inflammatory response patterns for individual siblings diagnosed with grade C molar-incisor pattern periodontitis (C-MIP) and between the related siblings within families. Sixty-nine siblings within 28 families with moderate-to-severe C-MIP were included. Clinical parameters were evaluated for symmetry regarding the affected type of teeth, side and/or arch, and bone loss pattern. The protein concentrations from in vitro whole blood cultures for 14 different lipopolysaccharide-stimulated inflammatory markers were correlated with the extent and severity of disease, within an individual sibling and among siblings within a family. A similar disease pattern was observed among all siblings and within families. The most common teeth affected were first molars and incisors or first molars only within the permanent dentition and only molars within the primary dentition (p<0.001). Symmetry involving molars was higher than in incisors in siblings, regardless of arch or side affected (p=0.020). Arc-shape/vertical bone defects were the most common (p=0.006) and higher symmetry was found for these defects in the permanent dentition (p=0.005). Positive correlations were found between age, clinical attachment loss, and percent affected sites with several inflammatory markers. The inflammatory responses for several inflammatory markers were correlated within and among families (p<0.050). Specifically, the intraclass correlation coefficient within families was highest (>0.5) for interleukin (IL)-8, IL-6, and IL-10. Families with C-MIP presented similar patterns of disease. The level of an inflammatory response to bacteria seemed to play a role in the extent and severity of this disease, exemplified by the high degree of correlation in these families.

Primary nephrotic syndrome in children in Cape Town, South Africa

Background. Histopathological patterns of childhood primary nephrotic syndrome (PNS) and clinical response to steroids have beenassociated with certain race groups in parts of South Africa. However, there are no recent studies of childhood PNS in Cape Town.Objectives. To describe the demographics, histological subtypes and steroid response of patients with PNS who underwent kidney biopsiesat Red Cross War Memorial Children’s Hospital (RCWMCH) over a 10-year period.Methods. Details of patients with PNS who underwent kidney biopsies in the Paediatric Nephrology Department at RCWMCH between2006 and 2015 were retrospectively recorded.Results. A total of 103 patients were included in the study. Most patients were either of mixed race (42%) or black (36%), with a mean age of6.8 years and a male-to-female ratio of 1.19:1. The most identified histopathological subtype was mesangioproliferative glomerulonephritis(MesPGN; 60% (n/N=62/103)). Of the patients with focal segmental glomerulosclerosis (FSGS), MesPGN and minimal change disease(MCD) 45% (n/N=43/95) were steroid-resistant, and 54% (n/N=51/95) were steroid-sensitive. There was no significant associationbetween any race group and steroid response. Patients with FSGS were more likely to be black, while MCD was more common in mixed-race patients (p=0.04). There was no difference in the likelihood of being mixed race or black between patients with FSGS and MesPGN(p=0.472).Conclusion. MesPGN was the most common histopathological subtype found in our study. There was no significant association betweenrace and steroid response. Patients with FSGS were more likely to be black than mixed race when compared with MCD patients. Race wasnot otherwise significantly associated with any histopathological subtype

Multiparametric MRI radiomics fusion for predicting the response and shrinkage pattern to neoadjuvant chemotherapy in breast cancer.

During neoadjuvant chemotherapy (NACT), breast tumor morphological and vascular characteristics are usually changed. This study aimed to evaluate the tumor shrinkage pattern and response to NACT by preoperative multiparametric magnetic resonance imaging (MRI), including dynamic contrast-enhanced MRI (DCE-MRI), diffuse weighted imaging (DWI) and T2 weighted imaging (T2WI). In this retrospective analysis, female patients with unilateral unifocal primary breast cancer were included for predicting tumor pathologic/clinical response to NACT (n=216, development set, n=151 and validation set, n=65) and for discriminating the tumor concentric shrinkage (CS) pattern from the others (n=193; development set, n=135 and validation set, n=58). Radiomic features (n=102) of first-order statistical, morphological and textural features were calculated on tumors from the multiparametric MRI. Single- and multiparametric image-based features were assessed separately and were further combined to feed into a random forest-based predictive model. The predictive model was trained in the testing set and assessed on the testing dataset with an area under the curve (AUC). Molecular subtype information and radiomic features were fused to enhance the predictive performance. The DCE-MRI-based model showed higher performance (AUCs of 0.919, 0.830 and 0.825 for tumor pathologic response, clinical response and tumor shrinkage patterns, respectively) than either the T2WI or the ADC image-based model. An increased prediction performance was achieved by a model with multiparametric MRI radiomic feature fusion. All these results demonstrated that multiparametric MRI features and their information fusion could be of important clinical value for the preoperative prediction of treatment response and shrinkage pattern.

