Bergenin inhibits growth of human cervical cancer cells by decreasing Galectin-3 and MMP-9 expression.

Cervical cancer is still the leading cause of cancer mortality worldwide even after introduction of vaccine against Human papillomavirus (HPV), due to low vaccine coverage, especially in the developing world. Cervical cancer is primarily treated by Chemo/Radiotherapy, depending on the disease stage, with Carboplatin/Cisplatin-based drug regime. These drugs being non-specific, target rapidly dividing cells, including normal cells, so safer options are needed for lower off-target toxicity. Natural products offer an attractive option compared to synthetic drugs due to their well-established safety profile and capacity to target multiple oncogenic hallmarks of cancer like inflammation, angiogenesis, etc. In the current study, we investigated the effect of Bergenin (C-glycoside of 4-O-methylgallic acid), a natural polyphenol compound that is isolated from medicinal plants such as Bergenia crassifolia, Caesalpinia digyna, and Flueggea leucopyrus. Bergenin has been shown to have anti-inflammatory, anti-ulcerogenic, and wound healing properties but its anticancer potential has been realized only recently. We performed a proteomic analysis of cervical carcinoma cells treated with bergenin and found it to influence multiple hallmarks of cancers, including apoptosis, angiogenesis, and tumor suppressor proteins. It was also involved in many different cellular processes unrelated to cancer, as shown by our proteomic analysis. Further analysis showed bergenin to be a potent-angiogenic agent by reducing key angiogenic proteins like Galectin 3 and MMP-9 (Matrix Metalloprotease 9) in cervical carcinoma cells. Further understanding of this interaction was carried out using molecular docking analysis, which indicated MMP-9 has more affinity for bergenin as compared to Galectin-3. Cumulatively, our data provide novel insight into the anti-angiogenic mechanism of bergenin in cervical carcinoma cells by modulation of multiple angiogenic proteins like Galectin-3 and MMP-9 which warrant its further development as an anticancer agent in cervical cancer.

Implementation of the recommended immunohistochemistry algorithm for classification of peripheral T-cell lymphoma, not otherwise specified into the prognostically significant GATA3 and TBX21 subtypes.

INTRODUCTION: Current molecular research has shown the several oncogenic pathways that give rise to the peripheral T-cell lymphoma, not otherwise defined (PTCL, NOS) subtypes, which alter prognosis and might have predictive value. This study was conducted to assess the immunohistochemistry (IHC) algorithm by Amador et al for the subtyping of PTCL, NOS and determine its applicability in relation to the clinicopathological profile. METHODS: This study included 43 patients with PTCL, NOS diagnosis. Following the use of IHC for the transcription factors GATA3, TBX21, CCR4, and CXCR3, two pathologists subtyped the samples. Comprehensive clinicopathological correlation was carried out. RESULTS: Applying the algorithm of Amador et al., cases were classified into GATA3 (20), TBX21 (15), and unclassified (8) subtypes. No significant association with clinical parameters of subtypes or CD4/ CD8 positivity was observed. Although a higher proportion of cases in the TBX21 subgroup showed a polymorphic population compared with the GATA3 subgroup, which had a monomorphic population, no significant p-value (0.111) was observed. Two Lennert lymphomas were classified into the GATA3 subgroup. Multivariate analysis showed no significant difference in overall survival (p-value = 0.105) and progression-free survival (p-value = 0.0509) between IHC-defined subtypes; trends indicate that overall survival and progression-free survival are worse in the GATA3 subgroup. CONCLUSION: Although the algorithm is reproducible, a proportion of cases remains unclassifiable and may require additional investigation and gene expression profiling. The GATA3 subgroup was found to have a monomorphic population with a poor overall prognosis and thus requires a larger sample size for validation.

Autologous Stem Cell Transplantation in Adult Hodgkin Lymphoma at a Tertiary Care Center in India: Analysis of Outcomes and Prognostic Factors.

