Applications of Artificial Intelligence in Prostate Cancer Care: A Path to Enhanced Efficiency and Outcomes.

The landscape of prostate cancer care has rapidly evolved. We have transitioned from the use of conventional imaging, radical surgeries, and single-agent androgen deprivation therapy to an era of advanced imaging, precision diagnostics, genomics, and targeted treatment options. Concurrently, the emergence of large language models (LLMs) has dramatically transformed the paradigm for artificial intelligence (AI). This convergence of advancements in prostate cancer management and AI provides a compelling rationale to comprehensively review the current state of AI applications in prostate cancer care. Here, we review the advancements in AI-driven applications across the continuum of the journey of a patient with prostate cancer from early interception to survivorship care. We subsequently discuss the role of AI in prostate cancer drug discovery, clinical trials, and clinical practice guidelines. In the localized disease setting, deep learning models demonstrated impressive performance in detecting and grading prostate cancer using imaging and pathology data. For biochemically recurrent diseases, machine learning approaches are being tested for improved risk stratification and treatment decisions. In advanced prostate cancer, deep learning can potentially improve prognostication and assist in clinical decision making. Furthermore, LLMs are poised to revolutionize information summarization and extraction, clinical trial design and operations, drug development, evidence synthesis, and clinical practice guidelines. Synergistic integration of multimodal data integration and human-AI integration are emerging as a key strategy to unlock the full potential of AI in prostate cancer care.

Comparative Effectiveness of Anticoagulants in Patients With Cancer-Associated Thrombosis.

Importance: Patterns of clinical utilization and comparative effectiveness of anticoagulants for cancer-associated thrombosis (CAT) remain largely unexplored. Objectives: To assess patterns of and factors associated with anticoagulant use and to evaluate the comparative effectiveness of contemporary anticoagulants in patients with active cancer in a clinical setting. Design, Setting, and Participants: This retrospective cohort study obtained deidentified OptumLabs electronic health record claims data from January 1, 2012, to September 30, 2019. Adult patients (≥18 years of age) with a primary cancer diagnosis (except skin cancer) during at least 1 inpatient or 2 outpatient visits within 6 months before the venous thromboembolism (VTE) date were included. Data were analyzed from April 2020 to September 2021. Exposures: The patients were grouped according to the anticoagulant prescribed: (1) direct oral anticoagulants (DOACs), (2) low-molecular-weight heparin (LMWH), and (3) warfarin. Main Outcomes and Measures: Odds ratios (ORs) were used to present the association between factors of interest and utilization of anticoagulants. Main efficacy outcomes included risk of VTE recurrence and all-cause mortality. Main safety outcomes included the risk of hospitalization due to major bleeding. Relative treatment effect estimates were expressed as hazard ratios (HRs) with 95% CIs. Results: This study included 5100 patients (mean [SD] age, 66.3 [12.3] years; 2670 [52.4%] women; 799 [15.7%] Black, 389 [7.6%] Hispanic, and 3559 [69.8%] White individuals). Overall, 2512 (49.3%), 1488 (29.2%), and 1460 (28.6%) filled prescriptions for DOACs, LMWH, and warfarin, respectively. The median (IQR) treatment duration was 3.2 (1.0-6.5) months for DOACs, 3.1 (1.0-6.8) months for warfarin, and 1.8 (0.9-3.8) months for LWMH. Patients with lung (OR, 2.07; 95% CI, 1.12-3.65), urological (OR, 1.94; 95% CI,1.08-3.49), gynecological (OR, 4.25; 95% CI, 2.31-7.82), and colorectal (OR, 2.26; 95% CI, 1.20-4.32) cancer were associated with increased prescriptions for LMWH compared with DOACs. LMWH (HR, 1.47; 95% CI, 1.14-1.90) and warfarin (HR, 1.46; 95% CI, 1.13-1.87) were associated with an increased risk of VTE recurrences compared with DOACs. LMWH was associated with an increased risk of major bleeding (HR, 2.27; 95% CI, 1.62-3.20) and higher all-cause mortality (HR, 1.61; 95% CI, 1.15-2.25) compared with DOACs. Conclusions and Relevance: In this comparative effectiveness study of claims-based data, patients with CAT received anticoagulation for a remarkably short duration in clinical settings. DOACs was associated with a lower risk of VTE recurrence, major bleeding, and mortality. Warfarin may still be considered for patients with contraindications to DOACs and those with poor persistence on LMWH.

