Second Primary Malignancies Research Articles

The Fate(s) of CAR T-Cell Therapy: Navigating the Risks of CAR+ T-Cell Malignancy.

The introduction of chimeric antigen receptor (CAR) T-cell therapy represents a landmark advancement in treating resistant forms of cancer such as leukemia, lymphoma, and myeloma. However, concerns about long-term safety have emerged following an FDA investigation into reports of second primary malignancies (SPM) after CAR-T cell treatment. This review offers a thorough examination of how genetically modified T cells might transform into CAR+ SPM. It explores genetic and molecular pathways leading to T-cell lymphomagenesis, the balance between CAR T-cell persistence, stemness, and oncogenic risk, and the trade-off of T-cell exhaustion, which may limit therapy efficacy but potentially reduce lymphomagenesis risk. Significance: An FDA probe into 22 cases of second primary T-cell malignancies following CAR T-cell therapy stresses the need to investigate their origins. Few may arise from preexisting genetic and epigenetic alterations and those introduced during therapeutic engineering. Technological advances, regulatory oversight, and patient monitoring are essential to mitigate potential risks.

Final results of a phase II study of lenalidomide-elotuzumab as maintenance therapy post-autologous stem cell transplant (AuSCT) in patients (Pts) with multiple myeloma (MM).

7509 Background: Randomized controlled trials oflenalidomide (LEN) maintenance after AuSCT have shown a progression free survival (PFS) benefit in pts with MM. We report final results of a phase 2 trial evaluating the efficacy and safety of adding elotuzumab (ELO) to LEN as maintenance therapy post- AuSCT. Methods: On 28-day cycles, patients received ELO 10mg/kg iv weekly for cycles 1-2.Between 4/15/2015-1/27/2016, 27 pts received ELO 10mg/kg q2 weeks for cycles 3-6 and 20mg/kg monthly for cycles 7+. From 1/28/2016 forward, 74 pts received ELO 20 mg/kg monthly from cycle 3+. LEN was dosed at 10 mg/day for cycles 1-3 and increased to 15 mg/day at physician discretion starting with cycle 4 in the absence of non-hematologic (HEME) toxicity > grade 1, ANC < 1000/mL and platelet count < 100K/ml. For the 1st 8 weeks, pts <75 yrs received 28 mg of dexamethasone (DEX) 3-24 hours pre-infusion and pts ≥75yrs received 8 mg; pts received 4-10 mg iv DEX pre-infusion for all cycles. Zoster and thromboembolic prophylaxis were prescribed as per standard recommendations. The primary endpoint was PFS, defined as time from AuSCT to progressive disease (PD) or death (whichever occurred first), or censored at last contact date. Secondary objectives were best response, overall survival (OS), incidence of second primary malignancies (SPMs) and adverse event (AE) profile. Enrollment was completed on 6/5/2019. Eligible pts received ≤2 induction lines of therapy (LOT) and were 60-210 days post-AuSCT. Results: Pts (n=100) were treated for a median of 40 cycles (2-109). With a median follow up of 74.3 mos, 78% of pts (n=79) remain alive. Median PFS was 75.4 months. Median OS has not been reached; 5-year OS rate was 86.7%. At study entry, rate of ≥VGPR was 77.3% and ≥CR was 37.7%. On study, this improved to 91.1% ≥VGPR and 69.3% ≥CR. Of pts in ≥VGPR and tested for minimal residual disease (10-5 sensitivity by flow cytometry), 37/44 were negative. High-risk cytogenetics (n=44; p<0.0001), International Staging System (ISS) Stage III (n=10/95, p=0.049) and Revised-ISS Stage III (n = 3/89; p= 0.026) predicted shorter median PFS (39.2, 53.2 and 32.2 mos. respectively). Median PFS on next LOT was 21.8 mos. Grade 3-4 HEME AEs (n=102) were: neutropenia 35%, thrombocytopenia 7%, and anemia 10% . Grade 3-4 non-HEME AEs in >3 pts were: respiratory infections 23%, hypophosphatemia 19%, diarrhea 13% , fatigue 11% , peripheral neuropathy 7%, other infections 6%, myalgias 4%, and high ALT 4%. Incidence of HEME, non-invasive and solid tumor SPMs was 8%, 8% and 7%. Median time to HEME SPM diagnosis was 45.5 mos. Conclusions: ELO-LEN is a well-tolerated maintenance therapy on which 53% of patients had improved quality of response. Median PFS and 5-year OS compare favorably with results from CALGB 100104 and IFM 2005-02 trials of lenalidomide alone. SPM incidence is similar to rates reported in these trials. Clinical trial information: NCT02420860 .

