Primary Malignancy Research Articles

Imaging features and management of focal liver lesions

Notably, the number of incidentally detected focal liver lesions (FLLs) has increased dramatically in recent years due to the increased use of radiological imaging. The diagnosis of FLLs can be made through a well-documented medical history, physical examination, laboratory tests, and appropriate imaging methods. Although benign FLLs are more common than malignant ones in adults, even in patients with primary malignancy, accurate diagnosis of incidental FLLs is of utmost clinical significance. In clinical practice, FLLs are frequently evaluated non-invasively using ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). Although US is a cost-effective and widely used imaging method, its diagnostic specificity and sensitivity for FLL characterization are limited. FLLs are primarily characterized by obtaining enhancement patterns through dynamic contrast-enhanced CT and MRI. MRI is a problem-solving method with high specificity and sensitivity, commonly used for the evaluation of FLLs that cannot be characterized by US or CT. Recent technical advancements in MRI, along with the use of hepatobiliary-specific MRI contrast agents, have significantly improved the success of FLL characterization and reduced unnecessary biopsies. The American College of Radiology (ACR) appropriateness criteria are evidence-based recommendations intended to assist clinicians in selecting the optimal imaging or treatment option for their patients. ACR Appropriateness Criteria Liver Lesion-Initial Characterization guideline provides recommendations for the imaging methods that should be used for the characterization of incidentally detected FLLs in various clinical scenarios. The American College of Gastroenterology (ACG) Clinical Guideline offers evidence-based recommendations for both the diagnosis and management of FLL. American Association for the Study of Liver Diseases (AASLD) Practice Guidance provides an approach to the diagnosis and management of patients with hepatocellular carcinoma. In this article, FLLs are reviewed with a comprehensive analysis of ACR Appropriateness Criteria, ACG Clinical Guideline, AASLD Practice Guidance, and current medical literature from peer-reviewed journals. The article includes a discussion of imaging methods used for the assessment of FLL, current recommended imaging techniques, innovations in liver imaging, contrast agents, imaging features of common nonmetastatic benign and malignant FLL, as well as current management recommendations.

The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities

Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow. Despite therapeutic advances, MM remains incurable, and better risk stratification as well as new therapies are therefore highly needed. The proteome of MM has not been systematically assessed before and holds the potential to uncover insight into disease biology and improved prognostication in addition to genetic and transcriptomic studies. Here we provide a comprehensive multiomics analysis including deep tandem mass tag-based quantitative global (phospho)proteomics, RNA sequencing, and nanopore DNA sequencing of 138 primary patient-derived plasma cell malignancies encompassing treatment-naive MM, plasma cell leukemia and the premalignancy monoclonal gammopathy of undetermined significance, as well as healthy controls. We found that the (phospho)proteome of malignant plasma cells are highly deregulated as compared with healthy plasma cells and is both defined by chromosomal alterations as well as posttranscriptional regulation. A prognostic protein signature was identified that is associated with aggressive disease independent of established risk factors in MM. Integration with functional genetics and single-cell RNA sequencing revealed general and genetic subtype-specific deregulated proteins and pathways in plasma cell malignancies that include potential targets for (immuno)therapies. Our study demonstrates the potential of proteogenomics in cancer and provides an easily accessible resource for investigating protein regulation and new therapeutic approaches in MM.