Image‐based response assessment during immunotherapy in skin cancer

Immune-checkpoint inhibitors and further immunotherapeutic treatment strategies have significantly extended therapy options for melanoma and other skin cancer entities over the last decade. In the context of a broader application of immunotherapeutic approaches, sufficient ways to monitor the course of the disease during therapy are required. Immunotherapies are based on different ways of modulating the immune system. This leads to complex clinical response patterns including pseudoprogression and others, requiring an adaptation of conventional diagnostic imaging tools or the introduction of novel technologies. In this review, current non-invasive imaging approaches for response assessment during immunotherapies in skin cancers as well as their limitations are discussed. To overcome present hurdles, promising alternatives to better address novel imaging features during immunotherapy are depicted giving an outlook on what can be expected in the future.

Deep brain stimulation effect in genetic dyskinetic cerebral palsy: The case of ADCY5- related disease.

Cerebral Palsy (CP) represents a frequent cause of disability in childhood. Early in life, genetic disorders may present with motor dysfunction and diagnosed as CP. Establishing the primary, genetic etiology allows more accurate prognosis, genetic counselling, and planning for symptomatic interventions in homogeneous etiological groups. Deep brain stimulation (DBS) is recommended in refractory movement disorders, including isolated pediatric dystonias. For dystonia evolving in more complex associations in genetic CP, the effect of DBS is still understudied and currently only sporadically described. To report the effect of DBS applied to the globus pallidus pars interna (GPi) in children with complex movement disorders caused by pathogenic ADCY5 variants, diagnosed as dyskinetic CP previous to genetic diagnostic. We conducted a retrospective study on evolution of treatment with DBS in ADCY5-related disease. A standardized proforma including the different type of movement disorders and associated neurological signs was completed at each follow-up time, based on video recordings, as well as functional assessments used in children with CP. Four children (mean of age, 13 ± 2.9 years) received GPi-DBS. The same de novo pathogenic missense variant (c.1252C > T, p.R418W) was identified in three out of four and a splice site variant (c.2088 + 2G > T) in one subject. Developmental delay and overlapping features including axial hypotonia, chorea, dystonic attacks, myoclonus, and cranial dyskinesia were present. The median age at DBS was 9 years and follow-up with DBS, 2.6 years. We identified a pattern of clinical response with early suppression of dystonic attacks, followed by improvement of myoclonus and facial dyskinesia. Effect on chorea was delayed and more limited. Two patients gained notable functional benefit related to sitting, standing, gait, use of upper limbs and speech. ADCY5-related disease may benefit from GPi-DBS. The most significant clinical response relates to the early and sustained benefit on dystonic attacks and a variable but still positive response on the other hyperkinetic features. Genetic etiology of CP will contribute to further elucidate genotype-phenotype correlations and to refine DBS indication as network-related symptomatic interventions.

Analysis of clinical features, treatment, and prognosis of primary Xlymphoepithelioma-like carcinoma of the lung.

Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare lung malignancy occurring most frequently in young non-smokers from Southeast Asia. Given its low incidence, PPLELC clinical features, treatment methods, and the factors affecting its prognosis remain elusive. To date, PPLELC data are mainly derived from clinical case reports, and no cohort studies are available. Therefore, we retrospectively analyzed a group of PPLELC cases and summarized the clinical features of patients, treatment responses, and the factors affecting patient prognosis. A total of 91 patients having primary pulmonary lymphoepithelioma-like carcinoma were recruited in this study. These included sex, age, place of birth, smoking history, pre-treatment symptoms, tumor location, tumor markers, maximum tumor diameter, treatment regimen, lymph node presence metastasis after an operation, pathological picture, immunohistochemistry, genetic findings, and tumor stage grading. We determined the overall survival (OS), progression-free survival (PFS), basic clinical characteristics, treatment option, treatment response, and recurrence pattern among the patients. In addition, we understood the influence of sex, age, tumor, nodes, and metastases (TNM) stage, tumor size, and surgery over patient prognosis. Primary pulmonary lymphoepithelioma-like carcinoma is more common among young non-smokers, with a slightly higher incidence in women than in men. The expression of Epstein-Barr virus-encoded small RNA (EBER), pancytokeratin (PCK), Cytokeratin 5/6 (CK5/6), and tumor protein 63 (P63) was positive in immunohistochemistry. Serum cytokeratin 19 fragment antigen (CYFRA21-1) and Epstein-Barr DNA (EB-DNA) could be used as markers to diagnose primary pulmonary lymphoepithelioma-like carcinoma. TNM stage and surgery were independent prognostic factors. Primary pulmonary lymphoepithelioma-like carcinoma is rare, showing a good prognosis.

