Advanced Metastatic Disease Research Articles

Rare Ewingoid Dedifferentiated Liposarcoma of the Spermatic Cord Causing Testicular Artery Compression: A Case Report

Liposarcomas of the spermatic cord are rare and often clinically and histologically misdiagnosed, leading to ineffective management and poor outcomes. We present a case of metastatic dedifferentiated liposarcoma of the spermatic cord, which recurred after excision of a misdiagnosed well-differentiated liposarcoma 3 years prior. Due to its size and high-grade metastasis, the tumor was unresectable, leading to treatment with systemic chemotherapy. Complications arose including partial compression of the testicular artery and urethral obstruction secondary to local mass effect. Tumor biopsy was characterized by a unique immunohistochemical profile which helped to explain the unique processes leading to mass effect, vascular and urethral compression, and bilateral scrotal swelling. The patient’s family history of malignancy and 22/22q trisomy identified in the tumor biopsy were also interesting contributors. In conclusion, accurate diagnosis of spermatic cord tumors is essential for effective treatment, and further data collection is required to improve management of advanced metastatic disease.

Cardiovascular complications of treatment for prostate cancer.

Prostate cancer, an androgen-dependent disease, is one of the leading causes of mortality in men. It can present as localised disease, locally advanced or distant metastatic disease. Treatment options for patients with prostate cancer include surgery, chemotherapy, brachytherapy, radiation therapy and hormonal therapy. There are multiple treatment options for each stage of the disease, but hormone therapy is usually reserved for advanced stages. Cardiovascular disease is the leading cause of death in patients with prostate cancer and both diseases share common risk factors. Hormone therapy improves prognosis in patients with more advanced disease, albeit at the cost of cardiovascular toxicity. Hormone therapy can be achieved with the use of agonists and antagonists of gonadotropin-releasing hormone receptors, androgen receptor blockers and enzyme inhibitors of androgen synthesis. Drug-specific cardiotoxicity caused by treatments for prostate cancer has not been fully elucidated. Cardiovascular disease in patients with prostate cancer is mainly managed via an ABCDE approach, a strategy to optimise common risk factors. With newer agents improving the prognosis for patients with prostate cancer, cardiovascular toxicity will have a greater impact on the outcomes of these patients. This article reviews cardiovascular risks associated with therapy for prostate cancer with a focus on hormonal therapy.

Single centre retrospective review of outcome of 177 Lu-DOTATATE peptide receptor radionuclide therapy in the treatment of progressive metastatic neuroendocrine tumours: Survival, toxicity, and prognostic factors.

The aim of this study was to evaluate the efficacy and safety of 177 Lu-DOTATATE therapy in advanced metastatic disease. A retrospective analysis of 395 patients (180 female, 215 males, mean age 62) with progressive metastatic neuroendocrine tumours (NETs) who were treated with 177 Lu-DOTATATE was performed. Overall, 115 patients had less than four cycles and 280 completed four cycles of treatment. Progression-free survival (PFS) and overall survival (OS) was performed using Kaplan-Meier analysis. Analysis of survival predictors was performed using Cox regression model. Toxicity was defined using the Common Terminology Criteria for Adverse Events version 5 (CTCAE 5.0). The percentage of patients with liver and skeletal metastases were 91 and 57%, respectively. Median PFS and OS were calculated at 33 months (95% CI: 29-37 months) and 46 months (95% CI: 48-56 months), respectively. End of treatment response assessment was performed using cross sectional imaging demonstrated partial response in 22%, stable disease in 64% and progressive disease in 14% of patients. Overall, grade 3 and 4 bone marrow toxicity was seen in 8%. One patient (0.3%) developed irreversible grade 4 nephrotoxicity. Myelodysplastic disease was recorded in one patient (0.3%). Univariate analysis of PFS predictors showed that body mass index (BMI), baseline chromogranin A (CgA) >400 ng/l, baseline alkaline phosphatase (ALP) >130 mg/dl, liver tumour volume and overall tumour burden were significant. On multivariate analysis only Ki67, high CgA and low BMI retained significance. 177 Lu-DOTATATE is an effective treatment in advanced NETs with generally high-volume metastases. It is well-tolerated. Ki-67, CgA and BMI appear to be predictors for PFS.