High-dose chemotherapy and autologous stem cell transplant (ASCT) is the standard of care treatment in relapsed/refractory Hodgkin lymphoma (rrHL). Published long-term follow-up data concerning this modality from the Indian subcontinent is lacking. In this retrospective study, the data on adults (> 16 years) with biopsy-confirmed rrHL who were autografted from 1 January 2000 to 31 December 2021 at our transplant unit were analyzed. Progression-free survival (PFS) was defined as time from transplant to disease progression or death due to any cause. Overall survival (OS) was determined from date of transplant to date of death due to any cause. Overall, 134 patients with Hodgkin lymphoma underwent ASCT. At a median follow-up of 38.2 (range, 0.1-240) months, 5 years PFS was 45.3% (95% CI 35.4-54.4). The probability of OS at 5 years was 60.5% (95% CI 49.6-69.6). Eleven (8.2%) patients suffered transplant-related mortality by 100 days. Post-transplant persistent disease, pre-transplant serum hypoalbuminemia (< 3.5 g/dl) and chemo-resistance (< PR after last salvage regimen) of tumour at transplant were independent prognostic factors associated with worse PFS in multivariable analysis. Likewise, age ≥ 30 years, ECOG performance status ≥ 1 and residual disease after transplantation correlated with inferior OS. Long-term outcomes of rrHL patients undergoing ASCT in India match those from the developed world in the era of peripheral blood stem cell transplantation. Pre-transplant performance status, chemo-sensitivity of disease, serum albumin and post-transplant remission status determined survival in our cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01690-x.

Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature.

Philadelphia (Ph) chromosome (9;22)(q34;q11) comprises 90-95 % of chronic myeloid leukemia (CML), while 5-10 % of CML have translocations involving three or more chromosomes. The outcome of treating patients harbouring complex Ph-positive cytogenetics with tyrosine kinase inhibitors (TKI) is unclear. In the present systematic review, we aim to summarise the response of patients with complex Ph-positive cytogenetics to treatment with TKI therapy. We collated all available literature from databases such as PubMed, Google Scholar, Web of Science database, Cochrane library, Scopus and Embase (up until January 31st, 2024), which describe cases of patients with CML, harbouring complex Ph-positive variations (three and four-way translocations), and summarised their response to TKI therapy. The studies were screened for the following criteria: documented TKI intervention and outcome (whether CR was achieved). Studies that did not report the same, were excluded. Additionally, we report a case from our center of a 55-year-old patient with CML, positive for the Ph-chromosome, harbouring a three-way translocation involving chromosome 15 i.e. 46XX, t(9;15;22) (q34;p11;q11). Identification of BCR::ABL and involvement of chromosome 15 was carried out using conventional cytogenetics, fluorescence in situ hybridization (FISH), and quantitative PCR (qPCR). Based on the inclusion criteria, a total of 15 studies were included from which a total of 87 cases were covered. Overall, we identified 38 unique complex three- and four-way translocations across 87 Ph-positive cases and found that 85 patients with complex Ph-positive cytogenetics achieved complete remission upon treatment and did not appear to have a lesser response to TKI therapy.

A Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Effect of Topical Urea for Secondary Prophylaxis of Hand Foot Skin Reaction in Renal Cell Cancer Patients on Sunitinib Therapy.

INTRODUCTION: Hand foot skin reaction (HFSR) is a common dose-limiting adverse effect of multi kinase inhibitors (MKI) whose mechanism is not fully understood, and the prophylaxis is inadequate. OBJECTIVE: In this pilot study, a double-blind, randomized placebo-controlled trial was conducted to evaluate the effect of topical urea in secondary prevention of sunitinib-induced HFSR in renal cell cancer patients. METHODS: Out of 55 screened patients, 14 were randomized to receive topical urea or placebo for four weeks. The association of HFSR with drug levels of sunitinib and its metabolite (n-desethyl sunitinib), genetic polymorphism of VEGFR2 gene, quality of life (QOL) and biochemical markers was also assessed. RESULTS: The results showed that urea-based cream was not superior to placebo (P = .075). There was no change in the QOL in both the groups. Single nucleotide polymorphism was checked for two nucleotides rs1870377 and rs2305948 located in VEGFR2 gene on chromosome 4. SNP (variant T > A) at rs1870377 was associated with appearance of new HFSR as compared to the wild type, although the association was not statistically significant (OR 0.714). There was no statistically significant difference between mean plasma levels of sunitinib and N-desethyl sunitinib in urea arm as compared to placebo arm as compared to placebo. The best fit population pharmacokinetic model for sunitinib was one compartment model with first order absorption and linear elimination. The median (IQR) of population parameters calculated from the population pharmacokinetics model for Ka, V and Cl was 0.22 (0.21-0.24) h-1, 4.4 (4.09-4.47) L, 0.049 (0.042-0.12) L/hr, respectively. CONCLUSION: The study suggested that the urea-based cream was not superior to placebo in decreasing the appearance of new HFSR in renal cancer patients receiving 4:2 regimen of sunitinib.

