Occurrence Of Second Malignancies Research Articles

Association of plasma kynurenine (KYN) with plasma osteopontin (OPN) in patients with locally invasive breast cancer.

e12551 Background: OPN is a matricellular protein implicated in several aggressive malignancies as both a prognostic marker and mechanistic driver of tumor development and metastasis, but little is known about what drives its increased expression in these settings. KYN, the biochemically active metabolite of tryptophan metabolism, is known to be involved in cancer immune evasion, cancer cell proliferation, chromosomal instability, angiogenesis, metastatic dissemination, and chemoresistance. In this study, we demonstrate that OPN levels are significantly elevated in plasma of patients requiring breast surgery for suspicious masses and is directly correlated with KYN plasma levels, which were also elevated in this population. Methods: We prospectively collected peripheral blood samples of 60 patients who required routine breast surgery for either benign or malignant masses. Plasma was obtained by centrifugation from the collected blood samples that were stored at -80℃. Samples were collected prior to any treatments or surgeries. This study is IRB approved, and participants provided written informed consent. High-performance liquid chromatography (HPLC) tandem mass spectrometry was carried out by the Dartmouth Clinical Pharmacology Shared Resource. Logistic regression was used to assess relationships among variables in the study population using the R language. Results: There is strong evidence to suggest that plasma KYN is directly related to OPN plasma levels in this group of 60 patients’ plasma samples with a correlation coefficient of 0.296 (p=0.024), 95% CI [0.0414-0.515]. Based on the p-value and confidence interval, there is statistical evidence to suggest a positive significant linear relationship between plasma KYN and OPN levels. Increased age and BMI, menopausal status, KYN’s substrate Tryptophan (TRP), and TNFα correlated neither with OPN levels nor event free survival (as defined by disease progression, complications including fractures, development of metabolic disease, or occurrence of secondary malignancy). Conclusions: Our data demonstrates a statistically significant linear relationship between KYN and OPN in plasma samples of patients undergoing breast surgery for suspicious lesions—offering new mechanistic insights into OPN—a biomarker implicated in cancer metastasis across several different cancer types. This data suggests that KYN, which is a known agonist of several harmful cancer-driving pathways, is directly related to OPN concentration in plasma of patients with early breast cancer. Further research investigating systemic concentrations of OPN in plasma is essential for gaining a comprehensive understanding of its mechanisms in tumor metastasis, as well as for exploring targeted therapeutic strategies to mitigate its detrimental effects.

Incidence of second malignancies in patients with thymic carcinoma and thymic neuroendocrine tumor

ObjectivesThymic carcinoma and thymic neuroendocrine tumor (NET) are rare and are more likely to develop second malignancies. The purpose of this study was to explore the incidence and lifetime risk of second malignancies in thymic carcinoma and thymic NET.MethodsThe standardized incidence ratio (SIR) and the age-adjusted cancer incidence of the thymic carcinoma and thymic NET patients with second malignancies were retrospectively calculated by using the Surveillance, Epidemiology, and End Results (SEER) database. Prognosis results were also determined by Kaplan–Meier analysis and Cox regression.Results1130 patients with thymic carcinoma (73 patients had second malignancies) and 263 patients with thymic NET (19 patients had second malignancies) from 2000 to 2018 are included. Patients with thymic carcinoma (SIR: 1.36, 95% CI 1.08–1.69) and with thymic NET (SIR: 1.73, 95% CI 1.13–2.54) demonstrate an increased overall risk of developing second malignancies in various organ systems. The age-adjusted cancer incidence of second malignancies in patients with thymic carcinoma is 3058.48 per 100,000 persons (4178.46 per 100,000 persons in patients with thymic NET). Age at diagnosis is a significant risk factor for the development of second malignancies.ConclusionThe incidence of second malignancies in patients with thymic carcinoma and thymic NET is significantly higher than the patients in the normal population. The occurrence of second malignancies is not related to the use of different treatments. It is important to extend the follow-up period and add other screening methods.

Second Malignancy Probabilities in Patients With Breast Cancer Treated With Conventional Versus Hypofractionated External Beam Radiation Therapy in the Adjuvant Setting