Simultaneous care in oncology: Assessment of benefit in relation to symptoms, sex, and age in 753 patients.

BackgroundEarly activation of palliative care for patients with advanced cancer is central in the treatment trajectory. At the Veneto Institute of Oncology, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients are evaluated by an oncologist together with a palliative care team. Recently, we reported on consecutive patients admitted at SCOC from 2018 to 2021 in terms of appropriateness, process, and outcome indicators. Here, we report further analysis in the same group of 753 patients, evaluating other parameters and the correlation between symptom intensity, gender, age, and survival.MethodsSCOC data were retrieved from a prospectively maintained database.ResultsAmong the patients, 42.2% were women, and the median age was 68 years, with 46.7% of patients aged ≥70 years. The most prevalent disease type was gastrointestinal cancer (75.2%), and 90.9% of the patients had metastatic disease. The median score for the distress thermometer was 4; the vast majority of the patients (98.6%) reported physical problems, and 69.4% presented emotional issues. Younger women demonstrated a significantly greater median distress than other patients (p=0.0018). Almost all symptoms had a higher prevalence on the 0–3 Edmonton Symptom Assessment Scale (ESAS) score, except for fatigue. About 43.8% of the patients received systemic anticancer treatment (SAT) in the last 60 days of life, 15.0% of whom received SAT in the last month and 3.1% in the last 2 weeks. For some symptoms, women frequently had more ESAS >3. Pain and nausea were significantly less reported by older patients compared with younger adults. Men had a lower risk of having MUST score ≥ 2 (p=0.0311). Men and older patients showed a lower prognosis awareness (p=0.0011 and p=0.0049, respectively). Older patients received less SAT within the last 30 days of life (p=0.0006) and had death risk decreased by 20.0%.ConclusionOur study identified two subgroups of patients with advanced cancer who require special attention and support due to important symptoms’ burden detected by Patient Reported Outcome Measures tests: women and younger adults. These categories of patients require special attention and should be provided early access at SCOC. The role of an oncologist remains crucial to intercept all patients in need of early palliative care and balancing trade-offs of anticancer treatment in advanced metastatic disease.

S3411 Extensive Hepatic Lesions From a Primary Duodenal Neuroendocrine Carcinoma in a Young Male

Introduction: Neuroendocrine neoplasms (NEMs) are relatively rare, accounting for 0.5% of newly diagnosed malignancies. NEMs can be found throughout the body with two-thirds arising in the GI tract and incidence increasing among duodenal NEMs. These malignancies have a female predominance and generally occur in the 6th decade of life. This is a case of advanced metastatic disease from an unexpected duodenal neuroendocrine carcinoma in a healthy young male. Case Description/Methods: A 29-year-old male, with no PMH, acutely developed sharp RUQ abdominal pain. Prior to this, he was in his usual state of health. In the ED, the patient was hemodynamically stable with tenderness to palpation in the RUQ. Initial labs showed WBC 12.10 × 103/uL, Hgb 11.7 g/L, AST 55 U/L, ALT 173 U/L, ALP 127 U/L, and TBIL 0.8 mg/dL. CT A/P showed multiple well-circumscribed liver lesions, largest measuring 8.6 × 7.8 cm, with portal venous invasion (Figure A). CA 19-9 and CEA were negative. There was elevation of AFP 1,577 ng/mL and LDH 817 U/L, but negative hCG. A1AT, ANA, AMA, ASMA, ALKM, and ceruloplasmin were negative. Liver biopsy showed a poorly-differentiated malignant neoplasm of unknown primary. EGD was performed revealing a fungating mass in the second portion of the duodenum (Figure B). Pathology favored a high-grade poorly-differentiated neuroendocrine carcinoma (Figure C). He was discharged with palliative cisplatin/irinotecan initiation. Discussion: Gastrointestinal NEMs have been increasing in prevalence due to improved awareness. When carcinoid symptoms are absent, detection is dependent on imaging and endoscopy after the patient presents with complications from metastasis or mass effect. Following biopsy, GI NEMs are classified by WHO 2010 criteria into 3 groups based on mitotic count and Ki-67 index. Group 3 tumors are classified as poorly-differentiated neuroendocrine carcinomas with Ki-67 >20% with higher rates of angioinvasion and metastatic potential. Lymph node metastasis occurs in 60% of duodenal NETs, while liver mets occur in < 10%. In our case, the patient’s Ki-67% index was >90%, characterizing it as a Group 3 NEM. Characterization is important given the impact on prognosis and treatment. Group 3 NEMs have the overall worst prognosis. Since >90% of duodenal NEMs do not cause a clinical syndrome and are not associated with metastatic disease, surgical or endoscopic resection is preferred. However, if there is metastatic disease or high-grade histologic features, chemotherapy is the mainstay of treatment.Figure 1.: A, CT A/P with multiple large heterogeneously enhancing liver lesions concerning for metastatic malignancy of unknown primary (B) Large fungating mass located in the second portion of the duodenum (C) Duodenal mass, H&E stain, 20×, high-grade poorly differentiated epithelial malignancy composed of nested cells with indistinct nucleoli, moderate eosinophilic cytoplasm, and brisk mitosis.