Incidence of second primary malignancies in patients with multiple myeloma receiving anti-CD38 monoclonal antibodies: A systematic review and meta-analysis.

Anti-CD38 monoclonal antibodies (mAbs) are commonly used for treating newly diagnosed and relapsed/refractory (r/r) multiple myeloma (MM). However, concerns have been raised about the occurrence of second primary malignancies (SPMs) in patients receiving anti-CD38 mAbs. Assessing the safety data for rare adverse events like SPMs is challenging because individual clinical trials are typically focused on the primary endpoint. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) published between January 2005 and April 2022, including patients with newly diagnosed or r/r MM. Our aim was to compare SPM rate with the use of anti-CD38 mAb-based regimens with other anti-myeloma regimens. After a median follow-up of 35.3 months (range: 8.2-56.2), we found that exposure to anti-CD38 mAbs was associated with an increased risk of developing SPMs compared to the control group (6.8% vs. 5.2%; Peto odds ratio [OR]: 1.53 [95% confidence interval (CI): 1.20-1.95]; I2= 0%, p-value for heterogeneity= 0.44). This increased risk was primarily driven by non-melanoma cutaneous cancers (92 vs. 47; Peto OR: 1.77 [95% CI: 1.25-2.51]; I2 = 0%, p-value for heterogeneity = 0.54). However, there was no significant difference in the incidence of solid tumors (including malignant melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) or hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27]). In conclusion, the use of anti-CD38 mAb-based combination regimens is associated with a higher risk of non-invasive cutaneous SPMs, but not solid tumors or hematologic SPMs. The increased occurrence of non-invasive cutaneous SPMs may be due to enhanced monitoring resulting from longer treatment duration with anti-CD38 mAbs.

First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer: A Living Systematic Review and Network Meta-analysis.

Importance: The effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown. Objective: To assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups. Data Sources: For this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available. Study Selection: Phase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC. Data Extraction and Synthesis: Two independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022. Main Outcomes and Measures: Outcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life. Results: This report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT. Conclusions and Relevance: The potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Disparities in the Inclusion of Racial and Ethnic Minority Groups and Older Adults in Prostate Cancer Clinical Trials: A Meta-analysis.

Importance: Prostate cancer (PCa) is marked by disparities in clinical outcomes by race, ethnicity, and age. Equitable enrollment in clinical trials is fundamental to promoting health equity. Objective: To evaluate disparities in the inclusion of racial and ethnic minority groups and older adults across PCa clinical trials. Data Sources: MEDLINE, Embase, and ClinicalTrials.gov were searched to identify primary trial reports from each database's inception through February 2021. Global incidence in age subgroups and US population-based incidence in racial and ethnic subgroups were acquired from the Global Burden of Disease and Surveillance, Epidemiology, and End Results 21 incidence databases respectively. Study Selection: All phase 2/3 randomized PCa clinical trials were eligible for age disparity analyses. Trials recruiting exclusively from the US were eligible for primary racial and ethnic disparity analyses. Data Extraction and Synthesis: This study was reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Data were pooled using a random-effects model. Main Outcomes and Measures: Enrollment incidence ratios (EIRs), trial proportions (TPs) of participants 65 years or older or members of a racial and ethnic subgroup divided by global incidence in the corresponding age group, or US population-based incidence in the corresponding racial and ethnic subgroup, were calculated. Meta-regression was used to explore associations between trial characteristics and EIRs and trends in EIRs during the past 3 decades. Results: Of 9552 participants among trials reporting race, 954 (10.8%) were African American/Black, 80 (1.5%) were Asian/Pacific Islander, and 8518 (78.5) were White. Of 65 US trials, 45 (69.2%) reported race and only 9 (13.8%) reported data on all 5 US racial categories. Of 286 global trials, 75 (26.2%) reported the enrollment proportion of older adults. Outcomes by race and age were reported in 2 (3.1%) and 41 (15.0%) trials, respectively. Black (EIR, 0.70; 95% CI, 0.59-0.83) and Hispanic (EIR, 0.70; 95% CI, 0.59-0.83) patients were significantly underrepresented in US trials. There was no disparity in older adult representation (TP, 21 143 [71.1%]; EIR, 1.00; 95% CI, 0.95-1.05). The representation of Black patients was lower in larger trials (meta-regression coefficient, -0.06; 95% CI, -0.10 to -0.02; P = .002). Conclusions and Relevance: The results of this meta-analysis suggest that Black and Hispanic men are underrepresented in trials compared with their share of PCa incidence. The representation of Black patients has consistently remained low during the past 2 decades.