Incidental Hypercalcemia: The Sole Presentation of B-Cell Acute Lymphoblastic Leukaemia

This article aims to report a sole presentation of B-cell acute lymphoblastic leukaemia (ALL) as incidental hypercalcemia. ALL is the most frequent neoplastic disease in children, with an early peak at the age of 3–4 years. ALL presents with neutropenic fever, bruising, anaemia, lymphadenopathy and bone pain. Presenting features as manifestations of hypercalcemia in ALL is extremely rare, especially in adults. More than 90% of causes of hypercalcemia are primary hyperparathyroidism and malignancy. Hence, if parathyroid hormone (PTH) levels come low, malignancy is the most probable aetiology. Hypercalcemia associated with malignancy includes three distinct syndromes. Bone metastases may cause hypercalcemia. Direct bone marrow invasion occurs with hematologic malignancies such as leukaemia, lymphoma and multiple myeloma. Hypercalcemia is seen in <1% of cases of leukaemia. A 16-year-old male presented with nausea, vomiting, abdominal pain and burning micturition. Physical examination was unremarkable except for pallor. His laboratory studies showed haemoglobin 5.7g/dL, white cell count 5700/mm3, platelet count 51,000/dL, and serum calcium 17.1 mg/d. He was hydrated and given zoledronate IV, with which calcium level normalised and symptoms resolved. The patient had low PTH and low parathyroid hormone-related peptide (PTHrp). Peripheral smear and bone marrow showed lymphoblasts. Flow cytometry confirmed B-cell ALL with 43% blasts. Hypercalcemia revealed B-cell ALL in an adult after a thorough workup of low PTH and PTHrp, peripheral blood picture, bone marrow examination, and flow cytometry. Hence, ALL should be considered in the differential diagnosis of a young adult presenting with incidental hypercalcemia.

Subsequent Renal Cancer Among Childhood Cancer Survivors: Analysis of Surveillance, Epidemiology, and End Results.

Renal cancer, although still rare among individuals under 45 years of age, is on the rise in the general population. The risk and timing of subsequent renal cancer in survivors of childhood cancer is not well established. Using the SEER registry, we reported the incidence of subsequent malignant renal neoplasms after treatment for primary malignancy diagnosed under 20 years of age. We evaluated clinical characteristics, standardized incidence ratio (SIR), and Kaplan-Meier survival estimates. Fifty-three survivors developed subsequent renal cancer (54 total cases). Of these, 54.7% were female, 88.7% were white, and 13.2% were Hispanic. Mean ages at primary malignancy and subsequent renal cancer were 10.1 and 31.1 years, respectively. Forty-seven cases were second cancers, 6 were third, and 1 was fourth. For survivors of childhood cancer, the overall SIR for renal cancer was 4.52 (95% CI: 3.39-5.89). The 5-year overall survival rate after development of subsequent renal cancer was 73% (95% CI: 58%-83%). Renal cancer occurs 4.5 times more frequently in childhood cancer survivors than in the general population, necessitating long-term care considerations.

SEOM-GEMCAD-TTD clinical guidelines for the management of hepatocarcinoma patients (2023).

Hepatocellular carcinoma (HCC) is the most common primary malignancy in the liver and is the third cause of cancer-related death worldwide. Surveillance with abdominal ultrasound should be offered to individuals at high risk for developing HCC. Accurate diagnosis, staging, and liver function are crucial when determining the optimal therapeutic approach. The BCLC staging system is widely endorsed in Western countries. Managing this pathology requires a multidisciplinary, personalized approach, generally with a multimodal strategy. Surgery remains the only curative option, albeit local and systemic therapy may also increase survival when surgery is not suitable. In advanced disease, systemic treatment should be offered to patients with ECOG/PS 0-1 and Child-Pugh class A.

Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma

TBX3 behaves as a tumor suppressor or oncoprotein across cancer. However, TBX3 function remains undetermined in intrahepatic cholangiocarcinoma (iCCA), a deadly primary liver malignancy with few systemic treatment options. This study sought to investigate the impact of TBX3 on iCCA. We found that overexpression of TBX3 strongly inhibited human iCCA cell growth. In the Akt/FBXW7ΔF mouse iCCA model, overexpression of Tbx3 reduced cholangiocarcinogenesis in vivo, while inducible genetic knockout of Tbx3 accelerated iCCA growth. RNA-seq identified MAD2L1 as a downregulated gene in TBX3-overexpressing cells, and ChIP confirmed that TBX3 binds to the MAD2L1 promoter. CRISPR-mediated knockdown of Mad2l1 significantly reduced the growth of two iCCA models in vivo. Finally, we found that TBX3 expression is upregulated in ~20% of human iCCA samples, and its high expression is associated with less proliferation and better survival. MAD2L1 expression is upregulated in most human iCCA samples and negatively correlated with TBX3 expression. Altogether, our findings suggest that overexpression of TBX3 suppresses CCA progression via repressing MAD2L1 expression.