Optimizing the tumor shrinkage threshold for evaluating immunotherapy efficacy for advanced non-small-cell lung cancer.

The rise of immune checkpoint inhibitors (ICIs) in recent years has coincided with unusual clinical response patterns. Modification of the sum of longest diameters (SLD)-based threshold that reflecting dynamic change of the tumor burden and predicting response to ICIs, may markedly improve current treatment regimens. The baseline and post-treatment SLD of target lesion was recorded and the maximum percent change of the SLD from baseline was designated as SLD-change score. The optimal cut-off value was obtained using the X-tile program. The relationship between SLD-change score and survival outcome (PFS, OS) was evaluated. 10% cut-off value of SLD-change score was found to be most distinctive for PFS. Responders defined according to this cut-off value showed a significant improvement for PFS and OS. Bone metastasis and brain metastasis were also two independent prognostic factors of PFS and OS, respectively. 10% SLD change score could discriminate for ICIs treatment response, which holds great promise in promoting the development of precise immunotherapeutic strategy.

Abstract 3005: Establishment and characterization of a series of lymphoma PDX models representing varied clinical behaviors and treatment responses

Abstract Background: Lymphomas are comprised of a heterogeneous group of hematologic malignancies based on different origins with diverse patterns of clinical behavior and treatment response. Pathologically, lymphomas are divided into two main subtypes, Hodgkin (HL) and non-Hodgkin (NHL), which account for around 10% and 90% of cases, respectively. NHL is further divided into B cell, T cell and natural killer (NK) cell subtypes. Besides histopathology, cancer is increasingly recognized as a genetic disease with specific molecular alterations, such as ALK translocation in anaplastic large cell lymphoma, MYC/BCL2/BCL6 translocation in B cell lymphoma (often referred to as ‘double-hit' or ‘triple-hit') and other specific mutations or overexpression. Current clinical therapeutic options for lymphoma therefore need to consider not only the histological type, clinical aggressiveness and cancer stage, but also the molecular markers, cytokine signaling, epigenetic aberrations and lymphoma microenvironment. Preclinical modeling with diverse types of lymphomas and deep characterization are important for the drug discovery of new lymphoma treatments. Methods: We have established and characterized a number of different subtypes of lymphoma patient-derived xenograft (PDX) models including both mature T/NK cell neoplasms and B cell neoplasms. Immunodeficient mice were used for establishment of these lymphoma PDX models with subcutaneous or tail vein engraftment. Model classification and characterization were determined by histopathology and IHC, as well as genomic profiling by next-generation sequencing (NGS) and response to chemo- or targeted therapies. Results: We have developed and characterized a large panel of lymphoma PDX models with various subtypes, including mantle cell lymphoma, angioimmunoblastic T cell lymphoma, ALK negative anaplastic large cell lymphoma, adult T cell leukemia/lymphoma, peripheral T cell lymphoma, extranodal NK/T cell lymphoma and also other common B cell lymphomas such as DLBCL and follicular lymphoma. Histopathology analysis of these models is in line with clinical pathology diagnosis. Additionally, cancer type-specific biomarkers, such as CD3, CD20, BCL2, BCL6 and MYC, were used for characterization of these lymphoma models by IHC. The response to subtype-specific chemotherapy or targeted therapies, such as CHOP, BTK inhibitors, CD38 antibodies etc., are now tested in some of these lymphoma PDX models and will be presented at the meeting. Conclusions: Lymphomas have diverse subtypes, represented by different clinical features and treatment responses. We have established and characterized a series of lymphomas with varied types including a large cohort of B cell lymphoma and T/NK cell lymphoma PDX models for drug evaluation. Citation Format: Jessie J. Wang, Yanrui Song, Jitai Zheng, Guiqing Wu, Likun Zhang, Henry Q.X. Li, Davy Xuesong Ouyang. Establishment and characterization of a series of lymphoma PDX models representing varied clinical behaviors and treatment responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3005.

Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias

AbstractSelective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.

Clinical response in patients treated with once-monthly paliperidone palmitate: analysis of a therapeutic drug monitoring (TDM) database.