Quantifying absolute benefit for adjuvant treatment options in renal cell carcinoma: A living interactive systematic review and network meta-analysis.

OBJECTIVE: To assess comparative effectiveness of adjuvant therapies for renal cell carcinoma and quantify the absolute benefit of adjuvant treatments by clinicopathological risk groups. METHODS: This 'living' review was conducted using Living Interactive Evidence (LIvE) synthesis framework. RESULTS: The 'living' results are available on an interactive website. This network meta-analysis, including six RCTs with 7525 participants, showed that pembrolizumab (rank 1) significantly improved disease-free survival and overall survival compared with sunitinib but not when compared to pazopanib, and axitinib. The risk of treatment-related grade 3 or higher adverse events was increased with pembrolizumab as compared to placebo and axitinib but not when compared to sunitinib. The absolute benefit of adjuvant pembrolizumab increases substantially with larger tumor size, nodal positivity and higher Leibovich scores. CONCLUSION: Current evidence suggests that pembrolizumab delays disease progression compared to sunitinib. A risk-adapted strategy should be used in patients undergoing consideration for treatment with adjuvant pembrolizumab.

Direct Oral Anticoagulants Compared With Dalteparin for Treatment of Cancer-Associated Thrombosis: A Living, Interactive Systematic Review and Network Meta-analysis.

OBJECTIVE: To maintain living, interactive evidence (LIvE) on the benefits and harms of different treatment options in adults with cancer-associated thrombosis (CAT). METHODS: We have used a novel LIvE synthesis framework to maintain this living, interactive systematic review since September 19, 2018. Randomized controlled trials evaluating the efficacy and safety of direct oral anticoagulants (DOACs) compared with low-molecular-weight heparin for CAT are included in this analysis. Details of LIvE synthesis framework are available at the website https://cat.network-meta-analysis.com. RESULTS: The results are constantly updated as new information becomes available (https://cat.network-meta-analysis.com/CAT.html). The living, interactive systematic review currently includes 4 randomized controlled trials (N=2894). Direct comparisons show that DOACs significantly decrease recurrent venous thromboembolism (VTE) events compared with dalteparin (odds ratio [OR], 0.59; 95% CI, 0.41 to 0.86; I2, 25%) without significantly increasing major bleeding (OR, 1.34; 95% CI, 0.83 to 2.18; I2, 28%). Mixed treatment comparisons show that apixaban (OR, 0.41; 95% credible interval [CrI], 0.16 to 0.95) and rivaroxaban (OR, 0.58; 95% CrI, 0.37 to 0.90) significantly decrease VTE recurrent events compared with dalteparin. Edoxaban significantly increases major bleeding compared with dalteparin (OR, 1.73; 95% CrI, 1.04 to 3.16), and rivaroxaban significantly increases clinically relevant nonmajor bleeding compared with dalteparin and other DOACs. There are no significant differences between DOACs in terms of VTE recurrences and major bleeding. CONCLUSION: DOACs should be considered a standard of care for the treatment of CAT except in patients with a high risk of bleeding. Current evidence favors the use of apixaban for the treatment of CAT among other DOACs. REGISTRATION: Open Science Framework (https://osf.io/dth86).

Outcomes of Revascularization and Factors Associated With Major Amputation in Patients With Lower Limb Arterial Injury: A Single-Center Retrospective Analysis.

Objective To identify the amputation rates and causative factors for failed revascularization leading to amputation in patients undergoing primary limb salvage procedures for lower-extremity vascular injuries. Methods This retrospective study was conducted at the vascular surgery department, Shaheed Mohtarma Benazir Bhutto (SMBB) Institute of Trauma, Karachi, Pakistan. The data were collected from hospital record using the non-probability sampling technique. Patients aged 17-70 years, undergoing primary revascularization during April 2016 to March 2021, were included in the study. Patients with crush injuries/non-salvageable limbs underwent primary amputation, isolated deep femoral artery or crural arteries (non-limb threatening) injuries, and non-traumatic injuries like intravenous drug-induced or iatrogenic injuries were excluded. The data analysis is done using SPSS Version 20.0 (IBM Corp., Armonk, NY, USA). A P-value of <0.05 was considered as significant. Results This study includes 56 patients of mean age 30.82 ± 9.29 years with male gender four times more affected than their counterpart. About 32% of patients were smokers, while 58% of patients had no co-morbidities. All patients presented with a mean time of 7.66 ± 1.69 hours of injury with an average of 1.14 arterial segments involved. The most frequent artery involved was popliteal artery (both above and below the knee), followed by superficial femoral artery injury constituting 50% and 26%, respectively, with arterial laceration and transection being common findings on exploration. Out of 56 patients, 27 (48.2%) had open fractures, 21 (37.5% ) closed fractures, and eight patients (14.3 % ) presented with dislocation as associated injuries. Following the procedure, secondary amputation was recorded in 18 (32.1%) patients. Thrombosis and infection were the leading causes of revascularization failure. Type of injury, segment of arterial injury, and associated bony injuries were associated with limb amputation. Conclusion Type and site of injury along with concomitant bony injuries are associated with major amputations after revascularization in lower-extremity arterial injuries.