Prognosis of Second Primary Malignancies in Pediatric Acute Lymphoblastic Leukemia Survivors: A Multicenter Study by the Turkish Pediatric Hematology Society.

The improved survival rates of childhood cancers raise the long-term risk of second primary malignancy (SPM) in childhood and adolescent cancer survivors. The intensity of the treatment protocol used, the use of some groups of chemotherapeutics, and radiotherapy were found to be risk factors for the development of second primary malignancies (SPMs). Forty-one patients who developed acute myelocytic leukemia or any solid organ cancer within 25 years of follow-up, after completion of pediatric acute lymphoblastic leukemia (ALL) treatment, were included in the study. The mean duration of initial ALL diagnosis to SPM was 9.3 ± 6.1 years. The 3 most common SPMs were acute myelocytic leukemia, glial tumors, and thyroid cancer. Thirteen (81%) of 16 patients exposed to cranial irradiation had cancer related to the radiation field. In total 13/41 (32%) patients died, and the 5-year overall survival rate was 70 ± 8%. Patients older than 5 years old at ALL diagnosis had significantly worse overall survival than cases younger than 5 years old. In conclusion, children and adolescents who survive ALL have an increased risk of developing SPM compared with healthy populations, and physicians following these patients should screen for SPMs at regular intervals.

Association between postoperative radiotherapy for young-onset nonsmall cell lung cancer and risk of second primary malignancies: comparative study.

The most common form of therapy for nonsmall cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. The authors aimed to quantify the risks of SPM associated with PORT treatment for young‑onset NSCLC in early stage. The authors screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology, and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs. Among the 30308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies [relative risks (RR)=1.31; 95% CI: 1.17-1.46], lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74), and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR=1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60-69 years (RR=1.33), in white race (RR=1.36), diagnosed in 1975-2000 (RR=1.23) and 2001-2015 (RR=1.40), or diagnosed with lung adenocarcinoma (RR=1.55). PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer, as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients.

High incidence of lung cancer death after curative endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma.

Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. The 5-year survival rate of 187 patients was 92.6% during a median follow-up duration of 96.8 months. Thirty-one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol-voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91-6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41). SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.

Incidence of Second Primary Malignancies Following Thyroid Cancer Treatment with Radioactive Iodine

Background: Thyroid cancer is the most common endocrine malignancy, with an increasing incidence globally and in Oman. The standard treatment for differentiated thyroid cancer (DTC) involves radioactive iodine (RAI). However, previous studies have suggested that RAI treatment may increase the risk of second primary malignancies (SPM). Despite the high incidence of thyroid cancer in Oman, to our knowledge, there are no published reports on the association between RAI treatment and the risk of SPM in Oman.