Characterization of second primary malignancies post CAR T-cell therapy: real-world insights from the two global pharmacovigilance databases of FAERS and VigiBase

The FDA's alerts regarding the T-cell lymphoma risk post CAR-T therapy has garnered global attention, yet a comprehensive profile of second primary malignancies (SPMs) following CAR-T treatment is lacking. We extracted adverse event reports of hematological malignancies (HMs) patients with clearly definable SPMs from the FAERS and VigiBase databases (2017-2023). Disproportionality analysis using reporting odds ratio (ROR) and adjusted ROR was performed to assess associations between SPMs and CAR-T therapy. Time-to-onset analysis explored factors affecting SPM manifestation. SPMs post CAR T-cell therapy include HMs and solid tumors. T-cell lymphoma and myelodysplastic syndromes were consistently identified as positive signals across the overall and subgroup analyses. Hematological SPMs showed earlier onset with increasing annual incidence post CAR-T therapy, whereas solid tumors exhibit delayed manifestation. SPMs in CAR-T recipients had significantly earlier onset than non-recipients. Furthermore, age-specific characteristics reveal earlier SPM manifestations in pediatric, adolescent, and young adult populations compared to older populations post CAR-T therapy. The current SPM profile highlights the necessity of long-term safety monitoring for all CAR-T recipients given the observed yearly increase of SPMs. Customizing long-term SPM screening across different age groups may enhance early detection and intervention strategies, ultimately improving patient outcomes in the follow-up of CAR-T recipients. This work was supported by grants from the Natural Science Foundation of Guangdong Province (2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (2019A030317020), the National Natural Science Foundation of China (81802257, 81871859, 81772457, 82172750, 82172811, and 82260546), the Guangdong Basic and Applied Basic Research Foundation (Guangdong-Guangzhou Joint Funds) (2022A1515111212), and the Science and Technology Program of Guangzhou (2023A04J1257).

LncRNA PGM5-AS1 inhibits non-small cell lung cancer progression by targeting miRNA-423-5p/SLIT2 axis

Non-small cell lung cancer (NSCLC) is a common and aggressive primary malignancy worldwide. Dysregulation of long non-coding RNAs (lncRNAs) has been shown to play an essential regulatory role in multiple cancers. However, the role of PGM5-AS1 in NSCLC remains unclear. Here, we found that PGM5-AS1 was down-regulated in NSCLC tissues and cells. Furthermore, reduced PGM5-AS1 expression levels were associated with larger tumor size, positive lymph node metastasis, advanced TNM stage and worse prognosis. We found that overexpression of PGM5-AS1 inhibited cell proliferation and metastasis, and induced apoptosis and G0/G1 cell cycle arrest in NSCLC cell lines. Using dual luciferase gene reporter and RNA immunoprecipitation assays, we confirmed that miR-423-5p interacted with PGM5-AS1, and that their expression levels were negatively correlated in NSCLC tissues. miR-423-5p was also found to reverse PGM5-AS1-induced malignant biological behavior. Moreover, we identified slit guidance ligand 2 (SLIT2) as a target gene of miR-423-5p. Using a dual luciferase gene reporter assay, we confirmed the regulatory relationship between SLIT2 and miR-423-5p and demonstrated that their expression levels were negatively correlated. Our rescue experiments showed that SLIT2 knockdown reversed miR-423-5p-mediated effects. Overall, this study identifies PGM5-AS1 as a potential prognostic biomarker for NSCLC and shows that PGM5-AS1 suppresses NSCLC development by regulating the miR-423-5p/SLIT2 axis.