Pembrolizumab as monotherapy in locally advanced cutaneous squamous cell carcinoma

ABSTRACT Introduction Outcomes for patients with advanced cutaneous squamous cell carcinoma (cSCC) are poor, however recent approvals in programmed death-1 (PD-1) checkpoint inhibition have shown promise. Prior systemic treatments in this patient population included chemotherapy and anti-EGFR directed therapies, with limited long-term benefit. Studies investigating cemiplimab and pembrolizumab have recently revealed significant responses with many cases of sustained benefit in both locally advanced and recurrent and/or metastatic disease. While these treatments have shown improvement in outcomes, there are continued areas of need. Areas covered This review focuses on clinical evidence for PD-1 directed checkpoint inhibition in advanced cSCC. Excluded populations and new approaches involving immunotherapy are discussed. Expert opinion Immune checkpoint inhibition in advanced cSCC has shown impressive benefit. The clinical trials for both cemiplimab and pembrolizumab demonstrate similar responses and outcomes. Biomarkers for predicting response are an area of need. In addition, these trials excluded immunosuppressed patients due to hematological malignancies or prior organ transplant, which are populations with significantly increased risk of cSCC. Finally, a variety of novel approaches using checkpoint inhibition in cSCC are being investigated, with some encouraging preliminary results.

Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.

TP53 mutation is the most frequent genetic event in head and neck squamous cell carcinoma (HNSCC), found in more than 80% of patients with human papillomavirus-negative disease. As mutations in the TP53 gene are associated with worse outcomes in HNSCC, novel therapeutic approaches are needed for patients with TP53-mutated tumors. The National Cancer Institute sponsored a Clinical Trials Planning Meeting to address the issues of identifying and developing clinical trials for patients with TP53 mutations. Subcommittees, or breakout groups, were tasked with developing clinical studies in both the locally advanced and recurrent and/or metastatic (R/M) disease settings as well as considering signal-seeking trial designs. A fourth breakout group was focused on identifying and standardizing biomarker integration into trial design; this information was provided to the other breakout groups prior to the meeting to aid in study development. A total of 4 concepts were prioritized to move forward for further development and implementation. This article summarizes the proceedings of the Clinical Trials Planning Meeting with the goal of developing clinical trials for patients with TP53-mutant HNSCC that can be conducted within the National Clinical Trials Network.