Incidentally found parotid gland lesion in 18F-FDG PET/CT for staging evaluation of patients with hepatocellular carcinoma: remote possibility of metastatic tumor or second primary salivary gland malignancy

ObjectivesWe primarily aimed to evaluate whether parotid incidental lesion (PIL) in 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for staging evaluation of patients with hepatocellular carcinoma (HCC) would represent a possibility of extrahepatic metastasis or second primary malignancy (SPM). Additionally, we explored the incidence of PIL in HCC patients and examined any associated risk factors.MethodsWe retrospectively analyzed patients with HCC who underwent 18F-FDG PET/CT at our institution from 2010 to 2022. The pathological findings of PILs in HCC patients were investigated for confirmatory identification of the risk of HCC metastasis or SPM in parotid gland. Healthy controls received 18F-FDG PET/CT for health screening were also enrolled to compare the incidence of PILs with HCC patients. Various parameters associated with patient demographics and characteristics of HCC were analyzed to find the related factors of PILs.ResultsA total of 17,674 patients with HCC and 2,090 healthy individuals who had undergone 18F-FDG PET/CT scans were enrolled in the analyses. Among the 54 HCC patients who underwent pathological confirmation for PILs, benign primary parotid tumor was most commonly observed (n = 43 [79.6%]); however, no malignant lesions were detected, including HCC metastasis. The incidence of PILs was higher in patients diagnosed with HCC compared with the control group (485 [2.7%] vs. 23 [1.1%], p = 0.002). Analysis for the risk factors for PILs revealed that patient age, sex, and positive viral markers were significantly associated with the incidence of PILs in patients with HCC (all p < 0.001).ConclusionsOur study demonstrates that PILs are more frequently identified in patients with HCC on 18F-FDG PET/CT. However, no malignant PIL, including extrahepatic metastasis of HCC, was identified. Therefore, the presence of PIL should not impede or delay the treatment process for patients with HCC. Additionally, we suggested that for future swift and straightforward differential diagnoses of PIL, the development of additional protocols within the PET/CT imaging could be beneficial.

Long-term outcomes after haploidentical stem cell transplantation for hematologic malignancies

AbstractThe introduction of posttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy–based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

Incidence, risk and prognosis of second primary malignancy of patients with gastric adenocarcinoma

Due to the long-term low survival rates of gastric adenocarcinoma (GAC) patients, the occurrence and prognosis of second primary malignancies (SPMs) are often underreported and overlooked as a significant concern.To date, only a few studies have addressed this issue in the context of GAC. These studies, however, are limited by their small patient cohorts and lack of substantial, meaningful findings. Our study aims to fill this gap by investigating the incidence, risk factors, and prognostic significance of SPMs among GAC survivors. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we analysed data from patients diagnosed with GAC between 2000 and 2020. The study employs the standardized incidence ratio (SIR) to assess the relative risk of SPMs, competing risk regression to identify risk factors for SPM development after GAC, and Kaplan-Meier and COX regression analyses for survival outcomes. Out of 44,041 GAC patients analyzed, 2,032 (4.3%) developed SPMs, with a median latency period of 36 months. The incidence of SPMs was significantly higher in GAC patients (SIR 1.36, 95% CI 1.32-1.4, EAR 53.57) compared to the general population. Key factors including older age, sex, tumor grade, summary stage, and history of surgical and radiation therapy were related to the higher risk of developing SPMs following GAC. Interestingly, GAC patients without SPMs exhibited poorer overall survival compared to those with SPMs. Age, summary stage, and surgical history were identified as independent prognostic factors for GAC patients with SPMs. This comprehensive analysis underscores the necessity of vigilant monitoring and tailored follow-up for SPMs in GAC survivors, highlighting the study's contribution to enhancing GAC survivors care strategies.

Shortened telomere length in peripheral blood leukocytes is associated with cumulative radioactive iodine doses in patients with differentiated thyroid carcinoma.