[177Lu]Lu-PSMA-617 as first-line systemic therapy in patients with metastatic castration-resistant prostate cancer: a real-world study.

PURPOSE: The use of [177Lu]Lu-PSMA-617 radioligand therapy has become increasingly recognized as a viable therapeutic approach for patients in the advanced stages of metastatic castration-resistant prostate cancer (mCRPC). However, there is limited data regarding its effectiveness and safety in earlier lines. This study aims to present our institution's experience with [177Lu]Lu-PSMA-617 as a first-line systemic therapy for mCRPC. METHODS: We collected and analyzed data from consecutive mCRPC patients who underwent first-line treatment with [177Lu]Lu-PSMA-617 at our center from 2015 to 2023. The various outcome measures included best prostate-specific antigen-response rate (PSA-RR) (proportion of patients achieving a ≥ 50% decline in PSA); objective radiographic response rate (ORR) (proportion of patients achieving complete or partial radiographic responses); radiographic progression-free survival (rPFS) (measured from treatment initiation until radiographic progression or death from any cause); overall survival (OS) (measured from treatment initiation until death from any cause); and adverse events. RESULTS: Forty treatment-naïve mCRPC patients with PSMA-positive disease on [68Ga]Ga-PSMA-11 PET/CT were included (median age: 68.5 years, range: 45-78; median PSA: 41 ng/mL, range: 1-3028). These patients received a median cumulative activity of 22.2 GBq (range: 5.55-44.4) [177Lu]Lu-PSMA-617 over 1-6 cycles at 8-12 week intervals. A ≥ 50% decline in PSA was observed in 25/40 (62.5%) patients (best PSA-RR). Radiographic responses were evaluated for thirty-eight patients, with thirteen showing partial responses (ORR 34.2%). Over a median follow-up of 36 months, the median rPFS was 12 months (95% confidence interval, CI: 9-15), and the median OS was 17 months (95% CI: 12-22). Treatment-emergent grade ≥ 3 anemia, leucopenia, and thrombocytopenia were noted in 4/40 (10%), 1/40 (2.5%), and 3/40 (7.5%) patients, respectively. CONCLUSION: The findings suggest that [177Lu]Lu-PSMA-617 is a safe and effective option as a first-line treatment in mCRPC. Further trials are needed to definitively establish its role as an upfront treatment modality in this setting.

Carboplatin in Patients With Metastatic Castration-Resistant Prostate Cancer Harboring Somatic or Germline Homologous Recombination Repair Gene Mutations: Phase II Single-Arm Trial.

BACKGROUND: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. OBJECTIVE: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. METHODS: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0). RESULTS: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. CONCLUSIONS: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54086.

Immunophenotypic characterization of leukemic stem cells in acute myeloid leukemia using single tube 10-colour panel by multiparametric flow cytometry: Deciphering the spectrum, complexity and immunophenotypic heterogeneity.