Geographic variation in attitudes regarding management of locally advanced pancreatic cancer

BackgroundRecent literature suggests wide variations exist in the international management of locally advanced pancreatic cancer. This study sought to evaluate how geography contributes to variations in management of locally advanced pancreatic cancer. MethodsAn electronic survey investigating preferences for the evaluation and management of locally advanced pancreatic cancer was distributed to an international cohort of pancreatic surgeons. Surgeons were classified according to geographic location of practice, and survey responses were compared across locations. ResultsA total of 153 eligible responses were received from 4 continents: North and South America (n = 94, 61.4%), Europe (n = 25, 16.3%), and Asia (n = 34, 22.2%). Preferences for the use and duration of neoadjuvant chemotherapy and radiotherapy varied widely. For example, participants in Asia commonly preferred 2 months of neoadjuvant chemotherapy (61.8%), whereas North and South American participants preferred 4 months (52.1%), and responses in Europe were mixed (P = .006). Participants in Asia were less likely to consider isolated liver or lung metastases contraindications to exploration and consequently had a greater propensity to consider exploration in a vignette of oligometastatic disease (56.7% vs North and South America: 25.6%, Europe: 43.5%; P = .007). ConclusionIn an international survey of pancreatic surgeons, attitudes regarding locally advanced pancreatic cancer and metastatic disease management varied widely across geographic locations. Better evidence is needed to define optimal management of locally advanced pancreatic cancer.

SPCR-04 EFFECTS OF BRAIN METASTASES ON NEUROCOGNITIVE FUNCTION: BASELINE RESULTS OF A LONGITUDINAL TRIAL

PURPOSENeurocognitive dysfunction is common in patients with advanced metastatic cancer. The contribution of brain metastases (BrMets) to neurocognitive outcomes is uncertain. We examined the impact of BrMets on cognitive outcomes before CNS-directed treatment and compared findings to patients with advanced metastatic cancer without BrMets. Here we present results from an ongoing prospective, longitudinal study. METHODSEnglish-speaking adults followed at the brain metastases and lung cancer clinics underwent neurocognitive testing using a standardized battery (prior to cranial radiotherapy, if applicable), with follow-up assessments 3, 6, 9, 12, 18, and 24 months later. We calculated z-scores and impairment rates for composite neurocognitive function and memory, attention/working memory, processing speed and executive function domains. Impairment was defined according to International Cancer and Cognition Task Force criteria. RESULTS78 patients with BrMets (50% female; mean age (SD):61(11) years) and 28 patients with metastatic non-small cell lung cancer (mNSCLC) with no known BrMets (71% female; age 67(9) years) were included. Baseline neurocognitive composite scores were impaired in both groups (BrMets: 61.5%; nonBrMets: 60.7%). Impairment rates varied between groups and across domains (BrMets vs nonBrMets: memory: 35.9%vs25.0%; attention/working memory: 35.8%vs21.4%; processing speed: 10.3%vs7.1%; executive function: 44.0%vs35.7%). Subgroup comparisons between BrMets patients with mNSCLC (N=29) and mNSCLC patients without BrMets, none of whom had targetable mutations, revealed no differences in impairment rates, but BrMets patients had slower processing speed than nonBrMets patients (mean(SD): -0.6(1.4) vs -0.1(1.9); Wilcoxon signed-rank test, p = 0.043). CONCLUSIONNeurocognitive impairment in patients with advanced cancers is common. Our preliminary findings demonstrate no clear difference in cognitive outcomes between patients with BrMets and those with advanced metastatic disease not involving the brain. Our work examining how neurocognitive outcomes evolve over time in patients with and without BrMets, and demographic, disease, and treatment variables associated with those outcomes, is ongoing.

Plocabulin, a Novel Tubulin Inhibitor, Has Potent Antitumour Activity in Patient-Derived Xenograft Models of Soft Tissue Sarcoma.

A clinically relevant subset of patients with soft tissue sarcoma presents with either locally advanced or upfront metastatic disease, or will develop distant metastases over time, despite successful treatment of their primary tumour. The currently available systemic agents to treat such advanced cases only provide modest disease control and are not active in all histological subtypes. Thus, there is an unmet need for novel and more efficacious agents to improve the outcome of this rare disease. In the current preclinical in vivo study, we evaluated plocabulin, a novel tubulin inhibitor, in five distinct histological subtypes of soft tissue sarcoma: dedifferentiated liposarcoma, leiomyosarcoma, undifferentiated sarcoma, intimal sarcoma and CIC-rearranged sarcoma. The efficacy was tested in seven patient-derived xenograft models, which were generated by the engraftment of tumour fragments from patients directly into nude mice. The treatment lasted 22 days, and the efficacy of the drug was assessed and compared to the doxorubicin and vehicle groups by volumetric analysis, histopathology and immunohistochemistry. We observed tumour volume control in all the tested histological subtypes. Additionally, in three sarcoma subtypes, extensive central necrosis, associated with significant tumour regression, was seen. This histological response is explained by the drug’s vascular-disruptive properties, reflected by a decreased total vascular area in the xenografts. Our results demonstrate the in vivo efficacy of plocabulin in the preclinical models of soft tissue sarcoma and corroborate the findings of our previous study, which demonstrated similar vascular-disruptive effects in gastrointestinal stromal tumours—another subtype of soft tissue sarcoma. Our data provide a convincing rationale for further clinical exploration of plocabulin in soft tissue sarcomas.

