Patients Experienced Disease Progression Research Articles

Longitudinal assessment of the progression of severe keratoconus based on corneal topography

We aimed to assess long-term disease progression in patients with severe keratoconus (KC). Clinical records of 125 patients (201 eyes) with severe KC followed-up for > 12 months were retrospectively analyzed. From these, 28 patients (31 eyes) were included. Corneal topography parameters evaluated included thinnest corneal thickness (TCT), maximum keratometry (Kmax), anterior and posterior mean corneal radii of 3 mm (aKM, pKM), steep keratometry, and KC screening indices. All patients wore rigid gas permeable contact lenses (RGPCLs) for an extended period. The median patient age and follow-up period were 20 (interquartile range [IQR] 17–22) years and 25 (15–38) months, respectively. Compared to baseline, the aKM, Kmax, and KC screening indices on the anterior corneal surface were reduced at the final follow-up (P < 0.05). No changes were observed in RGP-corrected visual acuity, TCT, pKM, or KC screening indices on the posterior corneal surface. The higher the baseline value, the greater the reduction in aKM and Kmax. Five patients (16%) experienced disease progression during follow-up. Patients with severe KC showed reduced anterior corneal surface curvature and no change in corneal thickness during an average follow-up period of 2–3 years while wearing RGPCLs.

Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR-Mutant, Metastatic Nonsquamous Non-Small Cell Lung Cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non-small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum-based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837). Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS. Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients. Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Lenvatinib and pembrolizumab in patients with metastatic papillary renal cell carcinoma: A phase 2 pilot study.

109 Background: Traditionally, metastatic papillary renal cell carcinoma (papillary mRCC) has been treated with tyrosine kinase inhibitors, resulting in a 23% objective response rate and a progression-free survival of 9 months (SWOG 1500 trial). Combinations of immunotargeted therapy have shown improved outcomes in clear-cell mRCC. This prospective pilot study aimed to evaluate the preliminary efficacy of combining lenvatinib with pembrolizumab in patients with papillary mRCC. Methods: At study entry in August 2021, patients with papillary mRCC types 1 or 2, multiple measurable lesions per RECIST 1.1 criteria, and no prior therapy for advanced disease were included. The primary endpoint was the objective response rate. The study employed Simon's two-stage design (Simon, 1989) to test the null hypothesis that the true response rate is 23% against a one-sided alternative. In the first stage, 5 patients were enrolled. If there were 1 or fewer responses among these initial 5 patients, the study would be halted. The null hypothesis would be rejected if 6 or more responses were observed in the entire cohort of 12 patients. This design yields a type I error rate of 0.05 and power of 0.8 when the true response rate is 63%. Results: As planned, 5 patients were enrolled in the stage 1. The median age was 57.4 years. Among them, 4 patients were diagnosed with papillary RCC type 2, and 3 patients had an unresected primary tumor. Additionally, 1 patient presented with brain metastases. The objective response rate was 100%, of which there was 1 complete and 4 partial responses. As of the last follow-up, the status of patients on therapy was as follows: i) three patients remained on therapy for more than 12 months; ii) one patient experienced disease progression after 14.3 months of treatment; iii) one patient who initially had an ongoing response developed grade 3 uncontrolled diarrhea after 5.5 months from the start of therapy. Despite the positive outcomes observed in stage 1 of the study, the enrollment was stopped. This decision was influenced by emerging results from the large phase 2 trial KEYNOTE-B61, as reported by Chung-Han Lee et al. (ASCO 2023). Conclusions: All patients responded to lenvatinib and pembrolizumab therapy. These results suggest promising efficacy of the combination in metastatic papillary RCC. Clinical trial information: KCRB01012021 .

Evaluation of American Urological Association Renal Cell Carcinoma Risk Groups for Chromophobe Renal Cell Carcinoma