Epidemiological trends and factors associated with survival in patients with medulloblastoma: A 45-year population-based retrospective study

Medulloblastoma (MB) is a primary brain malignancy. However, updated epidemiological data and long-term outcomes are lacking.The clinical and epidemiological datasets of patients with MB in the current study were obtained from the Surveillance, Epidemiology, and End Results (SEER) databases. Joinpoint regression models were used to assess the rate of changes in the incidence, prevalence, and treatment trends in patients with MB. Cox hazard and competition risk model analyses were used to assess overall survival (OS) and cancer-specific survival (CSS).The age-adjusted incidence of MB remained relatively stable at 0.15 per 100,000 individuals in 2019. The annual percentage change (APC) of females remained stable, whereas that of males increased over time. The 20-year limited-duration prevalence of patients with MB increased significantly from 0.00016 % in 1999 to 0.00203 % in 2018. Patients aged 5–19 years accounted for 46.7 % of all age groups, and the trend for the three treatments was increased. Average annual percentage change (AAPC) for the chemotherapy group was increased in patients aged 20 + years MB [AAPC = 2.66 (95 % CI 0.93–6.31)]. Multivariate analysis revealed that OS and CSS varied significantly according to age, year of diagnosis, histology, stage, surgery, and radiotherapy. Subgroup analysis showed that chemotherapy was associated with a favorable prognosis in high-risk groups.The incidence of MB remained relatively stable, and its prevalence increased significantly. This current population-based study further identified the prognostic factors in patients with MB. Moreover, the use of chemotherapy was associated with better survival in high-risk groups.

Maintenance therapy after Autologous Stem Cell Transplantation in Multiple Myeloma – currents and perspectives

MM is non-curable cancer that arises from plasma cells and is the second most common type of blood cancer. Drug-refractory relapses are inevitable, making it essential to sustain long-lasting remissions as part of therapy. Lenalidomide maintenance until progression is a standard of care for transplant-eligible newly-diagnosed patients. However, poor outcomes of high-risk patients and the risk of secondary primary malignancies associated with maintenance underline the need for novel approaches. Significant changes in frontline treatment maintenance are expected, with the increasing importance of minimal residual disease monitoring and the development of novel drug combinations for maintenance. This article explores current standards and prospects for maintaining response after upfront in ASCT in MM.

A review of Radiological Imaging Features to ameliorate radiologists’ knowledge of Krukenberg Tumor (KT)

Object: Aim is to delineate the major radiological findings with US, CT and MR of the Krukenberg tumor. Method: Revision of the literature. Introduction: A Krukenberg tumor refers tipically to a gastrointestinal cancer that metastasizes to the ovaries; this tumor was named after Krukenberg, who originally described this pathologic condition of the ovaries in 1896. The prognosis of this tumor is uniformly poor.[1] Discussion: Krukenburg tumor (KT)is a metastatic malignancy of the ovary characterized by mucin-rich signet-ring adenocarcinoma that primarily arises from a gastrointestinal site in most cases and less commonly from other sites. Often these tumors are bilateral (over 80%), given their metastatic nature. The images of a Krukenberg tumor highlight that the masses are mostly: bilateral, lobulated, solid/mixed solid and cystic. Conclusion: On imaging, Krukenberg tumor should be suspected when bilateral solid, mixed solid and cystic, or predominantly cystic ovarian masses are seen in the presence of a known or suspected gastrointestinal primary malignancy. Krukenberg tumors should also be considered when a ovarian mass shows the so-called “lead vessel sign”[1-12-15].