Narrative review of the epidemiology, economic burden, and societal impact of metastatic bone disease.

As the prevalence of cancer continues to rise in the United States due to a combination of both early detection and increased life expectancy, the number of clinically symptomatic skeletal metastases will continue to grow. Healthcare expenditures on cancer treatment have steadily increased each decade to our estimated level of approximately $200 billion in 2020. Metastatic bone disease is a significant driver of this cost, accounting for nearly one-fifth of the total cost of oncologic treatment. Understanding the impact of metastatic bone disease can help to identify the gaps between diagnosis and initiation of treatment in an effort to decrease the socioeconomic and psychosocial implications of the disease. In this paper, we review the epidemiology and economic burden of metastatic bone disease in addition to other sequelae that affect patients, including financial hardship, caregiver burden, diminished quality of life and psychological impact. Upon literature review of multiple studies investigating these factors, we found that advanced metastatic bone disease had overall poor outcomes with regards to the socioeconomic and psychosocial effects on not only patients and their families, but also society at large. These consequences may be improved by early referral to orthopedic specialists and establishment of a multi-disciplinary team.

Abstract 652: An androgen receptor-associated transcription factor regulates fatty acid metabolism driving tumor growth in androgen receptor-positive breast cancer

Abstract Despite advances in the treatment of breast cancer, it is still the second leading cause of cancer-related death in women worldwide. A large number of patients develop recurrence and die of advanced metastatic disease. More than 70% of metastatic breast cancers (mBC) express androgen receptor (AR) representing a potential target for anti-hormone therapies. AR is suggested to directly interact with an associated transcription factor (ARaTF) in breast cancer, however the functional role of ARaTF and its interaction with AR remains to be elucidated. We find that AR expression highly correlates with ARaTF in patients. To study its functional role driving tumorigenesis and metastatic outgrowth, we utilize patient-derived xenograft cell lines derived from liquid biopsies of mBC patients which reflect the highly heterogenous disease. Using genetically manipulated PDX cell models, we demonstrate that repression of ARaTF significantly reduces tumor growth of AR positive (AR+) BC cells in vivo. Notably, we observe the opposite phenotype in an AR negative cell model suggesting a tumor suppressive function when AR is not present. Mechanistically, we find that ARaTF regulates key metabolic processes: (1) Pharmacological inhibition of AR or silencing of ARaTF restricts mitochondrial respiration activity resulting in decreased energy production. (2) We also find that ARaTF positively regulates genes encoding enzymes involved in de novo fatty acid biosynthesis in AR+ BC. We further observe upregulation of the CD36 fatty acid transporter facilitating fatty acid uptake as compensatory pathway upon downregulation of ARaTF. Finally, abolishing CD36 expression in AR+ BC cells significantly reduces cell viability upon ARaTF downregulation. These findings suggest that lipid and energy metabolism are transcriptionally regulated by ARaTF facilitating cell survival in nutrient-depleted environments and thus facilitating metastatic outgrowth. These findings provide knowledge about the functional role of ARaTF regulating the lipogenic metabolic profile of AR+ breast cancer, and might help to identify patients who benefit from an anti-androgen treatment. Citation Format: Sarah-Jane Neuberth, Corinna Schumacher, Marteinn Thor Snaebjörnsson, Roberto Würth, Franziska Maria Zickgraf, Ornella Kossi, Felix Geist, Andrea Geist, Vera Thiel, Jonas Schwickert, Mattia Falcone, Massimo Saini, Almut Schulze, Andreas Trumpp, Martin R. Sprick. An androgen receptor-associated transcription factor regulates fatty acid metabolism driving tumor growth in androgen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 652.