ObjectivesTo develop and compare various models for risk stratification in chromophobe renal cell carcinoma (chrRCC). Models have been developed to predict progression-free (PFS) and cancer-specific survival (CSS) following surgery for localized renal cell carcinoma (RCC). Notably, chromophobe RCC (chrRCC) is not included in American Urological Association (AUA) risk stratification, as nuclear grading is not recommended. MethodsWe queried our institutional registry to identify patients managed surgically for unilateral, sporadic, M0, chrRCC from 1970-2012. AUA risk groups were defined using reported criteria, excluding grade, and were compared to the Mayo system incorporating nodal involvement, perinephric/renal sinus fat invasion, and sarcomatoid differentiation. PFS and CSS were estimated using the Kaplan-Meier method. Predictive ability was summarized using c-indexes from Cox proportional hazard regression models. ResultsA total of 257 patients were identified. Thirty-nine patients experienced disease progression at a median 30 months (IQR 5.0-84) and 25 died from chrRCC at a median 34 months (IQR 15-79) following surgery. PFS and CSS rates at 10 years after surgery were 84% and 90%, respectively. C-indexes for modified AUA and Mayo risk groups were similar at 0.76 and 0.75, respectively, for PFS, and 0.77 and 0.76, respectively for CSS. ConclusionsThe modified AUA and Mayo risk stratification systems have similarly robust c-indexes for PFS and CSS in chrRCC. These models can be used to counsel patients based on pathologic features, inform clinicians on appropriate follow-up pathways, and identify patients at risk of disease progression for enrollment in adjuvant systemic therapy trials.

Combination Therapy of Pyrotinib and Metronomic Vinorelbine in HER2+ Advanced Breast Cancer After Trastuzumab Failure (PROVE): A Prospective Phase 2 Study.

Approximately 50-74% of patients with metastatic HER2-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cut-off date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI: 8.3-18.5). With all patients evaluated, an ORR of 38.9% (95% CI: 23.1-56.5%) and a DCR of 83.3% (95% CI: 67.2-93.6%) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

A Retrospective Evaluation of the Treatment Effects of Rituximab in Patients with Progressive and Symptomatic Fibrosing Mediastinitis.

Rationale: Fibrosing mediastinitis (FM) is an uncommon fibroinflammatory condition without established or effective medical therapies. Infiltrating B lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures, including blood vessels and airways, resulting in significant morbidity and mortality. Objective: To evaluate the benefits and side effects of rituximab in patients with progressive and symptomatic FM. Methods: We treated 22 patients (median age, 35 yr; range, 15-68 yr; 45% female) with metabolically active, progressive FM with rituximab on an off-label basis. Additionally, patients were administered pneumocystis and antifungal prophylaxis when immunosuppressed with rituximab. Modeling of longitudinal treatment response based on changes in relative lesion volume from baseline was performed retrospectively using functional data analysis, and time-to-event modeling was performed to estimate treatment response rates based on a >30% reduction in pretreatment volume. The primary endpoints were lack of disease progression and change in mediastinal lesion volume on computed tomography (evaluated retrospectively). Results: No patient experienced disease progression after rituximab therapy. Median clinical follow-up was 42 months (range, 7-94 mo) and imaging follow-up 21 months (range, 7-62 mo). A total of 82% of patients had confirmed histoplasmosis-associated FM. After rituximab treatment, a 49.6% (95% confidence interval, 17.5-64.4%) mean estimated decrease in pretreatment lesion volume was observed at 24 months. The estimated objective treatment response rate was 47.9% (95% confidence interval, 26.7-70.3%). Conclusions: This observational study suggests that rituximab is a well tolerated and potentially effective therapy in a cohort of patients with symptomatic and progressive FM.

Antibody-drug conjugates in metastatic breast cancer: sequencing, combinations and resistances.

Significant advancements have been made in treating metastatic breast cancer (MBC) with antibody drug conjugates (ADCs). However, due to the development of resistance, patients experience disease progression. The aim of this review is to summarize current evidence on ADCs sequencing strategies and combination approaches in the treatment of MBC. Concerning HER2 positive MBC, current evidence on the optimal ADC-sequencing is primarily about T-DXd, which demonstrated therapeutic value when used post-T-DM1. Conversely, data are limited about the reverse sequence. Similarly, in HER2-negative MBC, recent studies evaluated the sequential use of Sacituzumab Govitecan and T-DXd, which was associated with poor responses. Retrospective analyses have not demonstrated an optimal sequencing strategy for ADCs, and it is still very unclear whether switching the payload or targeting a different antigen may represent the best approach. Combinations may better overcome ADC resistance: interesting data associating immunotherapy or tyrosine kinase inhibitors to ADCs appear promising, albeit data are still immature. In MBC, ADCs have expanded treatment options but their sequential use requires further study. Evidence suggests that sequencing ADCs with similar payloads is ineffective, though current data are inconclusive. More research is needed to optimize treatment strategies, including potential combination therapies.

Diagnosis, management and follow-up of follicular lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

Detection of HPV DNA in Saliva of Patients with HPV-Associated Oropharyngeal Cancer Treated with Radiotherapy.