A review of Radiological Imaging Features to ameliorate radiologists’ knowledge of Krukenberg Tumor (KT)

Object: Aim is to delineate the major radiological findings with US, CT and MR of the Krukenberg Tumor. Method: Revision of the literature. Introduction: A Krukenberg Tumor refers tipically to a gastrointestinal cancer that metastasizes to the ovaries; this tumor was named after Krukenberg, who originally described this pathologic condition of the ovaries in 1896. The prognosis of this tumor is uniformly poor.[1] Discussion: Krukenburg tumor (KT)is a metastatic malignancy of the ovary characterized by mucin-rich signet-ring adenocarcinoma that primarily arises from a gastrointestinal site in most cases and less commonly from other sites. Often these tumors are bilateral (over 80%), given their metastatic nature. The images of a Krukenberg Tumor highlight that the masses are mostly: bilateral, lobulated, solid/mixed solid and cystic. Conclusion: On imaging, Krukenberg Tumor should be suspected when bilateral solid, mixed solid and cystic, or predominantly cystic ovarian masses are seen in the presence of a known or suspected gastrointestinal primary malignancy. Krukenberg Tumors should also be considered when a ovarian mass shows the so-called “lead vessel sign”[1-12-15].

Risk of Lymphoma and Leukemia in Thyroid Cancer Patients: A Retrospective Cohort Study in Germany.

Thyroid cancer is the ninth most common cancer worldwide. While differentiated thyroid cancer (DTC) has a high survival rate, concerns arise regarding optimal treatment strategies and potential long-term risks, including second primary malignancies (SPMs), associated with therapies such as radioiodine (RAI). The aim of the present study was to investigate the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia in Germany. This retrospective cohort study used the IQVIA TM Disease Analyzer database and included adults with a first documented diagnosis of thyroid cancer between January 2005 and December 2021 as well as propensity score matched individuals without thyroid cancer in 1284 general practices. Univariate Cox regression models were performed to examine the association between thyroid cancer and the incidence of subsequent lymphoma and leukemia. A total of 4232 thyroid cancer patients (mean age: 54.2 years; 73.6% female) and 21 160 controls (mean age: 54.2 years; 72.6% female) were available for analyses. Thyroid cancer was significantly associated with a higher lymphoma incidence (HR: 3.35, 95% CI: 2.04-5.52), especially in men (HR: 5.37) and those aged 61-70 years. Leukemia incidence was not significantly associated with thyroid cancer (HR: 1.79, 95% CI: 0.91-3.53), although associations were notable in younger age groups. Thyroid cancer is positively associated with a risk of subsequent lymphoma, highlighting the need for vigilant surveillance and tailored treatment strategies. While the association with leukemia is less pronounced, close surveillance remains critical, especially in younger patients.

Clinical implications of non-breast cancer related findings on FDG-PET/CT scan prior to neoadjuvant chemotherapy in patients with breast cancer

PurposeBreast cancer (BC) patients undergoing FDG-PET/CT scans for neoadjuvant chemotherapy (NAC) may have additional non-BC related findings. The aim of this study is to describe the clinical implications of these findings.MethodsWe included BC patients who underwent an FDG-PET/CT scan in our institute between 2011–2020 prior to NAC. We focused on patients with an additional non-BC related finding (i.e. BC metastases were excluded) for which diagnostic work-up was performed. Information about the diagnostic work-up and the clinical consequences was retrospectively gathered. A revision of all FDG-PET/CT scans was conducted by an independent physician to assess the suspicion level of the additional findings.ResultsOf the 1337 patients who underwent FDG-PET/CT, 202 patients (15%) had an non-BC related additional finding for which diagnostic work-up was conducted, resulting in 318 examinations during the first year. The non-BC related findings were mostly detected in the endocrine region (26%), gastro-intestinal region (16%), or the lungs (15%). Seventeen patients (17/202: 8%, 17/1337: 1.3%) had a second primary malignancy. Only 8 patients (8/202: 4%, 8/1337: 0.6%) had a finding that was considered more prognosis-determining than their BC disease. When revising all FDG-PET/CT scans, 57 (202/57: 28%) of the patients had an additional finding categorized as low suspicious, suggesting no indication for diagnostic work-up.ConclusionFDG-PET/CT scans used for dissemination imaging in BC patients detect a high number of non-BC related additional findings, often clinically irrelevant and causing a large amount of unnecessary work-up. However, in 8% of the patients undergoing diagnostic work-up for an additional finding, a second primary malignancy was detected, warranting diagnostic attention in selected patients.