Tumour burden and antigen-specific T cell magnitude represent major parameters for clinical response to cancer vaccine and TCR-engineered T cell therapy

BackgroundCancer vaccines and T-cell receptor (TCR) engineered T cells (Tg-T cell) represent two different therapeutic strategies that can target the same tumour epitopes. The first approach requires the induction of a specific immune response in patients, while the second relies on the efficacy of adoptively transferred T cells. Because the ratio of antigen-specific T cells to tumour cells engaged by these strategies may influence the clinical outcome, we evaluated the efficacy of these two therapeutic approaches in solid tumours according to the tumour burden. MethodsWe performed a meta-analysis restricted to the therapeutic vaccine and Tg-T cell trials, presenting annotated individual clinical data. We adapted a previously published mathematical model for tumour immune dynamics to estimate the clinical impact of the number of specific T cells in regard to the tumour burden. ResultsA focused analysis of Tg-T cell studies revealed that clinical responses were mostly observed with the highest doses of infused T cells, suggesting that exceeding a threshold of effector T cells may be required for clinical efficacy. In silico modelling of cancer vaccine and Tg-T cell therapies starting at different tumour burdens showed that therapeutic vaccines control low or moderate tumour burdens, whereas increasing the amount of infused Tg-T cells succeeds in controlling high tumour masses. ConclusionWe propose that therapeutic vaccines should be considered in the context of low or moderate tumour burden, whereas Tg-T cell strategies may be more adapted for the treatment of advanced metastatic diseases.

A Decade of Success in Melanoma Immunotherapy and Targeted Therapy: What Every Radiologist Should Know.

Treatment strategies for malignant melanoma have rapidly evolved over the past decade. Because of its propensity to develop advanced stage and metastatic disease, melanoma has contributed to the majority of mortalities among patients with skin cancer. The development of novel therapeutics such as immunotherapy and targeted molecular therapies has revolutionized the treatment of patients with advanced stage and metastatic malignant melanoma. Immune checkpoint inhibitors, BRAF/MEK inhibitors, and other revolutionary therapies have demonstrated remarkable success in the treatment of this common malignancy. Along with these advancements in systemic therapies, imaging has continued to play a critical role in the diagnosis and follow-up of patients with malignant melanoma. As the use of these novel therapies continues to expand, knowledge of the evolving therapeutic landscape of melanoma is becoming critical for radiologists. In this review, we provide a primer for radiologists outlining the evolution of immunotherapy and targeted therapy in the treatment of melanoma. We discuss the critical role of imaging in evaluation of treatment response, including a summary of current imaging response guidelines. Last, we summarize the essential role of imaging in the evaluation of potential adverse events seen in patients with malignant melanoma undergoing treatment with immune checkpoint inhibitors.

Predictors of poor serologic response to COVID-19 vaccine in patients with cancer: a systematic review and meta-analysis

BackgroundsPatients with cancer presented a lower probability to obtain seroconversion after a complete course of COVID-19 vaccination. However, little was known on the factors that predict poor seroconversion in this frail population. MethodsWe searched the PubMed, EMBASE, and China National Knowledge Infrastructure databases for all articles within a range of published years from 2019 to 2022 on the predictors of response to COVID-19 vaccine in patients with cancer (last search was updated on 2st March 2022). The odds ratio corresponding to the 95% confidence interval was used to assess the outcome. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics. The review was registered with PROSPERO (CRD42022315687) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ResultsTwenty cohort studies met the inclusion criteria for this study, with 5,499 patients with cancer. We found that advanced age, male patients, and metastatic disease increased negative seropositivity to COVID-19 vaccine. Immunoglobulin heavy chain variable mutation status, high concentration of Ig G, Ig M, and Ig A were correlated with seropositivity. Relating to cancer treatment strategy, anti-CD20 therapy within recent 12 months and chemotherapy were negatively correlated with seroconversion. Meta-analysis found no significant difference associated with targeted treatment, immunotherapy, and endocrine treatment. ConclusionsOur meta-analysis assessed the factors that predict poor seroconversion in order to plan better prevention strategies in this frail population. The results proposed that enhanced vaccination strategies would be beneficial for the special patients such as advanced male, or patients receiving active chemotherapy, and carefully prevention should be emphasised even after a complete course of vaccination.

Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response

PurposeAlthough recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the...

The safety and efficacy of psilocybin therapy in patients with cancer and major depressive disorder.

12097 Background: More than 17 million people in the U.S. live with cancer and up to 25% of them have major depression. Depression leads to lower treatment adherence, reduced quality of life, and higher rates of mortality in cancer. Yet, interventions used to treat depression in patients with cancer have limited success. Prior trials using psilocybin to treat anxiety and depression associated with cancer suggested improvements in psychological distress. However, treatment in a homogenous psychiatric sample has yet to be investigated. Further, psilocybin has not been given in groups, and in a setting conducive to the “whole person” approach to treatment. This trial built upon previous studies and tested the safety, feasibility, and efficacy of psilocybin therapy in cancer patients diagnosed with major depressive disorder (MDD), with the novel use of group treatment in a cancer center setting. Methods: Phase II, single-center, open label trial, where 30 patients received a dose of 25 mg of psilocybin. Inclusion criteria: 1) age ≥ 18 years, 2) met criteria for MDD, 3) a Hamilton Depression Rating Scale score ≥ 18 at baseline, 4) diagnosis of a malignant neoplasm. Patients who had curative treatment for cancer as well as those with advanced metastatic disease were included. Patients were divided into cohorts and they received 1 group preparation session, simultaneous administration of psilocybin, and 2 group integration sessions. Therapeutic care was also provided before, during, and after the session using the 1:1 model of psychological support. The primary outcome measures for safety were adverse events, vital signs, ECGs, blood tests, and suicidality scores (C-SSRS). The secondary and exploratory outcome measures consisted of 15 assessments conducted at baseline and post-treatment at day 1, week 1, week 3, and week 8 to determine the efficacy of treatment. Results: A total of 30 patients were enrolled over the course of only 8 months with an attrition rate of 0%. All completed the trial with no serious adverse events. Beyond high tolerability of the treatment, we also found a clinically meaningful change in depressive symptoms. After a single administration of psilocybin therapy, the average score on the Montgomery Asberg Depression Rating Scale (MADRS) dropped by 19.1 points (95% CI, 22.3 to 16.0, p &lt; 0.0001). A sustained response rate (a decrease of ≥ 50% in the MADRS score from baseline to week 8) was seen by 24 patients. 50% of patients showed complete remission of depression symptoms (a MADRS score &lt; 10) one week after treatment, which was sustained for up to 8 weeks. Conclusions: This study adds to the growing body of psilocybin research with promising results showing the safety, feasibility, and efficacy of simultaneous psilocybin treatment in patients with cancer with MDD. The value of group support for patients with cancer was also explored, with implications for increased scalability of psilocybin therapy in real-world settings. Clinical trial information: NCT04593563.

Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the cancer therapy landscape due to long-term benefits in patients with advanced metastatic disease. However, robust predictive biomarkers for response are still lacking and...

Theranostic pairing: ABY-025/251 targeting HER2 with 68Ga and 188Re—Minimized radioligands using Affibody peptide scaffold technology.