INTRODUCTION: Despite extensive research, comprehensive characterization of leukaemic stem cells (LSC) and information on their immunophenotypic differences from normal haematopoietic stem cells (HSC) is lacking. Herein, we attempted to unravel the immunophenotypic (IPT) characteristics and heterogeneity of LSC using multiparametric flow cytometry (MFC) and single-cell sequencing. MATERIALS AND METHODS: Bone marrow aspirate samples from patients with acute myeloid leukaemia (AML) were evaluated using MFC at diagnostic and post induction time points using a single tube-10-colour-panel containing LSC-associated antibodies CD123, CD45RA, CD44, CD33 and COMPOSITE (CLL-1, TIM-3, CD25, CD11b, CD22, CD7, CD56) with backbone markers that is, CD45, CD34, CD38, CD117, sCD3. Single-cell sequencing of the whole transcriptome was also done in a bone marrow sample. RESULTS: LSCs and HSCs were identified in 225/255 (88.2%) and 183/255 (71.6%) samples, respectively. Significantly higher expression was noted for COMPOSITE, CD45RA, CD123, CD33, and CD44 in LSCs than HSCs (p < 0.0001). On comparing the LSC specific antigen expressions between CD34+ (n = 184) and CD34- LSCs (n = 41), no difference was observed between the groups. More than one sub-population of LSC was demonstrated in 4.4% of cases, which further revealed high concordance between MFC and single cell transcriptomic analysis in one of the cases displaying three LSC subpopulations by both methods. CONCLUSION: A single tube-10-colour MFC panel is proposed as an easy and reproducible tool to identify and discriminate LSCs from HSCs. LSCs display both inter- and intra-sample heterogeneity in terms of antigen expressions, which opens the facets for single cell molecular analysis to elucidate the role of subpopulations of LSCs in AML progression.

Breaking the graft-versus-host-disease barrier: Mesenchymal stromal/stem cells as precision healers.

Mesenchymal Stromal/Stem Cells (MSCs) are multipotent, non-hematopoietic progenitor cells with a wide range of immune modulation and regenerative potential which qualify them as a potential component of cell-based therapy for various autoimmune/chronic inflammatory ailments. Their immunomodulatory properties include the secretion of immunosuppressive cytokines, the ability to suppress T-cell activation and differentiation, and the induction of regulatory T-cells. Considering this and our interest, we here discuss the significance of MSC for the management of Graft-versus-Host-Disease (GvHD), one of the autoimmune manifestations in human. In pre-clinical models, MSCs have been shown to reduce the severity of GvHD symptoms, including skin and gut damage, which are the most common and debilitating manifestations of this disease. While initial clinical studies of MSCs in GvHD cases were promising, the results were variable in randomized studies. So, further studies are warranted to fully understand their potential benefits, safety profile, and optimal dosing regimens. Owing to these inevitable issues, here we discuss various mechanisms, and how MSCs can be employed in managing GvHD, as a cellular therapeutic approach for this disease.

Promising Therapeutic Activity of 177 Lu-PSMA-617 in Synchronous High-Volume Metastatic Hormone-Sensitive Prostate Cancer : A Pilot Experience.

PURPOSE: 177 Lu-PSMA-617 has been shown to improve survival outcomes in patients with end-stage metastatic castration-resistant prostate cancer. However, data in earlier lines remain limited. In this study, we intended to evaluate the efficacy and safety of 177 Lu-PSMA-617 in patients with synchronous high-volume metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS: Hormone-sensitive prostate cancer patients with synchronous high-volume metastases (defined as ≥4 skeletal metastases with ≥1 extra-axial site or any visceral metastasis) showing high PSMA expression on 68 Ga-PSMA-11 PET/CT and ineligible/unwilling for conventional chemohormonal treatment options were selected. Approximately, ~5.55-7.4 GBq of 177 Lu-PSMA-617 was administered intravenously at 8-12 weeks intervals, up to 6 cycles. All patients underwent concomitant androgen deprivation therapy/orchiectomy. The outcome measures included the proportion of patients achieving an undetectable serum prostate-specific antigen (PSA) (ie, ≤0.2 ng/mL) at any time point after therapy, best PSA response rate, objective radiographic response rate, radiographic progression-free survival, overall survival, and adverse events. RESULTS: Ten patients with high-volume mHSPC received a median cumulative activity of 32.4 GBq (range, 7.4-44.4) of 177 Lu-PSMA-617 over 1-6 cycles. Five patients (50%) achieved an undetectable PSA with 9 patients (90%) showing a ≥50% decline in PSA from baseline. Nine patients underwent radiological follow-up, of which 7 (77.8%) had an objective response. The median radiographic progression-free survival was 24 months (95% confidence interval, 18-30), whereas the median overall survival was not reached. None of the patients had any grade 3/4 adverse event. CONCLUSIONS: 177 Lu-PSMA-617 seems to be a promising efficacious and safe treatment option for patients with synchronous high-volume mHSPC.

