PSMA-Targeted Therapy: Advancements in Detection and Treatment Modalities with Dr. Scott T. Tagawa.

Prostate cancer is one of the most challenging malignancies due to its high incidence and prevalence, as it is the most frequently diagnosed non-skin cancer in men. The timely identification of prostate cancer and its metastasis is paramount for ensuring favorable outcomes for patients. Prostate-specific membrane antigen (PSMA) emerges as a promising biomarker for its detection, due to its specificity. This makes it an ideal target for the early identification of a metastatic phenotype. Situated on the membrane of tumor cells, PSMA facilitates the attachment of PSMA-targeting particles, enabling their detection through positron emission tomography (PET) scans with relative ease. Utilizing these imaging agents in conjunction with PET scans enhances the accuracy of prostate cancer tumor detection compared to PET scans alone. The advancement in prostate cancer imaging has paved the way for innovative treatment modalities. Prostate-specific membrane antigen-targeted radionuclide therapies (PSMA-TRT) exploit PSMA imaging agents to target identified prostate cancer malignancies with precise radiation, thereby reducing or eliminating the tumor mass. PSMA-TRT exhibits significant promise in prostate cancer therapy, evident from the notable declines in prostate-specific antigen (PSA) levels post treatment. However, PSMA-TRT carries both beneficial and adverse effects. While it represents a substantial leap forward in tumor cell imaging, PSMA-based antigens, being larger particles than ligands, offer prolonged imaging capabilities. Yet, the long-term effects of PSMA-TRT remain unknown, with the short-term adverse ones including fatigue, nausea, pain flares, and potential radiation exposure to others.

Reimagining Colorectal Cancer Screening: Innovations and Challenges with Dr. Aasma Shaukat.

Colorectal cancer (CRC) currently ranks as the third most common cancer and the second leading cause of cancer-related deaths worldwide, posing a significant global health burden to the population. Recent studies have reported the emergence of a new clinical picture of the disease, with a notable increase in CRC rates in younger populations of <50 years of age. The American Cancer Society (ACS) now recommends CRC screening starting at age 45 for average-risk individuals. Dr. Aasma Shaukat's Keynote Conference highlights the critical need for updated screening strategies, with an emphasis on addressing the suboptimal adherence rates and the effective management of the growing burden of CRC. Lowering the adenoma detection screening age can facilitate early identification of adenomas in younger asymptomatic patients, altering the epidemiologic landscape. However, its implications may not be as profound unless a drastic shift in the age distribution of CRC is observed. Currently, various screening options are available in practice, including stool-based tests like multitarget stool DNA (mtDNA) tests, fecal immunochemical testing (FIT), and imaging-based tests. In addition to existing screening methods, blood-based tests are now emerging as promising tools for early CRC detection. These tests leverage innovative techniques along with AI and machine learning algorithms, aiding in tumor detection at a significantly earlier stage, which was not possible before. Medicare mandates specific criteria for national coverage of blood-based tests, including sensitivity ≥ 74%, specificity ≥ 90%, FDA approval, and inclusion in professional society guidelines. Ongoing clinical trials, such as Freenome, Guardant, and CancerSEEK, offer hope for further advancements in blood-based CRC screening. The development of multicancer early detection tests like GRAIL demonstrates a tremendous potential for detecting various solid tumors and hematologic malignancies. Despite these breakthroughs, the question of accessibility and affordability still stands. The ever-evolving landscape of CRC screening reflects the strength of the scientific field in light of an altered disease epidemiology. Lowering screening age along with the integration of blood-based tests with existing screening methods holds great potential in reducing the CRC-related burden. At the same time, it is increasingly important to address the challenges of adaptation of the healthcare system to this change in the epidemiologic paradigm.

Reviewing the Landscape of Cancer Survivorship: Insights from Dr. Lidia Schapira's Programs and Beyond.