The importance of ultrasound-guided biopsy: lesson from a case of liver metastasis from uveal melanoma

Melanoma is an extremely aggressive malignant neoplasm. Uveal melanoma is the most common primary intraocular malignancy in adults, representing 3–5% of all melanomas. Liver metastases can be clinically detected in 10–20% of patients with metastatic disease from cutaneous melanoma. However, while liver is typically not the first site of disease spread in cutaneous melanoma, ocular melanoma has been showed to primarily metastasize from the eye to the liver; indeed, liver metastases are detected in approximately 87% of patients with metastatic uveal melanoma. Therefore, liver metastasis can be challenging to identify in early stages, thus being essentially asymptomatic until the disease has advanced. Here we report the case of a patient who came to our ultrasound unit reporting a large liver mass. Both contrast-enhanced abdominal computed tomography and magnetic resonance imaging did not establish a definitive diagnosis. The final diagnosis was made only through an ultrasound-guided biopsy of the mass, thus revealing a uveal melanoma metastasis. This is followed by a review of the literature on imaging follow-up of patients with melanoma.

Outcomes of non-angiosarcoma radiation-associated soft tissue sarcomas of the chest.

Radiation-associated soft tissue sarcomas (RA-STS) are rare complications of patients receiving radiation therapy (RT) and are generally associated with a poor prognosis. Most of the literature surrounding RA-STS of the chest is centered on angiosarcoma. Therefore, we aim to document the management and outcome of patients with non-angiosarcoma RA-STS of the chest. We reviewed 17 patients (all female, median age 65 years) diagnosed with RA-STS. The most common primary malignancy was breast carcinoma (n = 15), with a median RT dose of 57.9 Gy. All patients underwent surgical resection; five patients (29%) received radiotherapy; and fivepatients (29%) received peri-operative chemotherapy. The 5-year local recurrence and metastatic-free survival were 61% and 60%, while the 5-year disease-specific survival was 53%. Local recurrence was associated with death due to disease (HR 9.06, p = 0.01). Complications occurred in nine of patients, most commonly due to a wound complication (n = 7). At the most recent follow-up, the median Musculoskeletal Tumor Society Score was 63%. RA-STS involving the chest wall are aggressive tumors with a high risk of local relapse and death due to disease. Local recurrence was associated with death due to disease; as such,we recommend aggressive surgical management with evaluation for adjuvant therapies.

P2X7 receptor antagonism by AZ10606120 significantly depletes glioblastoma cancer stem cells in vitro

Glioblastoma is the most aggressive and lethal primary brain malignancy with limited treatment options and poor prognosis. Self-renewing glioblastoma cancer stem cells (GSCs) facilitate tumour progression, resistance to conventional treatment and tumour recurrence. GSCs are resistant to standard treatments. There is a need for novel treatment alternatives that effectively target GSCs. The purinergic P2X receptor 7 (P2X7R) is expressed in glioblastomas and has been implicated in disease pathogenesis. However, the roles of P2X7R have not been comprehensively elucidated in conventional treatment-resistant GSCs. This study characterised P2X7R channel and pore function and investigated the effect of pharmacological P2X7R inhibition in GSCs. Immunofluorescence and live cell fluorescent dye uptake experiments revealed P2X7R expression, and channel and pore function in GSCs. Treatment of GSCs with the P2X7R antagonist, AZ10606120 (AZ), for 72 hours significantly reduced GSC numbers, compared to untreated cells. When compared with the effect of the first-line conventional chemotherapy, temozolomide (TMZ), GSCs treated with AZ had significantly lower cell numbers than TMZ-treated cultures, while TMZ treatment alone did not significantly deplete GSC numbers compared to the control. AZ treatment also induced significant lactate dehydrogenase release by GSCs, indicative of treatment-induced cytotoxic cell death. There were no significant differences in the expression of apoptotic markers, Annexin V and cleaved caspase-3, between AZ-treated cells and the control. Collectively, this study reveals for the first time functional P2X7R channel and pore in GSCs and significant GSC depletion following P2X7R inhibition by AZ. These results indicate that P2X7R inhibition may be a novel therapeutic alternative for glioblastoma, with effectiveness against GSCs resistant to conventional chemotherapy.