To investigate the technical feasibility of RT-PCR and direct sequencing to quantify HPV DNA in the saliva of patients with Human-Papilloma-Virus related oropharyngeal cancer (HPV-OPC), the level of which is known to predict prognosis after treatment. Nine patients with locally advanced HPV-OPC treated with definitive radiotherapy with chemotherapy or cetuximab, or radiotherapy alone between April 2016 and September 2017, were enrolled, two of whom also received induction chemotherapy. Saliva was collected before (baseline), during (mid-RT) and after (post-RT) radiotherapy. HPV-16 DNAs (E6 and E7) in saliva were quantified by RT-PCR and sequencing, the latter using a custom cancer panel. Correlations between HPV DNA levels and clinical outcomes were assessed. Compared to the baseline, the relative cycle threshold (Ct) value of E6 and E7 reduced at the point of mid-RT in the majority of the patients (100% and 75% for E6 and E7, respectively). Similarly, the relative Ct value from the baseline to post-RT reduced in 86% and 100% of the patients for E6 and E7, respectively. During the follow-up period, three patients (33%) experienced disease progression. The relative baseline Ct values of these three patients were in the top 4 of all the patients. The sequences of HPV DNA were detected in five (83%) of six samples of the baseline saliva that underwent DNA sequencing, along with several gene mutations, such as TP53,CDKN2A and PIK3CA. This study demonstrates that, in addition to detection and quantification of HPV DNA by RT-PCR, detection by sequencing of HPV-DNA using a customized cancer panel is technically possible.

Prognostic Role of Pre-Treatment Body Composition Parameters in Patients Undergoing First-Line Immunotherapy for Metastatic Renal Cell Carcinoma.

We investigated the relationship between body mass index (BMI), radiological body composition, and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) underwent first-line immune checkpoint inhibitor (ICI)-based therapy. Analyzing data from 102 patients treated between November 2019 and March 2023, pre-treatment computed tomography (CT) scans assessed fat and muscle areas. BMI and body composition indices were examined, including skeletal muscle index, subcutaneous fat index (SFI), visceral fat index, and total fat index. Kaplan-Meier curves and Log rank tests compared progression-free survival (PFS) and overall survival (OS), while multivariable Cox proportional regression analysis was performed to identify the variables significantly associated with survival outcomes. 54 patients (52.9%) experienced disease progression, and 26 (25.5%) died during a median follow-up of 17.4 months. High SFI was significantly associated with improved OS (p = 0.018) but not PFS (p = 0.090). Multivariable analysis confirmed the positive impact of high SFI on OS (adjusted HR: 0.37, p = 0.029) and suggested a trend towards improved PFS (adjusted HR: 0.61, p = 0.088). Notably, in the ipilimumab + nivolumab subgroup, high SFI significantly correlated with both PFS and OS (p = 0.047 and p = 0.012, respectively). High SFI predicts favorable OS in patients with mRCC receiving first-line ICI-based therapy, especially patients treated with ipilimumab + nivolumab displayed a significant association between high SFI and favorable PFS and OS.

Baseline 18F-FDG PET/CT radiomics for prognosis prediction in diffuse large B cell lymphoma with extranodal involvement.

The objective of this investigation is to explore the capability of baseline 18F-FDG PET/CT radiomics to predict the prognosis of diffuse large B-cell lymphoma (DLBCL) with extranodal involvement (ENI). 126 patients diagnosed with DLBCL with ENI were included in the cohort. The least absolute shrinkage and selection operator (LASSO) Cox regression was utilized to refine the optimum subset from the 1328 features. Cox regression analyses were employed to discern significant clinical variables and conventional PET parameters, which were then employed with radiomics score to develop combined model for predicting both progression-free survival (PFS) and overall survival (OS). The fitness and the predictive capability of the models were assessed via the Akaike information criterion (AIC) and concordance index (C-index). 62 patients experienced disease recurrence or progression and 28 patients ultimately died. The combined model exhibited a lower AIC value compared to the radiomics model and SDmax/clinical variables for both PFS (507.101 vs. 510.658 vs. 525.506) and OS (215.667 vs. 230.556 vs. 219.313), respectively. The C-indices of the combined model, radiomics model, and SDmax/clinical variables were 0.724, 0.704, and 0.615 for PFS, and 0.842, 0.744, and 0.792 for OS, respectively. Kaplan--Meier curves showed significantly higher rates of relapse and mortality among patients classified as high-risk compared to those classified as low-risk (all P < 0.05). The combined model of clinical variables, conventional PET parameters, and baseline PET/CT radiomics features demonstrates a higher accuracy in predicting the prognosis of DLBCL with ENI.