Telomere length is associated with cancer risk and cancer aggressiveness. Radioactive iodine (RAI) therapy for thyroid cancer has raised concerns for second primary malignancy (SPM) in patients with high cumulative doses. The association between RAI dose and peripheral blood leukocyte telomere length was examined. A total of 425 patients were included who underwent total thyroidectomy and were followed up for at least 1year with or without RAI treatment. The relative telomere length (RTL) of the patients was assessed via a quantitative polymerase chain reaction amplification method. RAI doses were divided into five groups on the basis of cumulative dose, and a comparison was made among these groups. The number of patients with RAI treatment was 287 (67.5%), and the cumulative RAI dose was 3.33GBq (range, 1.11-131.35 GBq). The mean RTL was significantly shorter in the highest RAI group (>22.2GBq) compared to both the no-RAI and lower dose groups. The association between RAI dose and RTL was positive in the lower RAI group (1.1-3.7GBq) and negative in the highest RAI group in both univariate and multivariate analyses. We observed 59 (13.9%) SPMs and 20 (4.7%) mortalities, and RTL did not show a significant risk effect for all-cause, thyroid cancer-specific, or SPM-specific mortality. In patients with thyroid cancer who underwent total thyroidectomy, peripheral blood leukocyte telomere length exhibited a significant association with cumulative RAI dose higher than 22.2GBq. These results suggest the possibility of telomere length shortening in patients who undergo high-dose RAI treatment.

Secondary primary malignancies among patients with GU cancer.

98 Background: The risk of secondary primary malignancies (SPM) among the survivors of GU cancer is not well-established. In this study, we attempt to describe the patterns of SPMs in patients diagnosed with GU cancers. Methods: The Surveillance, Epidemiology, and End Results (SEER) database (SEER*Stat 8.4.2) was searched to obtain data on the incidence of SPM in adult patients (age &gt;18 years) diagnosed with GU cancers, including prostate, renal, and bladder cancer. Standardized incidence ratios (SIRs) with a 95% confidence interval (CI) were calculated. SIR was defined as the observed SPMS from each category divided by the expected number of SPMs in the age-matched US population for the same period. The data was further stratified by age (&lt;50y, 50-70y, &gt;70y), race (White, Black, Asian/Pacific Islander), ethnicity (Hispanic, non-Hispanic), chemotherapy, and radiotherapy exposure. Results: A total of 1,041,217 patients were included in this analysis. In patients diagnosed with GU cancer, the incidence of overall SPM was 11%. Particularly, patients with GU cancers were observed to have a high incidence of Endocrine system SPM (1.52; 1.45-1.59), and urinary system SPM (1.51; 1.49-1.53) These results were consistent by different sociodemographic groups. In patients diagnosed with prostate cancer, the incidence of thyroid SPM was increased (1.31; 1.23-1.39). Particularly, prostate cancer patients treated with radiation therapy had increased incidence rates of SPM in the peritoneum, omentum and mesentery (1.57; 0.79-2.81) and urinary bladder (1.36;1.32-1.40) was higher as compared to those with no exposure to radiation therapy (1.11;1.08-1.13 and 1.03;1-1.06 respectively). Bladder cancer patients had an overall increased incidence of SPM in the esophagus (1.21; 1.08-1.35), lung, bronchus, trachea, and other respiratory organs (1.97;1.92-2.01), prostate (3.50;3.4-3.6) and kidney (1.86;1.76-1.97). A higher incidence of renal pelvis, ureter and other urinary organ SPM (11.08;10.48-11.07) was also notable in this population. Similarly, kidney cancer patients had a higher incidence of the endocrine system (3.00;2.74-3.27), prostate (1.24;1.2-1.29) and bladder 1.78;1.68-1.79 SPMs. Conclusions: This population-based study shows an increased risk of SPM development in GU cancer survivors compared to the general population. Clinicians should keep a high index of suspicion for SPMs and initiate appropriate workups at early warning signs.

Assessment of second primary malignancies among treated and untreated patients with chronic lymphocytic leukemia using real-world data from the USA.