Daratumumab in Indian patients with relapsed and refractory multiple myeloma: a prospective, multicenter, phase IV study.

Aim: To assess the safety and effectiveness of daratumumab monotherapy in Indian patients with relapsed/refractory multiple myeloma. Methods: In this prospective, multicenter, phase IV study, patients (aged ≥18 years) received intravenous daratumumab (16 mg/kg) in six cycles. Safety was the primary end point. Results: Of the 139 patients included, 121 (87.1%) experienced ≥1 treatment-emergent adverse events (TEAEs; 53 [38.1%] drug-related), 32 (23%) had ≥1 serious TEAEs (five [3.6%] drug-related) and 16 (11.5%) deaths were reported (one death [0.7%] was drug-related). Overall response rate was 26.3%; 62.7% of patients had stable disease. Median time to first response and median progression-free survival were 5.2 and 5.9 months, respectively. Functional status and well-being were improved. Conclusion: Daratumumab showed an acceptable and expected safety profile with consistent efficacy, providing a novel therapeutic option for relapsed/refractory multiple myeloma management in India.

Daratumumab is a monoclonal antibody approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). This study evaluated the outcome of daratumumab single therapy in Indian patients who were not cured with other drugs used for the same disease. 139 adult patients were included in this study from 15 institutes across India. Daratumumab (16 mg/kg) was diluted with 500 or 1000 ml of saline solution and given slowly through the intravenous route 16-times within 6 months. The study examined whether the safety profile and benefits of daratumumab reported in Indian patients were similar to those reported in the RRMM populations of other countries. The study found that most of the adverse events were not severe and could be easily treated by the study physician. 16 patients died (one might have been due to daratumumab treatment). Daratumumab treatment provided life support and recovery benefits to many patients. Daratumumab single therapy provides an appropriate and acceptable safety profile with no new adverse events and consistent benefits in RRMM patients. Clinical Trial Registration: NCT03768960 (ClinicalTrials.gov), CTRI/2019/06/019546.

Nuclear and Mitochondrial Genome Assemblies of the Beetle, Zygogramma bicolorata, a Globally Important Biocontrol Agent of Invasive Weed Parthenium hysterophorus.

Implementing a genetic-based approach to achieve the full potential of classical biocontrol programs has been advocated for decades. The availability of genome-level information brings the opportunity to scrutinize biocontrol traits for their efficacy and evolvability. However, implementation of this advocacy remains limited to few instances. Biocontrol of a globally noxious weed, Parthenium hysterophorus, by the leaf-feeding beetle, Zygogramma bicolorata, has been in place for more than four decades now, with varying levels of success. As the first step in providing genetic-based improvement to this biocontrol program, we describe the nuclear and mitochondrial assemblies of Z. bicolorata. We assembled the genome from the long-read sequence data, error corrected with high-throughput short reads and checked for contaminants and sequence duplication to produce a 936 Mb nuclear genome. With 96.5% Benchmarking Universal Single-Copy Orthologs completeness and the long terminal repeat assembly index 12.91, we present a reference-quality assembly that appeared to be repeat rich at 62.7% genome-wide and consists of 29,437 protein-coding regions. We detected signature of nuclear insertion of mitochondrial fragments in 80 nuclear positions comprising 13 kb out of 17.9 kb mitochondria genome sequence. This genome, along with its annotations, provides a valuable resource to gain further insights into the biocontrol traits of Z. bicolorata for improving the control of the invasive weed P. hysterophorus.

Multiobjective optimization of membrane in hybrid cryogenic CO2 separation process for coal-fired power plants.

Post-combustion carbon dioxide (CO2) capture is considered a potential method to mitigate CO2 emissions from fossil fuels burned in power plants. In recent years, combining two different methods of post-combustion CO2 capture such as membrane and cryogenic distillation has been explored for availing the advantages of each method. This study focuses on the optimization of membranes for developing the membrane-cryogenic distillation process. For this purpose, a process flow sheet is developed, and simulation with model components such as compressor, heat exchanger, turbo expander, and distillation column is carried out using Aspen Plus. A membrane model is developed using in-house MATLAB code, and optimization is done to achieve higher concentration and recovery of CO2 using the MOJAYA algorithm. The membrane model is coupled to Aspen Plus through component object model (COM) technology. In this investigation, a hollow fiber membrane is considered. The optimized specifications of membrane modules are length, number of hollow fibers, feed pressure, and permeate pressure which are 0.3 m, 100,000, 5.76 bar, and 0.1 bar, respectively. This analysis results in the purity and recovery of the process of 99.8 and 90%, respectively, and an energy penalty of around 1.74 MJ/kg of CO2. A comparison of other processes available in the literature reveals that the current study renders maximum purity and recovery with a minimum energy penalty.