The constantly escalating population of cancer survivors worldwide has prompted a focused exploration of their unique needs and experiences within the context of healthcare medicine. This review initiates its analysis inspired by Dr. Lidia Schapira's insightful keynote conference on the Survivorship 1.0 and Survivorship 2.0 Programs, shedding light on their implementation challenges and setting the stage for a comprehensive analysis of cancer survivorship initiatives. Within the transformed landscape of cancer care, patient-centric strategies embedded in cancer survivorship programs comprising vital elements such as connection, support, and education are presented. While placing cancer recurrence surveillance at the forefront, the review underlines concern regarding the potential oversight of the enduring impact on mental and physical health. Dr. Schapira's insights further extend into the exploration of mental health challenges faced by survivors, promoting an examination of diverse strategies to address these concerns. Furthermore, the discussion continues toward promising areas of research, notably Precision Medicine's role in de-escalating cancer therapies, and advocates for measures such as early cancer awareness and timely referrals to supportive services. Highlighting the significance of education, the role of online resources in enhancing the knowledge of healthcare practitioners and future generations in cancer care is then explored. The paper concludes by presenting some of the most prominent global current survivorship programs, identifying critical knowledge gaps in cancer care and projecting future developments aimed at delivering accurate and holistic care, improving the quality of life for survivors, and enhancing both mental and physical well-being. Drawing upon the insights from Dr. Schapira, this review lays the groundwork for a nuanced exploration of cancer survivorship and its multifaceted implications.

Innovations in Thoracic Oncology and the Promise of Liquid Biopsies with Dr. Luis Raez.

Thoracic oncology continues to pose a great threat to human health as one of the most common forms of cancer. Liquid biopsies present a transformative approach to treating patients affected by these types of diseases by providing a less invasive genetic overview of the tumor, aiding in both diagnostic and treatment measures. The primary objective of this article is to examine the prospects of liquid biopsies in managing thoracic malignancies and to present barriers to their usage as demonstrated by Dr. Luis Raez. In examining why molecular diagnostics continue to be employed together with more traditional methods, this article presents the next steps in the clinical application of blood-based cancer screening. Future cancer diagnosis and treatment aim to prioritize circulating biomarker analyses based on their potential for the detection and monitoring of thoracic cancers. Liquid biopsies are favored thanks to their reduced invasiveness with respect to traditional treatments. The further study of clinical biomarkers and technological advancements are thus pivotal to enhance the clinical applicability of this method. In conclusion, this blood-based analysis offers a promising route by which the diagnosis, treatments, and outcomes of thoracic cancer can be improved.

Cholangiocarcinoma Insights: Established Foundations and Cutting-Edge Innovations from Dr. James Cleary's Pioneering Research.

This paper provides insights into the conventional understanding of biliary tract malignancies, with a specific focus on cholangiocarcinoma (CCA). We then delve into the groundbreaking ideas presented by Dr. James Cleary. CCA, originating from biliary tree cells, manifests diverse subtypes contingent upon anatomical localization and differentiation status. These variants exhibit discrete genetic aberrations, yielding disparate clinical phenotypes and therapeutic modalities. Intrahepatic, perihilar, and distal CCAs intricately involve distinct segments of the biliary tree, further categorized as well-differentiated, moderately differentiated, or poorly differentiated adenocarcinomas based on their histological differentiation. Understanding the etiological factors contributing to CCA development assumes paramount importance. Stratifying these factors into two groups, those unrelated to fluke infestations (e.g., viral hepatitis and fatty liver conditions) and those associated with fluke infestations (e.g., chronic liver inflammation), facilitates predictive modeling. The epidemiology of CCA exhibits global variability, with Southeast Asia notably displaying higher incidences attributed primarily to liver fluke infestations. Jaundice resulting from bile duct obstruction constitutes a prevalent clinical manifestation of CCA, alongside symptoms like malaise, weight loss, and abdominal pain. Diagnostic challenges arise due to the symptomatic overlap with other biliary disorders. Employing comprehensive liver function tests and imaging modalities such as computed tomography assumes a pivotal role in ensuring accurate diagnosis and staging. However, the definitive confirmation of CCA necessitates a biopsy. Treatment modalities, predominantly encompassing surgical resection and radiation therapy, hold curative potential, although a considerable subset of patients is deemed unresectable upon exploration. Challenges intensify, particularly in cases classified as cancer of unknown origin, underscoring the imperative for early intervention. Advancements in genomic sequencing have revolutionized precision medicine in CCA. Distinct genomic markers, including fibroblast growth factor receptor 2 (FGFR2) alterations and isocitrate dehydrogenase 1 (IDH1) mutations, have emerged as promising therapeutic targets. FGFR2 alterations, encompassing mutations and rearrangements, play pivotal roles in oncogenesis, with FGFR inhibitors demonstrating promise despite identified resistance mechanisms. Similarly, IDH1 inhibitors face challenges with resistance, despite encouraging early clinical trial results, prompting exploration of novel irreversible inhibitors. Dr. James Cleary's illuminating discourse underscores the significance of diverse FGFR2 alterations and the potential of IDH1 inhibition in reshaping the treatment landscape for CCA. These findings unveil critical avenues for targeted therapeutic interventions, emphasizing the critical need for ongoing research to optimize outcomes in this challenging cancer subtype, incorporating innovative insights from Dr. Cleary.

Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3.

PURPOSE: Pembrolizumab is standard therapy for patients with metastatic urothelial cancer (mUC) who progress after first-line platinum-based chemotherapy; however, only approximately 21% of patients respond. Sacituzumab govitecan (SG) is a trophoblast cell surface antigen-2-directed antibody-drug conjugate with US Food and Drug Administration-accelerated approval to treat patients with locally advanced or mUC who previously received platinum-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report the primary analysis of TROPHY-U-01 cohort 3. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Patients were CPI-naïve and had mUC progression after platinum-based chemotherapy in the metastatic setting or ≤12 months in the (neo)adjuvant setting. Patients received 10 mg/kg of SG once on days 1 and 8 and 200 mg of pembrolizumab once on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per central review. Secondary end points included clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS) per central review, and safety. RESULTS: Cohort 3 included 41 patients (median age 67 years; 83% male; 78% visceral metastases [29% liver]). With a median follow-up of 14.8 months, the ORR was 41% (95% CI, 26.3 to 57.9; 20% complete response rate), CBR was 46% (95% CI, 30.7 to 62.6), median DOR was 11.1 months (95% CI, 4.8 to not estimable [NE]), and median PFS was 5.3 months (95% CI, 3.4 to 10.2). The median overall survival was 12.7 months (range, 10.7-NE). Grade ≥3 treatment-related adverse events occurred in 61% of patients; most common were neutropenia (37%), leukopenia (20%), and diarrhea (20%). CONCLUSION: SG plus pembrolizumab demonstrated a high response rate with an overall manageable toxicity profile in patients with mUC who progressed after platinum-based chemotherapy. No new safety signals were detected. These data support further evaluation of SG plus CPI in mUC.

The Evolving Landscape: Exploring the Future of Myelodysplastic Syndrome Treatment with Dr. Rami Komrokji.

This perspective delves into the evolving landscape of Myelodysplastic Syndrome (MDS) treatment. MDS presents a significant clinical challenge, often progressing to acute myeloid leukemia. For low-risk MDS, the emphasis is on personalized care through comprehensive risk assessment, clinical monitoring, and tailored interventions, including promising agents like erythropoiesis-stimulating agents, lenalidomide, and luspatercept, with the anticipation of an expanding therapeutic arsenal and early intervention for improved outcomes. In contrast, high-risk MDS treatment is evolving towards upfront doublet or triplet therapies with a focus on minimal residual disease (MRD) monitoring. A holistic approach integrates various modalities, including stem cell transplant and post-transplant maintenance, all guided by individual patient circumstances. Risk-adapted strategies are crucial for enhancing patient outcomes. Precision medicine for MDS treatment is budding, largely driven by Next Generation Sequencing (NGS). NGS aids in early diagnosis, prognostication, and the targeting of specific mutations, with molecular data increasingly informing treatment responses and allowing for tailored interventions. Clinical trials within homogeneous patient groups with similar molecular profiles are becoming more common, enhancing treatment precision. In conclusion, the future of MDS treatment is moving towards personalized medicine, leveraging advanced technologies like NGS and molecular insights to improve outcomes in the realm of hematological malignancies.

The Potential of Lifestyle Medicine: Strategies to Optimize Health and Well-Being in Oncology Care with Dr. Amy Comander.