A two-stage maintenance trial of cetuximab-based treatment in RAS and BRAF wild-type unresectable metastatic colorectal cancer: a retrospective real-world study.

To investigate the effectiveness and safety of maintenance regimens based on cetuximab, we conducted a real-world, single-arm, retrospective study at a single center. In Fujian Medical University Union Hospital, patients with unresectable metastatic colorectal cancer (mCRC) who received cetuximab-based maintenance therapy between December 2020 and December 2021 were included. All patients had RAS and BRAF wild-type. The maintenance regimen consisted of 6-12 cycles of cetuximab plus irinotecan (Phase 1) and cetuximab (Phase 2). Patients could receive reintroduction therapy in case of disease progression during Phase 2. Progression-free survival (PFS), overall survival (OS), and safety data were collected. According to the inclusion and exclusion criteria of the study, a total of 108 subjects who received maintenance therapy were included- 51 experienced disease progression during Phase 1, with PFS (1) of 7.3 months. Among the 52 patients who entered Phase 2, 17 were still in this phase at the end of follow-up, with PFS (2) of 10.1 months. In Phase 2, 35 patients experienced disease progression, of whom 24 received reintroduction therapy, with PFS (3) of 6.7 months. The overall PFS (total) during the maintenance period was 11.9 months, and the OS was 39.2 months. Grade III or higher adverse events were 4.6% during Phase 1 and 0% during Phase 2. Innovative cetuximab-based maintenance therapy showed a trend toward improving the prognosis of mCRC patients with RAS and BRAF wild-type, while the toxic side effects of maintenance therapy were manageable. https://www.chictr.org.cn, identifier ChiCTR2000040940.

Post-Progression Analysis of EGFR-Mutant NSCLC Following Osimertinib Therapy in Real-World Settings.

Platinum-based chemotherapy is the current standard treatment option in patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who progress on osimertinib. However, outcomes with chemotherapy are dismal, and the treatment of central nervous system (CNS) disease is an unmet need in this setting. Patients with EGFR-mutant NSCLC who were candidates to receive osimertinib in the metastatic setting at our Center from 2015 to 2022 were retrospectively evaluated to identify patients who received standard platinum-based chemotherapy post-osimertinib. Data were collected on treatment outcomes, with a focus on brain metastases and progression patterns. A total of 220 patients received indication for osimertinib in the study period; n = 176 had adequate follow-up data. Overall, n = 117 patients experienced disease progression on osimertinib. The median time to osimertinib progressive disease (PD) was 15 months (95% confidence interval CI 13-18). Of them, 51 patients (45%) had no access to further treatments. Of the remaining patients, n = 8 received experimental treatments, and n = 55 received standard platinum-based chemotherapy and were considered for this study. Median duration of chemotherapy was 3 months (95% CI 2-5); the best responses among 53 evaluable patients were observed as follows: 15% partial response/complete response (PR/CR), 40% stable disease (SD), 45% PD. Median progression-free survival (PFS) and overall survival (OS) were 3 (95% CI 2-5) and 10 (95% CI 6-15) months, respectively. All patients had baseline and follow-up brain radiologic assessments, and n = 23 had brain metastases at the start of chemotherapy. With a median follow-up of 13 months, intracranial PD occurred in 47% patients, being the first site of PD in 59% of cases. The median time for intracranial (IC) PD was 2 months (95% CI 2-7). IC PD occurred as oligometastatic in 29%, whereas in 71% of cases, it was associated with systemic PD. Access to subsequent treatments and CNS progression are confirmed unmet needs in EGFR-mutant NSCLC patients. Clinical and CNS-specific outcomes in patients receiving standard chemotherapy after the failure of osimertinib are dismal. Novel upfront treatment options with demonstrated prolonged PFS and better CNS outcomes may help address this important issue.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

Robot-assisted laparoendoscopic single-site retroperitoneal nephroureterectomy with bladder cuff excision for upper tract urothelial carcinomas: Preliminary experience