Head-to-head comparison of [68Ga]Ga-DOTA.SA.FAPi with [18F]F-FDG PET/CT in radioiodine-resistant follicular-cell derived thyroid cancers.

PURPOSE: In the context of radioiodine-resistant follicular-cell derived thyroid cancers (RAI-R-FCTC), [18F]F-FDG PET/CT serves as a widely used and valuable diagnostic imaging method. However, there is growing interest in utilizing molecular imaging probes that target cancer-associated fibroblasts (CAFs) as an alternative approach. This study sought to compare the diagnostic capabilities of [68Ga]Ga-DOTA.SA.FAPi and [18F]F-FDG PET/CT in patients with RAI-R-FCTC. METHODS: In this retrospective study, a total of 117 patients with RAI-R-FCTC were included. The study population consisted of 68 females and 49 males, with a mean age of 53.2 ± 11.7 years. The aim of the study was to perform a comprehensive qualitative and quantitative assessment of [68Ga]Ga-DOTA.SA.FAPi and [18F]F-FDG PET/CT scans in RAI-R-FCTC patients. The qualitative assessment involved comparing patient-based and lesion-based visual interpretations of both scans, while the quantitative assessment included analyzing standardized uptake values corrected for lean body mass (SULpeak and SULavg). The findings obtained from the scans were validated by correlating them with morphological findings from diagnostic computed tomography and/or histopathological examination. RESULTS: Among the 117 RAI-R-FCTC patients, 60 had unilateral local disease, and 9 had bilateral lesions with complete concordance in the detection rate on both PET scans. [68Ga]Ga-DOTA.SA.FAPi had a higher detection rate for lymph nodes (95.4% vs 86.6%, p<0.0001), liver metastases (100% vs. 81.3%, p<0.0001), and brain metastases (100% vs. 39%, p<0.0001) compared to [18F]F-FDG. The detection rates for pleural and bone metastases were similar between the two radiotracers. For lung metastases, [68Ga]Ga-DOTA.SA.FAPi showed a detection rate of 81.7%, whereas [18F]F-FDG had a detection rate of 64.6%. Remarkably, [68Ga]Ga-DOTA.SA.FAPi was able to detect a bowel metastasis that was missed on [18F]F-FDG scan. The median standardized uptake values (SUL) were generally comparable between the two radiotracers, except for brain metastases (SULpeak [68Ga]Ga-DOTA.SA.FAPi vs. [18F]F-FDG: 13.9 vs. 6.7, p-0.0001) and muscle metastases (SULpeak [68Ga]Ga-DOTA.SA.FAPi vs. [18F]F-FDG: 9.56 vs. 5.62, p-0.0085), where [68Ga]Ga-DOTA.SA.FAPi exhibited higher uptake. CONCLUSION: The study results demonstrate the superior performance of [68Ga]Ga-DOTA.SA.FAPi compared to [18F]F-FDG PET/CT in detecting lymph nodal, liver, bowel, and brain metastases in patients with RAI-R-FCTC. These findings highlight the potential of [68Ga]Ga-DOTA.SA.FAPi as a theranostic tool that can complement the benefits of [18F]F-FDG PET/CT in the imaging of RAI-R-FCTC.

Long-term survival outcomes of salvage [225Ac]Ac-PSMA-617 targeted alpha therapy in patients with PSMA-expressing end-stage metastatic castration-resistant prostate cancer: a real-world study.