The field of lifestyle medicine in cancer care and survivorship is undergoing significant transformation, presenting both challenges and opportunities. This collection of insights and reflections by an esteemed speaker aims to address critical facets of this evolving landscape and the intersection of healthcare, lifestyle, and cancer. With a focus on optimizing the health of cancer survivors, the speaker emphasizes the correlation between general population health and strategies for mitigating cancer risk. Evidence-based resources have a key role in their comprehensive insights into lifestyle changes' role in cancer prevention and survivorship. Lifestyle interventions also have a promising role in mitigating the late effects in the pediatric context. Therefore, encouraging the early adoption of healthy practices in childhood cancer survivors emerges as a pivotal strategy. Furthermore, challenges in enhancing education and access to lifestyle medicine are addressed. This highlights the importance of patient-centered communication, motivational interviewing, and personalized guidance in facilitating lifestyle changes with patients. Finally, the role of nutritionists in advising breast cancer patients to consider calorie restriction to lower IGF-1 levels is explored. This collection underscores the multifaceted nature of lifestyle medicine in cancer care, highlighting challenges, opportunities, and the transformative power of passion and curiosity in shaping healthcare careers.

Cancer and COVID-19: unravelling the immunological interplay with a review of promising therapies against severe SARS-CoV-2 for cancer patients.

Cancer patients, due to their immunocompromised status, are at an increased risk for severe SARS-CoV-2 infection. Since severe SARS-CoV-2 infection causes multiple organ damage through IL-6-mediated inflammation while stimulating hypoxia, and malignancy promotes hypoxia-induced cellular metabolic alterations leading to cell death, we propose a mechanistic interplay between both conditions that results in an upregulation of IL-6 secretion resulting in enhanced cytokine production and systemic injury. Hypoxia mediated by both conditions results in cell necrosis, dysregulation of oxidative phosphorylation, and mitochondrial dysfunction. This produces free radicals and cytokines that result in systemic inflammatory injury. Hypoxia also catalyzes the breakdown of COX-1 and 2 resulting in bronchoconstriction and pulmonary edema, which further exacerbates tissue hypoxia. Given this disease model, therapeutic options are currently being studied against severe SARS-COV-2. In this study, we review several promising therapies against severe disease supported by clinical trial evidence-including Allocetra, monoclonal antibodies (Tixagevimab-Cilgavimab), peginterferon lambda, Baricitinib, Remdesivir, Sarilumab, Tocilizumab, Anakinra, Bevacizumab, exosomes, and mesenchymal stem cells. Due to the virus's rapid adaptive evolution and diverse symptomatic manifestation, the use of combination therapies offers a promising approach to decrease systemic injury. By investing in such targeted interventions, cases of severe SARS-CoV-2 should decrease along with its associated long-term sequelae and thereby allow cancer patients to resume their treatments.

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer.

BACKGROUND: Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown. METHODS: In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival. RESULTS: The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively). CONCLUSIONS: In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)-PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment. METHODS: We conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment. RESULTS: From June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected. CONCLUSIONS: Radioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.).

Nicotine does not reduce blood flow to healthy bone in rats.

Given the increased incidence of orthopedic complications among smokers, we tested the null hypothesis that nicotine, the most vasoactive substance in cigarettes, does not reduce blood flow to long bones. Nicotine was administered to adult rats at a rate of 2.4 or 3.6 mg/kg/d for 2 weeks to determine if nicotine has a dose-dependent effect on bone blood flow. Control rats received nicotine-free solution. After 2 weeks, the rats were anesthetized. The microsphere technique was used to measure flow to femurs and tibias. Blood was collected to measure plasma nicotine. The lower dose established a plasma level of 14 ng/mL (SEM, 4 ng/mL); the higher dose elevated nicotine to 43 ng/mL (SEM, 11 ng/mL). Neither dose altered blood flow to tibias or femurs. A higher dose or longer treatment may be required to reduce bone blood flow. Alternatively, nicotine may not reduce blood flow to healthy bone at any dose but may delay bone healing by other mechanisms (ie, inhibiting angiogenesis and/or osteogenesis).