3093 Background: HER2 expressing tumors such as subsets of metastatic breast cancer and gastro-esophageal tumors can be targeted using specific antibodies or antibody-drug-conjugates (ADCs). However, some tumors remain refractory to treatment. External radiation therapy is unsuited to advanced metastatic disease. Targeted molecular radiation therapy has proven useful in other tumors such as neuroendocrine tumors or prostate cancer using 177Lu. 188Re is a beta emitting isotope that when chelated to the ABY-251 Affibody molecule has the potential to precisely target HER2 expressing tumors locally. The ABY-251 Affibody molecule is a very small, structured protein scaffold with a molecular weight of only 7 kDa targeting HER2 with high affinity (KD = 100pM). ABY-251 can be manufactured by chemical synthesis. A diagnostic analog molecule ABY-025 was also developed with chelation to 68Ga ideal for PET visualization. Methods: A pre-clinical study in mice was conducted to investigate tumor/tissue uptake, followed by a clinical diagnostic study for visualization in HER+ patients with metastatic breast cancer, to be followed by a theranostic study in humans. Results: Pre-clinical Study: A preclinical study in mice has previously demonstrated high contrast uptake in HER2 tumor tissue using the diagnostic analog ABY-025. Off target accumulation was seen in kidney tissue using the diagnostic ABY-025, which in the ABY-251 therapeutic molecule has been reduced by further engineering of the molecule. This molecule has now been proven to increase survival in mice bearing HER2+ tumors. Median survival in the treated animals was 68 days as compared to 29 and 27.5 days in animals treated with vehicle and non-labelled peptide respectively. Clinical diagnostic study ph1/2: ABY-025 was studied in HER2+ patients with metastatic breast cancer. In a study of 16 women with refractory metastatic breast cancer (&gt;2 prior lines of therapy, 12 IHC positive and 4 IHC negative) 9 out of 10 patients showed high HER2 expression levels as measured with ABY-025 PET despite ongoing treatment with HER2 targeted therapy. Persistent high 68Ga-ABY-025 tumor uptake in patients despite treatment with standard HER2-targeted therapies is a sign of therapeutic drug resistance. These patients would be eligible for treatment with the therapeutic analog ABY-251 using 188Re generated beta radiation for tumor eradication. Clinical therapeutic study (planned): ABY-251 is in development to soon enter therapeutic clinical Ph1/2a trials in patients with refractory HER2+ tumors and positive tumor imaging using ABY-025 as a theranostic pair. Conclusions: A radiopharmaceutical theranostic approach diagnosing HER2+ patients with metastatic disease using 68Ga-ABY-025 for targetability and subsequent treatment using 188Re-ABY-251 seems feasible and is currently in clinical trials. Clinical trial information: NCT01858116.

Outcomes and Predictors of 28-Day Mortality in Patients With Solid Tumors and Septic Shock Defined by Third International Consensus Definitions for Sepsis and Septic Shock Criteria

Data assessing outcomes of patients with solid tumors demonstrating septic shock using the Third International Consensus Definitions for Sepsis and Septic Shock are scarce. What are the independent predictors of 28-day mortality in critically ill adults with solid tumors and septic shock? Cohort of solid tumor patients admitted to the ICU with septic shock. Demographic and clinical characteristics were gathered from the electronic health records. We developed a reduced multivariate logistics regression model to identify independent predictors of 28-day mortality and used Kaplan-Meier plots to assess survival. A total of 271 patients were included. The median age was 62 years (range, 19-94 years); 57.2%were men and 53.5%were White. The most common underlying malignancies were lung (19.2%), breast (7.7%), pancreatic (7.7%), and colorectal (7.4%) cancers. Most patients (84.5%) harbored metastatic disease. Twenty-eight days after ICU admission, 188 patients (69.4%) had died. Nonsurvivors showed a higher rate of advanced cancer, longer hospital stays before ICU admission, and higher Sequential Organ Failure Assessment scores at admission and throughout the ICU stay (P< .001 for all). The multivariate analysis identified metastatic disease (OR, 3.17; 95%CI, 1.43-7.03), respiratory failure (OR, 2.34; 95%CI, 1.15-4.74), elevated lactate levels (OR, 3.19; 95%CI, 1.90-5.36), and Eastern Cooperative Oncology Group performance scores of 3 or 4 (OR, 2.72; 95%CI, 1.33-5.57) as independent predictors of 28-day mortality. Only 38 patients (14%) were discharged home without medical assistance. The 28-day mortality rate of patients with solid tumors and septic shock was considerably high. Factors associated with worse survival included advanced oncologic disease, poor performance status, high lactate level, and concomitant acute respiratory failure. Early goals-of-care discussions should be considered for frail patients with septic shock and advanced metastatic disease without denying access to the appropriate level of care.