ObjectiveTo present a modified technique for robot-assisted laparoendoscopic single-site retroperitoneal nephroureterectomy (RLESS-RNU) with bladder cuff excision and evaluate its effectiveness as a minimally invasive approach for managing upper tract urothelial carcinoma (UTUC). MethodsFifteen patients who underwent RLESS-RNU for UTUC between April 2020 and June 2021 were reviewed by our medical institution (The Second Affiliated Hospital of Nanjing Medical University), from our prospectively maintained institutional database. The da Vinci® Xi system (Intuitive Surgical, Sunnyvale, CA, USA) was utilized for surgical procedures on all patients. An in-depth analysis was conducted on their baseline demographic characteristics, pathological factors, and perioperative details. The complete surgical process and details are elaborated. ResultsThe median age of 15 patients was 67 years. The final pathology demonstrated 46.67% (7/15) patients with the pT1 stage or lower and 46.67% (7/15) with the pT3 stage; one patient could not undergo pathological staging because of preoperative chemotherapy. The perioperative outcomes revealed that the mean operative time was 185 (standard deviation [SD] 23.05) min. The time for the trocar placement including primary docking was 15 (SD 0.85) min and the time of second docking was 8 (SD 0.52) min. The median of estimated blood loss was 55 mL. The mean drainage tube duration and postoperative stay were 7.50 days and 11.00 days, respectively. After a mean follow-up period of 24.20 months, the relapse-free survival rate was 86.67%. Two patients experienced disease progression; one patient exhibited multifocal evidence of non-muscle invasive bladder cancer, and another patient developed systemic recurrence. ConclusionsThis study demonstrates the modified technique for RLESS-RNU is safe and satisfactory for UTUC.

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: Extended follow-up of a multicenter, retrospective real-world experience with 321 cases outside of controlled clinical trials.

The ELOQUENT-3 trial demonstrated the superiority of the combination of elotuzumab, pomalidomide, and dexamethasone (EloPd) in terms of efficacy and safety, compared to Pd in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor. The present study is an 18-month follow-up update of a previously published Italian real-life RRMM cohort of patients treated with EloPd. This revised analysis entered 319 RRMM patients accrued in 41 Italian centers. After a median follow-up of 17.7months, 213 patients (66.4%) experienced disease progression or died. Median progression-free survival (PFS) and overall survival (OS) were 7.5 and 19.2months, respectively. The updated multivariate analysis showed a significant reduction of PFS benefit magnitude both in advanced International Staging System (ISS) (II and III) stages and previous exposure to daratumumab cases. Instead, advanced ISS (II and III) stages and more than 2 previous lines of therapy maintained an independent prognostic impact on OS. Major adverse events included grade three-fourths neutropenia (24.9%), anemia (13.4%), lymphocytopenia (15.5%), and thrombocytopenia (10.7%), while infection rates and pneumonia were 19.3% and 8.7%, respectively. A slight increase in the incidence of neutropenia and lymphocytopenia was registered with longer follow-up. In conclusion, our real-world study still confirms that EloPd is a safe and possible therapeutic choice for RRMM. Nevertheless, novel strategies are desirable for those patients exposed to daratumumab.

Short-term efficacy of microwave ablation in the treatment of liver cancer and its effect on immune function

BACKGROUND Hepatectomy is the first choice for treating liver cancer. However, inflammatory factors, released in response to pain stimulation, may suppress perioperative immune function and affect the prognosis of patients undergoing hepatectomies. AIM To determine the short-term efficacy of microwave ablation in the treatment of liver cancer and its effect on immune function. METHODS Clinical data from patients with liver cancer admitted to Suzhou Ninth People’s Hospital from January 2020 to December 2023 were retrospectively analyzed. Thirty-five patients underwent laparoscopic hepatectomy for liver cancer (liver cancer resection group) and 35 patients underwent medical image-guided microwave ablation (liver cancer ablation group). The short-term efficacy, complications, liver function, and immune function indices before and after treatment were compared between the two groups. RESULTS One month after treatment, 19 patients experienced complete remission (CR), 8 patients experienced partial remission (PR), 6 patients experienced stable disease (SD), and 2 patients experienced disease progression (PD) in the liver cancer resection group. In the liver cancer ablation group, 21 patients experienced CR, 9 patients experienced PR, 3 patients experienced SD, and 2 patients experienced PD. No significant differences in efficacy and complications were detected between the liver cancer ablation and liver cancer resection groups (P &gt; 0.05). After treatment, total bilirubin (41.24 ± 7.35 vs 49.18 ± 8.64 μmol/L, P &lt; 0.001), alanine aminotransferase (30.85 ± 6.23 vs 42.32 ± 7.56 U/L, P &lt; 0.001), CD4+ (43.95 ± 5.72 vs 35.27 ± 5.56, P &lt; 0.001), CD8+ (20.38 ± 3.91 vs 22.75 ± 4.62, P &lt; 0.001), and CD4+/CD8+ (2.16 ± 0.39 vs 1.55 ± 0.32, P &lt; 0.001) were significantly different between the liver cancer ablation and liver cancer resection groups. CONCLUSION The short-term efficacy and safety of microwave ablation and laparoscopic surgery for the treatment of liver cancer are similar, but liver function recovers quickly after microwave ablation, and microwave ablation may enhance immune function.