PURPOSE: Despite the existence of various treatment options, the prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unfavorable. One potential therapeutic approach is the use of [225Ac]Ac-PSMA-617, a targeted alpha therapy (TAT) that administers alpha-particle radiation specifically to prostate cancer cells expressing PSMA. In this study, we report the long-term survival outcomes of this novel therapy in a series of patients with mCRPC who have exhausted all standard treatment options. METHODS: The study enrolled patients with mCRPC who had shown resistance to standard lines of therapies, including next-generation anti-androgen therapies and taxane-based chemotherapies. These eligible patients received treatment with [225Ac]Ac-PSMA-617 at 100-150 kBq/kg doses administered every 8 weeks. The primary objective of the study was to assess overall survival (OS), while secondary objectives included evaluating radiological progression-free survival (rPFS), monitoring serum prostate-specific antigen (PSA) levels as a measure of biochemical response, and assessing adverse events using the CTCAE v5.0 grading system. RESULTS: Among the 63 initially enrolled patients, a total of 56 patients who had completed at least two cycles of [225Ac]Ac-PSMA-617 were included in this study. The mean age was 67 years (range, 39-87) and patients received a total of 204 cycles of [225Ac]Ac-PSMA-617 TAT. 91% of patients exhibited any PSA decline, with 67.8% experiencing a decline of 50% or more. The median follow-up was of 22 months (range: 6-59 months). Imaging-based disease progression was observed in 68% of patients, and 66% of patients succumbed to the disease. The median OS was 15 months (95% CI: 10-19). In univariate analysis, factors such as lack of >50% PSA decline (P=0.031), Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher (P=0.048), and radiological progression (rPD) (P<0.001) were found to be predictors of poor OS. However, in multivariate analysis, only rPD emerged as an independent prognostic factor with a hazard ratio (HR) of 8.264 (95% CI: 1.429-16.497, P=0.004). The estimated median rPFS was 9 months (95% CI: 7-15). Moreover, patients who demonstrated any PSA decline had a median rPFS of 10 months compared to only 3 months in patients without any PSA decline (multivariate HR: 6.749; 95% CI: 1.949-23.370; P=0.002). Fatigue was one of the most common treatment-emergent adverse events, with grades 1/2 occurring in 70% of patients and grades 3 or higher in 3.5% of patients. This fatigue was transient and resolved before the next treatment cycle. Additionally, approximately one-third of patients experienced xerostomia (grades 1/2: 32.1%). CONCLUSION: [225Ac]Ac-PSMA-617 targeted alpha therapy, was found to be well-tolerated with acceptable adverse events and effective in the treatment of patients with end-stage mCRPC.

Quality of life assessment in testicular non-seminomatous germ cell tumour survivors.

PURPOSE: Patients with Germ cell tumours (GCT) are at risk of long-term toxicities due to multimodality therapy. It is debatable whether there is an impact on the quality of life(QoL) of GCT survivors. METHODS: A case-control study was conducted at a tertiary care centre in India, using the EORTC QLQ C30 questionnaire, to compare the QoL between GCT survivors(disease free > 2 years) and healthy matched controls. A multivariate regression model was used to identify factors affecting QoL. RESULTS: A total of 55 cases and 100 controls were recruited. Cases had a median age of 32 years (interquartile range, IQR 28-40 years), ECOG PS of 0-1(75%), advanced stage III (58%), chemotherapy (94%) and 66% were > 5 years from diagnosis. The median age of controls: 35 years (IQR 28-43 years). A statistically significant difference was seen for emotional (85.8 ± 14.2 vs 91.7 ± 10.4, p 0.005), social(83.0 ± 22.0 vs 95.2 ± 9.6, p < 0.001) and global scales (80.4 ± 21.1 vs 91.3 ± 9.7, p < 0.001). Cases had more nausea and vomiting(3.3 ± 7.4 vs 1.0 ± 3.9, p 0.015), pain(13.9 ± 13.9 vs 4.8 ± 9.8, p < 0.001), dyspnea(7.9 + 14.3 vs 2.7 ± 9.1, p 0.007), and appetite loss(6.7 ± 14.9 vs 1.9 ± 7.9, p 0.016) and greater financial toxicity(31.5 ± 32.3 vs 9.0 ± 16.3, p < 0.001). Adjusting for age, performance status, BMI, stage, chemotherapy, RPLND, recurrent disease, and time since diagnosis, no predictive variables were significant. CONCLUSION: There is a detrimental impact of history of GCT in long term survivors of GCT.