Adjuvant Tyrosine Kinase Inhibitors in Renal Cell Carcinoma: A Concluded Living Systematic Review and Meta-Analysis.

PURPOSE: Multiple large clinical trials have investigated adjuvant tyrosine kinase inhibitors (TKIs) to reduce the risk of cancer recurrence and progression to metastasis in high-risk renal cell carcinoma. We sought to maintain living and interactive evidence on this topic, until a high level of certainty is reached for key clinical outcomes such that further updates become unnecessary and unlikely to change clinical practice. METHODS: We created a living interactive evidence synthesis platform to maintain a continuously updated meta-analysis on TKI monotherapy in adjuvant renal cell carcinoma. We implemented an automated search strategy with weekly updates to identify randomized phase 2 and 3 clinical trials. Study selection, appraisal, and data extraction were done in duplicate. Cumulative meta-analysis was performed using Analyzer Module in Living Interactive Evidence platform. For each outcome (overall survival [OS], disease-free survival [DFS], and all-cause and treatment-related adverse events), we assessed certainty of evidence using GRADE approach and conducted trial sequential analysis. RESULTS: This final update includes five randomized trials including recently updated data from PROTECT trial. Meta-analysis shows that adjuvant TKI monotherapy offers no benefit in OS (hazard ratio, 1.01; 95% CI, 0.91 to 1.12, high certainty) or DFS (hazard ratio, 0.92; 95% CI, 0.86 to 1.00, high certainty) and significantly increases adverse event risk. Lack of benefit was consistent across subgroups including highest-risk patients (test for subgroup differences: P = .32). Optimal information size criteria were met, and there was high certainty of evidence for lack of DFS and OS benefit for adjuvant TKIs. CONCLUSION: There is no guidance on when to stop maintaining a living review. In this example, we used trial sequential analysis and high certainty of evidence (future clinical trials unlikely to change current conclusions) as a benchmark to conclude a living review in view of convincing evidence.

A Living, Interactive Systematic Review and Network Meta-analysis of First-line Treatment of Metastatic Renal Cell Carcinoma.

CONTEXT: Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations. OBJECTIVE: To maintain living evidence for contemporary first-line treatment for previously untreated mRCC. EVIDENCE ACQUISITION: We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence-assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner. EVIDENCE SYNTHESIS: As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps. CONCLUSIONS: This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons. PATIENT SUMMARY: It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.

Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma: A Systematic Review and Network Meta-analysis.

Importance: The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials. Objective: To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy. Data Sources: We searched various databases for abstracts and full-text articles published from database inception through March 2020. Study Selection: We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting. Data Extraction and Synthesis: The reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model. Main Outcomes and Measures: Outcomes of interest included overall (OS) and progression-free survival (PFS). Findings: Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others. Conclusions and Relevance: This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.

Thyroid and Heart: Severe Three Vessel Coronary Artery Disease in a Middle-Aged Female with Hypothyroidism.

Hypothyroidism is a common medical condition. The low metabolic state in hypothyroidism leads to significant cardiovascular and hemodynamic changes. Hypothyroidism is associated with heart failure, diastolic hypertension, atherosclerosis, coronary artery disease (CAD), and decreased insulin sensitivity. Similarly, the administration of levothyroxine worsens the cardiovascular disease by establishing a supply-demand mismatch. Here, we present a case of a 45-year-old woman with hypothyroidism who presented to us with exertional chest pain and later got diagnosed with severe three-vessel disease. Coronary artery bypass grafting (CABG) surgery was planned after the establishment of euthyroid state.