Aim: Improved management of chronic lymphocytic leukemia (CLL) has resulted in a growing population of CLL survivors; these patients have a higher risk of developing second primary malignancies (SPMs) versus the general population. This retrospective cohort study aims to assess the timing, frequency, incidence and types of SPMs in treated and untreated patients with CLL in the USA, using the Surveillance, Epidemiology, and End Results (SEER) Medicare database, which links a nationally representative cancer registry with Medicare claims data. Patients & methods: Patients aged ≥66years with newly diagnosed CLL between 1January2010 and 31December2016, who were enrolled in Parts A and B of Medicare for ≥12months pre-diagnosis of CLL were selected from the database. Patients were assessed for ≥36months until the end of continuous enrollment in Medicare Parts A, B and D, a switch to a health maintenance organization, death, or end of the study period (December2019). Results: Of 3053 patients included in the analyses, 620 (20.3%) were treated and 2433 (79.7%) were untreated within 36months of diagnosis. Overall, 638 (20.9%) patients developed a SPM, 26.8% of patients in the treated cohort and 19.4% of patients in the untreated cohort. The most common SPMs for both cohorts were squamous cell carcinoma and acute myeloid leukemia. Among the 166 treated patients who developed a SPM, a greater proportion developed their first SPM after treatment initiation versus those who developed their first SPM prior to treatment initiation (p<0.001). A significantly lower percentage of patients who received targeted therapy developed a SPM (p<0.05) versus patients treated with anti-CD20+ chemotherapy. Conclusion: Findings indicate that treatment type and timing can affect SPM development in patients with CLL. Combined with previous findings, this can help inform best practices in monitoring for SPM in patients with CLL.

Hematological Second Primary Malignancy in Pediatric Retinoblastoma: A Case Report and Systematic Review.

The impact of heredity and treatment modalities on the development of hematologic second primary malignancies (SPMs) is unclear. This study primarily reviewed the literature on patients with hematologic SPMs after retinoblastoma. The PubMed and Web of Science databases were searched to identify all cases of hematologic SPMs after retinoblastoma through December 2023 (International prospective register of systematic reviews CRD42023488273). Sixty-one patients from 35 independent publications and our case were included. Within the cohort, 15 patients (51.7%) were male, and 14 patients (48.3%) were female. Of the 43 cases with known heritability status, 27 (62.8%) were classified as heritable and 16 (37.2%) as nonheritable. The median age at diagnosis was 18 months (IQR: 7.00-36.00). The geographic distribution of patients was diverse, with North America accounting for 35.0% (21/60) of cases. The following treatment strategies were used: 11.9% (5/42) of patients received neither chemotherapy nor radiotherapy, 33.3% (14/42) received chemotherapy alone, 11.9% (5/42) received radiotherapy alone, and 42.9% (18/42) received a combination of chemotherapy and radiotherapy. The median delay between retinoblastoma diagnosis and SPM diagnosis was 40 months (IQR: 22.00-85.00). Among the 61 cases, acute myeloid leukemia accounted for 44.3% (27/61), followed by acute lymphoblastic leukemia in 21.3% (13/61), Hodgkin's lymphoma in 11.5% (7/61), non-Hodgkin's lymphoma in 9.8% (6/61), chronic myeloid leukemia in 3.3% (2/61), and acute natural killer cell leukemia in 1.6% (1/61). Vigilant systemic surveillance for hematologic SPMs in retinoblastoma survivors, especially those treated with systemic chemotherapy and those with hereditary conditions, is warranted to improve management strategies and patient outcomes.

Safety outcomes in patients with metastatic castration-resistant prostate cancer treated with radium-223 following external beam radiation therapy: REASSURE US subset.