To investigate pharmacokinetic correlates of clinical response in patients treated with once-monthly paliperidone palmitate (PP1M) injections at steady state. Plasma concentrations and dose-adjusted-plasma concentrations (C/D) of paliperidone from a naturalistic therapeutic drug monitoring (TDM) database were compared between responders and non-responders using the Clinical Global Impressions-Improvement scale (CGI-I) ratings. Analyses were based on the non-parametric Mann-Whitney U test and the Pearson Chi-squared test (χ2) with a significance level of 0.05. Subgroup analyses were performed separately in patients with schizophrenia spectrum, schizoaffective disorders and bipolar disorders. Comparing 93 responders with 80 non-responders, we detected no significant differences in the proportion of females, age, and body mass index (p's ranging 0.18-0.83); there were more smokers in the group of non-responders (p = 0.04), which also included more patients with bipolar disorders (p = 0.014). Despite the lack of differences for prescribed PP1M doses and dose intervals (p = 0.42 and p = 0.11, respectively), non-responders had higher paliperidone plasma concentrations and C/D levels (p = 0.033 and p = 0.021, respectively). Subgroup analyses did not yield differences for paliperidone plasma and C/D levels between non-responders and responders with schizophrenia spectrum (p = 0.099 and p = 0.14, respectively) and bipolar disorders (p = 0.95 and p = 0.75, respectively); dose-adjusted plasma concentrations were higher in non-responders compared to responders with schizoaffective disorders (p = 0.039), while no differences were reported for plasma levels (p = 0. 15). Our results show that paliperidone plasma concentrations over injection doses may be associated with patterns of clinical response suggesting potential utility of TDM as part of PP1M-based maintenance treatment.

Gamma Knife Thalamotomy for a Medically Refractory Tremors: Longitudinal Evaluation of Clinical Effects and MRI Response Patterns.

The present longitudinal study evaluated the results of Gamma Knife surgery (GKS) for medically refractory tremors. The outcome after Gamma Knife thalamotomy targeting the ventral intermediate nucleus (VIM) was analyzed in 17 patients (9 men and 8 women; mean age 72years) with either Parkinson's disease or an essential tremor, who were followed up for at least 2years after treatment. Clinical and magnetic resonance imaging (MRI) examinations were done before and every 3months after GKS. The mean rates of symptom improvement (a decrease in the tremor frequency) were 6%, 39%, 63%, and 64% at 3, 6, 12, and 24monthsafter treatment, respectively. The defined MRI response patterns included a minimum reaction (in 3 patients), a normal reaction (in 11 patients), and a hyperreaction (in 3 patients). They were not associated with any evaluated pretreatment, radiosurgical, or outcome parameter, although 2 patients with a hyperreaction exhibited mild-to-moderate motor weakness in the contralateral limbs. Linear contrasting of the border between the thalamus and the internal capsule adjacent to the lesion site was noted on follow-up MRI in 13 cases and was associated with a higher symptom improvement rate. GKS allows effective and safe management of medically refractory tremors. The treatment is characterized by variable MRI response patterns. Some imaging findings during follow-up may be associated with clinical effects.

S0447 Sex-Stratified Clinical Course and Treatment Response Patterns in an Adult Eosinophilic Esophagitis Cohort, and Protective Effects of Estradiol Ex Vivo

S0447 Sex-Stratified Clinical Course and Treatment Response Patterns in an Adult Eosinophilic Esophagitis Cohort, and Protective Effects of Estradiol Ex Vivo

Clinical efficacy, predictive biomarkers and response patterns of immunotherapy combinations for patients with cancer.

Clinical efficacy, predictive biomarkers and response patterns of immunotherapy combinations for patients with cancer.

Biliary tract cancer and genomic alterations in homologous recombinant deficiency: exploiting synthetic lethality with PARP inhibitors.

Biliary tract cancers (BTC) are a group of rare, chemoresistant solid tumor malignancies that arise from the bile ducts. BTC are typically associated with poor outcomes. Most patients present with advanced disease, where treatment is palliative with platinum based cytotoxic therapy. Response to chemotherapy is variable with limited duration of response. A subset of patients that will receive durable and meaningful responses to platinum-based chemotherapy is deemed to be platinum sensitive. The availability and implementation of next-generation sequencing allowed genomic profiling of BTC, which have identified potential targetable somatic genetic aberrations, which include kinases (FGFR, BRAF, ALK, ERBB2), oncogenes (IDH1/2, CCND1) and tumor suppressor genes, including germline or somatic mutations involved in DNA damage response (DDR) genes. These genes include, but are not limited to: ATM, ATR, BRCA1/2, RAD51, PALB2, PTEN, FANC, NBN, EMSY, MRE11, ARID1A. In BTC, alterations in DDR genes are identified in up to 20% of patients, with a higher proportion identified in those with extrahepatic cholangiocarcinoma. Patients harboring mutations exhibit varying patterns of clinical behavior and response to therapy. The presence of these mutations typically predicts for susceptibility to DNA damaging chemotherapy, such as platinum agents.