Dose-response relationship between volume base dose and tumor local control in definitive radiotherapy for vaginal cancer

ObjectiveThis study aimed to establish the dose-response relationship between volume base dose and tumor local control for vaginal cancer, including primary vaginal cancer and recurrent gynecologic malignancies in the vagina.Materials and methodsWe identified studies that reported volume base dose and local control by searching the PubMed, the Web of Science, and the Cochrane Library Database through August 12, 2023. The regression analyses were performed using probit model between volume based dose versus clinical outcomes. Subgroup analyses were performed according to stratification: publication year, country, inclusion time of patients, patients with prior radiotherapy, age, primaries or recurrent, tumor size, concurrent chemoradiotherapy proportion, dose rate, image modality for planning, and interstitial proportion.ResultsA total of 879 patients with vaginal cancer were identified from 18 studies. Among them, 293 cases were primary vaginal cancer, 573 cases were recurrent cancer in the vagina, and 13 cases were unknown. The probit model showed a significant relationship between the HR-CTV (or CTV) D90 versus the 2-year and 3-year local control, P values were 0.013 and 0.014, respectively. The D90 corresponding to probabilities of 90% 2-year local control were 79.0 GyEQD2,10 (95% CI: 75.3–96.6 GyEQD2,10).ConclusionsA significant dependence of 2-year or 3-year local control on HR-CTV (or CTV) D90 was found. Our research findings encourage further validation of the dose-response relationship of radical radiotherapy for vaginal cancer through protocol based multicenter clinical trials.

Casticin induces ferroptosis in human osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4

Osteosarcoma is a primary solid bone malignancy, and surgery + chemotherapy is the most commonly used treatment. However, chemotherapeutic drugs can cause a range of side effects. Casticin, a polymethoxyflavonoid, has anti-tumor therapeutic effects. This study is aim to investigate the anti-osteosarcoma activity of casticin and explore the mechanism. Crystal violet staining, MTT assay, colony formation assay, wound healing assay, transwell assay, hoechst 33,258 staining, and flow cytometry analysis were used to investigate the effects of casticin on proliferation, migration, invasion, and apoptosis of osteosarcoma cells in vitro. The intracellular Fe2+, ROS, MDA, GSH/GSSG content changes were detected using the corresponding assay kits. The mRNA sequencing + bioinformatics analysis and western blot were used to detect the possible mechanism. We found that casticin caused G2/M phase cell cycle arrest in human osteosarcoma cells, inhibited the migration and invasion, and induced cell apoptosis and ferroptosis. Mechanistic studies showed the ferroptosis pathway was enriched stronger than apoptosis. Casticin up-regulated the expression of HMOX1, LC3 and NCOA4, meanwhile it activated MAPK signaling pathways. Animal experiments proved that casticin also inhibited the growth and metastasis of osteosarcoma cell xenograft tumor in vivo. In conclusion, casticin can induce ferroptosis in osteosarcoma cells through Fe2+ overload and ROS production mediated by HMOX1 and LC3-NCOA4. This provides a new strategy for osteosarcoma treatment.

Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.