106 Background: In the Phase 3 ALSYMPCA trial, radium-223 (Ra-223) demonstrated an overall survival (OS) benefit and a favorable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC). REASSURE (NCT02141438) is a global, prospective, single-arm, observational study of Ra-223 use in patients with mCRPC with bone metastases within routine clinical settings. Utilizing data from the second planned interim analysis, we evaluated safety outcomes in patients with mCRPC treated with Ra-223 following external beam radiation therapy (EBRT) in the US. Methods: In this descriptive analysis (data cutoff 3-20-2019), we included patients who received EBRT to bone prior to Ra-223 (≤2 years prior to Ra-223 first dose); results are presented relative to the overall US subset of patients enrolled into REASSURE. The focus of this abstract is on incidence of hematological toxicities, bone fractures, and second primary malignancies (SPM). Results: Of N=498 patients in the US subset, 118 patients received prior EBRT to bone. Median duration of observation was 11.7 months among patients who received EBRT and 11.9 months for the overall US subset. Any-grade drug-related hematological treatment-emergent adverse events (TEAEs) occurred in 8% (10/118) and 9% (47/498) of patients who received EBRT and the overall subset, respectively (Table). Grade ≥3 drug-related hematological TEAEs occurred in 5% (6/118) and 6% (32/498) of patients who received EBRT and the overall subset, respectively. Bone fractures occurred in 7% (8/118) and 4% (19/498) of patients who received EBRT and the overall subset, respectively. Six SPMs occurred in 5/118 patients who received EBRT (4%), and 11 SPMs occurred in 10/498 patients in the overall subset (2%). Results of bone fracture events by bone health agent use will be included in the full presentation. Conclusions: In this descriptive analysis of real-world data, patients who received EBRT prior to Ra-223 did not demonstrate an increased incidence of hematological toxicities relative to the overall US subset. Although percent of SPMs and bone fractures seems higher among patients treated with EBRT relative to the overall US subset, the real-world incidence of these events remains low. [Table: see text]

Effectiveness and risk of second primary malignancies after radiotherapy in major salivary gland carcinomas: A retrospective study using SEER database.

To investigate the effectiveness of radiotherapy and its association with second primary malignancies (SPMs) risk in major salivary gland carcinomas (MSGCs) patients. Cohort 1 included 7274 surgically treated MSGC patients from the Surveillance, Epidemiology, and End Results database, assessing the effectiveness of radiotherapy. Cohort 2 (n = 4213) comprised patients with ≥5-year survival in Cohort 1 to study SPMs. Radiotherapy decreased overall survival in MSGCs patients, but improved it in high-grade MSGCs. Cumulative SPMs incidences at 25 years were 16.5% in the radiotherapy (RT) group compared to 14.5% in the non-radiotherapy (NRT) group. For second head and neck carcinomas (SHNCs), incidences were 3.4% in RT versus 1.6% in NRT. Radiotherapy increased the relative risks of tumors, particularly SHNCs (RR = 1.78). The 10-year OS rates of SHNCs after radiotherapy were significantly lower. Radiotherapy improves survival in advanced-stage MSGCs but increases the risk of developing SPMs, particularly SHNCs.

Lifetime risks of second primary malignancies after pediatric Hodgkin lymphoma and non-Hodgkin lymphoma

ObjectivesSurvivors after pediatric Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are with lifetime risk for second primary malignancy (SPM). This necessitates a thorough analysis to better understand the potential long-term health implications for these individuals.MethodsWe used a US-wide population-based cancer registry data to quantify the SPM risk and identify its incidence patterns among pediatric lymphoma patients.ResultsWe observed 4.74-fold (95% CI 4.27–5.25) and 3.40-fold (95% CI 2.78–4.10) increased risks of SPM in survivors after pediatric HL and NHL, respectively. Through over 40 years’ follow-up, the cumulative incidence of SPM for pediatric lymphoma was persistently increasing, and here we firstly report the high 40-year cumulative incidence rates of SPM, 22.2% for HL and 12.6% for NHL, suggesting that SPM accounts for a great proportion of deaths among survivors. Of 6805 pediatric lymphomas, 462 (6.36%) developed a SPM, especially second breast and thyroid cancer, followed by hematologic neoplasms including leukemia and NHL. The competing risk analysis demonstrated gender, lymphoma subtype and radiotherapy were significantly associated with SPM. Different risk patterns of SPM were identified between pediatric HL and NHL. Chemotherapy accelerated SPM development but did not increase its incidence risk.ConclusionOverall, patients after pediatric lymphoma can be with high lifetime risk of SPM, and more attention should be paid to SPM-related signs for early detection and intervention.

T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy.