Combination Targeted Therapy with Pembrolizumab and Lenvatinib in Progressive, Radioiodine-Refractory Differentiated Thyroid Cancers.

Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients. We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days. In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0-17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1. Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib.

A Systematic Review of Modeling Approaches to Evaluate Treatments for Relapsed Refractory Multiple Myeloma: Critical Review and Considerations for Future Health Economic Models.

Multiple myeloma is a rare incurable hematological cancer in which most patients relapse or become refractory to treatment. This systematic literature review aimed to critically review the existing economic models used in economic evaluations of systemic treatments for relapsed/refractory multiple myeloma and to summarize how the models addressed differences in the line of therapy and exposure to prior treatment. Following a pre-approved protocol, literature searches were conducted on 17 February, 2023, in relevant databases for models published since 2014. Additionally, key health technology assessment agency websites were manually searched for models published as part of submission dossiers since 2018. Reported information related to model conceptualization, structure, uncertainty, validation, and transparency were extracted into a pre-defined extraction sheet. In total, 49 models assessing a wide range of interventions across multiple lines of therapy were included. Only five models specific to heavily pre-treated patients and/or those who were refractory to multiple treatment classes were identified. Most models followed a conventional simple methodology, such as partitioned survival (n = 28) or Markov models (n = 9). All included models evaluated specific interventions rather than the whole treatment sequence. Where subsequent therapies were included in the model, these were generally only considered from a cost and resource use perspective. The models generally used overall and progression-free survival as model inputs, although data were often immature. Sensitivity analyses were frequently reported (n = 41) whereas validation was only considered in less than half (n = 19) of the models. Published economic models in relapsed/refractory multiple myeloma rarely followed an individual patient approach, mainly owing to the higher need for complex data assumptions compared with simpler modeling approaches. As many patients experience disease progression on multiple treatment lines, there is a growing need for modeling complex treatment strategies, leading to more sophisticated approaches in the future. Maintaining transparency, high reporting standards, and thorough analyses of uncertainty are crucial to support these advancements.

Epigenetic and Genomic Hallmarks of PARP-Inhibitor Resistance in Ovarian Cancer Patients.

Patients with advanced-stage epithelial ovarian cancer (EOC) receive treatment with a poly-ADP ribose-polymerase (PARP) inhibitor (PARPi) as maintenance therapy after surgery and chemotherapy. Unfortunately, many patients experience disease progression because of acquired therapy resistance. This study aims to characterize epigenetic and genomic changes in cell-free DNA (cfDNA) associated with PARPi resistance. Blood was taken from 31 EOC patients receiving PARPi therapy before treatment and at disease progression during/after treatment. Resistance was defined as disease progression within 6 months after starting PARPi and was seen in fifteen patients, while sixteen patients responded for 6 to 42 months. Blood cfDNA was evaluated via Modified Fast Aneuploidy Screening Test-Sequencing System (mFast-SeqS to detect aneuploidy, via Methylated DNA Sequencing (MeD-seq) to find differentially methylated regions (DMRs), and via shallow whole-genome and -exome sequencing (shWGS, exome-seq) to define tumor fractions and mutational signatures. Aneuploid cfDNA was undetectable pre-treatment but observed in six patients post-treatment, in five resistant and one responding patient. Post-treatment ichorCNA analyses demonstrated in shWGS and exome-seq higher median tumor fractions in resistant (7% and 9%) than in sensitive patients (7% and 5%). SigMiner analyses detected predominantly mutational signatures linked to mismatch repair and chemotherapy. DeSeq2 analyses of MeD-seq data revealed three methylation signatures and more tumor-specific DMRs in resistant than in responding patients in both pre- and post-treatment samples (274 vs. 30 DMRs, 190 vs. 57 DMRs, Χ2-test p < 0.001). Our genome-wide Next-Generation Sequencing (NGS) analyses in PARPi-resistant patients identified epigenetic differences in blood before treatment, whereas genomic alterations were more frequently observed after progression. The epigenetic differences at baseline are especially interesting for further exploration as putative predictive biomarkers for PARPi resistance.