Fertility and pregnancy in chronic myeloid leukemia: real-world experience from an Indian tertiary care institution.

Chronic myeloid leukemia (CML) management during pregnancy is challenging. In this retrospective study, hospital records of CML patients treated between 2000 and 2021 were screened to identify patients who tried to conceive/got pregnant (planned and unplanned) on TKIs (tyrosine kinase inhibitors)/were pregnant at CML onset/fathered a child. We found ninety-three pregnancies involving thirty-three women and thirty-eight men, and they were analyzed for the pregnancy outcomes and the strategies utilized for CML management during pregnancy and the pre-conception period. There were two women and four men with primary infertility and five women with secondary infertility. TKIs were discontinued before conception in four planned pregnancies and at the time of recognition of pregnancy in unplanned pregnancies (n = 21). Unplanned pregnancy outcomes were two miscarriages, eight elective terminations, and eleven live births. Planned pregnancies led to four healthy babies. Outcomes of pregnancies at CML onset (n = 17) were six live births, one stillbirth, five elective terminations, and five abortions. Except for one child with congenital micro-ophthalmia, no other child born to the women on TKI had any malformations. Thirty-eight men fathered 51 healthy children. All but two patients (one planned and one unplanned pregnancy) lost their hematological responses during pregnancy and gained their previous best response after restarting TKI. In women who were pregnant at CML onset, complete cytological remission (CCYR) was achieved between 7 and 24 months (median:14 months) after starting TKI. During pregnancy, intermittent hydroxyurea ± TKI (in the second and third trimesters) was used to keep WBCs less than 30,000/mm3. Outcomes of pregnancies in CML patients can be optimized with our approach. TKIs (Imatinib and Nilotinib) can be safely used in the second and third trimesters. Delayed initiation or interruption of TKI during pregnancy does not negatively affect response to TKIs.

[177Lu]Lu-PSMA-Radioligand Therapy Efficacy Outcomes in Taxane-Naïve Versus Taxane-Treated Patients with Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Metaanalysis.

Radioligand therapy (RLT) with 177Lu-prostate-specific membrane antigen (PSMA) inhibitors ([177Lu]Lu-PSMA) is currently approved for patients with metastatic castration-resistant prostate cancer (mCRPC) after progression with at least 1 taxane and 1 androgen-receptor-pathway inhibitor. However, the impact of prior chemotherapy on [177Lu]Lu-PSMA-RLT outcomes is debatable, with various studies showing inconsistent results. This study was conducted to precisely evaluate the impact of prior taxane chemotherapy on response and survival outcomes in mCRPC patients after [177Lu]Lu-PSMA-RLT. Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches in PubMed, Scopus, and Embase were made using relevant key words, and articles up to December 2022 were included. The endpoints included prostate-specific antigen (PSA) response rate (RR), progression-free survival, and overall survival (OS). Individual patient data were pooled when feasible. Univariate odds ratios (ORs) and hazard ratios (HRs) were extracted from the individual articles, and pooled estimates and 95% CIs were generated using metaanalysis. Results: Thirteen articles comprising 2,068 patients were included. In 6 articles (553 patients), taxane-naïve patients had significantly better odds of biochemical response after [177Lu]Lu-PSMA-RLT (pooled OR, 1.82; 95% CI, 1.21-2.71). Individual patient data metaanalysis for PSA RRs in 3 articles revealed a significantly higher PSA RR in the taxane-naïve versus taxane-treated patients (57.1% vs. 39.5%; difference, 17.6%; 95% CI, 5.6%-28.9%). Further, taxane-naïve status was also a predictor of significantly better progression-free survival (5 articles; 1,027 patients; pooled HR, 0.60; 95% CI, 0.51-0.69) and OS (8 articles; 1,594 patients; pooled HR, 0.54; 95% CI, 0.43-0.68) after [177Lu]Lu-PSMA-RLT. There was no evidence of publication bias. Conclusion: mCRPC patients with no prior taxanes had significantly better outcomes after [177Lu]Lu-PSMA-RLT than did taxane-treated patients. Further trials evaluating [177Lu]Lu-PSMA-RLT in the taxane-naïve setting are now required.