We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8+ cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T.

Optimal Cumulative I-131 Activity in Metastatic Differentiated Thyroid Cancer: Balancing Efficacy and Adverse Events.

The optimal cumulative activity (CA) of I-131 therapy for patients with metastatic differentiated thyroid cancer (mDTC) remains contentious. This study aimed to determine the maximum CA of I-131 that could be administered without a significant increase in adverse events (AEs) by analyzing a long-term cohort of patients. Data from mDTC patients treated with I-131 therapy and followed for at least two years from 1967 to 2019 were reviewed. Patients were categorized into three groups based on the received CA: Group-A (≤600mCi), Group-B (>600-1000mCi), and Group-C (>1000mCi). The study assessed long-term AEs and survival outcomes. The study included 671 adult mDTC patients (mean age 48 years, range: 19-81) with a median follow-up of 122 months (IQR: 82-180). Group A, Group B, and Group C comprised 269 (40.0%), 212 (31.6%), and 190 (28.4%) patients, respectively. Ten-year survival rates were 72%, 42.7%, and 29% in Groups A, B, and C, respectively. A total of 40/671 (6%) AEs were observed in 38 patients: 3 (1.1%), 12 (5.7%), and 25 (13.2%) in Groups A, B, and C, respectively. Five patients developed second primary malignancy (SPM): 3 in Group A and one each in Group B and C. However, CA >1000mCi of I-131 was associated with significant increase in bone marrow suppression, decreased pulmonary function, and xerostomia (p < 0.001). The study suggests that a maximum CA of up to 1000mCi strikes a favorable balance between keeping AEs low and benefiting a subset of patients with extensive metastases showing intense I-131 concentration.

Second primary malignancies: A clinicopathological study from a tertiary care centre

Abstract Background: Second primary malignancy (SPM) is defined as a second de novo malignant neoplasm arising in a patient with known primary malignancy. SPM is common and can occur synchronously or metachronously. Methods: We retrospectively studied the epidemiological factors, patterns of occurrence and common associations of SPMs seen in our Department of Pathology during the period January 2016 and December 2020. The case details were retrieved from the medical records. SPM were diagnosed as per the International Association of Cancer Registries and International Agency for Research on Cancer criteria. Results: During the study period, 22 cases were seen. Their age ranged from 36 to 80 years; females had outnumbered males (female:male = 3.4:1). The most common site for metachronous primary was breast and the most common site for SPMs was head and neck. The median age for diagnosis of metachronous SPM was 59.2 years (range 41–80 years). The time interval for development of metachronous SPMs ranged from 6 months to 9 years. Conclusions: Our observations suggest that increased awareness regarding the entity and regular follow-up of patients can aid in early diagnosis of SPMs.

Causal effect of thyroid cancer on secondary primary malignancies: findings from the UK Biobank and FinnGen cohorts.

Existing epidemiological data indicated a correlation between thyroid cancer (THCA) and the risk of secondary primary malignancies (SPMs). However, the correlation does not always imply causality. The Mendelian randomization (MR) analyses were performed to investigate the causal relationships between THCA and SPMs based on international multicenter data. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The Cancer Genome Atlas (TCGA) was used to explore potential mechanisms shared by THCA and bladder cancer (BLCA). Summary datasets of genome-wide association studies (GWAS) on 30 types of cancers were obtained from the United Kingdom Biobank (UKB) and FinnGen database. Meta-analysis of the UKB and FinnGen results revealed that THCA was significantly positively correlated with BLCA (OR = 1.140; 95% CI, 1.072-1.212; P < 0.001). Four genes, including WNT3, FAM171A2, MLLT11, and ULBP1, were identified as key genes shared by both TCHA and BLCA. Correlation analysis indicated that THCA may increase the risk of secondary BLCA through augmentation of N2 neutrophil infiltration. This study showed that THCA was causally related to BLCA. It is recommended to conduct more rigorous screenings for BLCA during the follow-up of THCA patients.