AimsFor women with breast cancer, seminal studies have shown that adjuvant hypofractionated external beam radiation therapy (hEBRT) maintains similar outcomes and may reduce overall costs compared with conventionally fractionated external beam radiation therapy (cEBRT). However, it is unclear whether hEBRT may be associated with differential risk of development of radiation-induced second malignancies compared with cEBRT. Because the occurrence of second malignancies is small, large databases may improve our understanding of the relative risk of second malignancies between hEBRT and cEBRT. Materials and methodsUsing the National Cancer Database, we carried out a retrospective cohort analysis of women diagnosed with non-metastatic, stage 0–III breast cancer from 2004 to 2017. All patients had a lumpectomy or mastectomy and a follow-up time of at least 60 months after diagnosis. The probability of second malignancies in women receiving adjuvant cEBRT or hEBRT was compared using multivariable logistic regression adjusting for sociodemographic, geographical, clinical and treatment factors, allowing for relative (but not absolute) comparison of second malignancy risk. Temporal sensitivity analyses stratified by year of diagnosis and length of follow-up time were also conducted. ResultsOf the 125 228 women in our study, 115 576 (92.3%) received cEBRT and 9652 (7.71%) received hEBRT. The median age of the cohort was 60 (interquartile range 51–68) years at diagnosis and the median follow-up time was 99.61 (interquartile range 77.5–128.49) months. Upon adjusting for sociodemographic and clinical factors, patients who received hEBRT had no difference in relative risk than patients who received cEBRT (odds ratio 0.937, 95% confidence interval 0.869–1.010, P = 0.091). In analyses stratified by year of diagnosis, and stratified by length of follow-up, there was no difference in second malignancy probability between patients who completed hEBRT and patients who completed cEBRT. ConclusionsIn this analysis of over 120 000 women with non-metastatic breast cancer, hEBRT was not associated with different odds of developing second malignancies compared with cEBRT. Our findings may inform patient counselling in the choice of radiation regimens for breast cancer and further support the safety of hypofractionated regimens for breast cancer.

Radiation Therapy Changed the Second Malignancy Pattern in Rectal Cancer Survivors.

Background and Objectives: Radiotherapy (RT) plays an important role in the treatment for locally advanced rectal cancer patients. It can bring radio exposure together with the survival benefit. Cancer survivors are generally at an increased risk for second malignancies, and survivors receiving RT may have higher risks than survivors not receiving RT. Whether the risk of an all-site second malignancy may increase after RT is still debated. This study aims to compare the second malignancy pattern in rectal cancer survivors after RT. Materials and Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used for analysis. In total, 49,961 rectal cancer patients (20-84 years of age) were identified between 2000 and 2012 from 18 SEER registries. All patients underwent surgery. The occurrence of second malignancies diagnosed after rectal cancer diagnosis was compared in patients who received and did not receive RT. The standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were used. SEER*Stat was used to generate the 95% CIs for the SIR statistics using the exact method. Results: Of the total 49,961 patients, 5582 developed second malignancies. For all-site second primary malignancies, the age-adjusted SIRs were 1.14 (95% CI 1.1-1.18) and 1.00 (95% CI 0.96-1.04) in the no RT and RT groups, respectively. In 23,192 patients from the surgery-only group, 2604 had second malignancies, and in 26,769 patients who received RT, 2978 developed second malignancies. With respect to every site, the risk of secondary prostate cancer was significantly lower in the RT group (SIR = 0.39, 95% CI 0.33-0.46) than that in the surgery-only group (SIR = 1.04, 95% CI 0.96-1.12). Moreover, the risk of thyroid cancer was significantly higher in the RT group (SIR = 2.80, 95% CI 2.2-3.51) than that in the surgery-only group (SIR = 1.29, 95% CI 0.99-1.66). Conclusions: RT may change the second malignancy pattern in rectal cancer survivors; the risk of prostate cancer decreased, and the risk of thyroid cancer increased most significantly.

Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

Real-world Data From the Swiss Lenalidomide in MDS del(5q) (SLIM)-Registry Identify New Chances and Challenges in Lenalidomide Treatment of Patients With MDS del(5q).

Twenty years of experience of a tertiary cancer center in total body irradiation with focus on oncological outcome and secondary malignancies

PurposeTotal body irradiation (TBI) is a common part of the myelo- and immuno-ablative conditioning regimen prior to an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to concerns regarding acute and long-term complications, there is currently a decline in otherwise successfully established TBI-based conditioning regimens. Here we present an analysis of patient and treatment data with focus on survival and long-term toxicity.MethodsPatients with hematologic diseases who received TBI as part of their conditioning regimen prior to allo-HSCT at Frankfurt University Hospital between 1997 and 2015 were identified and retrospectively analyzed.ResultsIn all, 285 patients with a median age of 45 years were identified. Median radiotherapy dose applied was 10.5 Gy. Overall survival at 1, 2, 5, and 10 years was 72.6, 64.6, 54.4, and 51.6%, respectively. Median follow-up of patients alive was 102 months. The cumulative incidence of secondary malignancies was 12.3% (n = 35), with hematologic malignancies and skin cancer predominating. A TBI dose ≥ 8 Gy resulted in significantly improved event-free (p = 0.030) and overall survival (p = 0.025), whereas a total dose ≤ 8 Gy and acute myeloid leukemia (AML) diagnosis were associated with significantly increased rates of secondary malignancies (p = 0.003, p = 0.048) in univariate analysis. No significant correlation was observed between impaired renal or pulmonary function and TBI dose.ConclusionTBI remains an effective and well-established treatment, associated with distinct late-toxicity. However, in the present study we cannot confirm a dose–response relationship in intermediate dose ranges. Survival, occurrence of secondary malignancies, and late toxicities appear to be subject to substantial confounding in this context.

Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study

Metabolic syndrome (MetS) is associated with cardiovascular disease in the general population and is also a potential cardiovascular risk factor in survivors of haematopoietic cell transplantation (HCT). We report an EBMT cross-sectional, multi-centre, non-interventional study of 453 adult HCT patients surviving a minimum of 2 years post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. The overall prevalence of MetS was 37.5% rising to 53% in patients >50 years of age at follow-up. There were no differences in rates of MetS between autologous and allogeneic HCT survivors, nor any association with graft-versus-host disease (GvHD) or current immunosuppressant therapy. Notably, there was a significantly higher occurrence of cardiovascular events (CVE, defined as cerebrovascular accident, coronary heart disease or peripheral vascular disease) in those with MetS than in those without MetS (26.7% versus 9%, p < 0.001, OR 3.69, 95% CI 2.09–6.54, p < 0.001), and, as expected, MetS and CVE were age-related. Unexpectedly, CVE were associated with occurrence of second malignancy. Screening for and management of MetS should be integrated within routine HCT long-term follow-up care for both allogeneic and autologous HCT survivors. Further research is warranted, including randomised controlled trials of interventional strategies and mechanistic studies of cardiovascular risk in HCT survivors.

Importance of diagnostics and risk of secondary malignancies in primary cutaneous lymphomas.

Primary cutaneous lymphomas (PCL) often strongly differ in clinical behavior and prognosis from systemic lymphomas of the same histopathologic type. The aim of the study was to investigate the distribution of PCL subtypes, the average time from disease manifestation to diagnosis, the importance of diagnostic procedures, the occurrence of secondary malignancies and the different treatment modalities. Retrospective analysis of 152 patients with PCL examined at the Department of Dermatology of the University Hospital Tübingen from 2010-2012. 105 patients with CTCL (69.1%) and 47 patients with CBCL (30.9%) were included. The average time from disease manifestation to diagnosis was four years. The most common diagnosed lymphoma was mycosis fungoides (MF) (47.4%). First-line therapies here include phototherapy only (psoralen-UV-A [PUVA], n=48; UVB 311nm, n=7) or combination therapies primarily phototherapy with systemic retinoids (n=18). Most frequent second-line therapy was interferon (INF)-α plus PUVA (n=15). The outcome was favorable (45.2% remission, 28.6% stable disease, 22.6% progressive disease). Malignant comorbidities were observed more frequently compared to a healthy control group. The diagnosis of lymphoma often takes several years. The value of staging procedures is still low and the treatment modalities for MF in earlier stages are mainly based on phototherapy.

Analysis of a cohort of 279 patients with hairy-cell leukemia (HCL): 10 years of follow-up

In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.

Long-term evaluation of outcomes and survival of patients treated for retinoblastoma

PurposeThe purpose of our study was to assess long-term outcomes of patients suffering from retinoblastoma who underwent systemic chemotherapy using vincristine, etoposide, and carboplatin (VEC protocol) followed by other local treatments. Material and methodsA retrospective review of patients diagnosed with retinoblastoma from 1997 to 2012 in the Department of Ophthalmology and Ocular Oncology of the University Hospital in Krakow was performed. A total of 58 eyes of 42 patients were analyzed. The main outcome measures were survival rate of the patient, final visual acuity, preservation of affected eyeball, intraocular relapse, extraocular orbital tumor recurrence, and occurrence of other neoplasms. ResultsThe overall survival rate was 97.6%. The majority of eyes (67.2%) had retinoblastomas of group V in the Reese-Ellsworth Classification (REC). Ocular preservation was achieved in 41.4% eyes. Of the 24 preserved eyes, 41.7% had a final visual acuity of 6/12 or better, 12.5% had visual acuity worse than 6/12 but better than 6/60, and 45.8% had visual acuity of 6/60 or worse. Three patients (7.1%) experienced orbital recurrence of retinoblastoma and one patient (2.4%) developed a second malignancy (chronic myeloid leukemia associated with the Philadelphia chromosome). ConclusionsRetinoblastomas, especially in Reese-Ellsworth group V (RE group V), not only impair vision, but may lead to metastases and death. Early diagnosis and prompt treatment are essential to salvage the eye and vision, and to avoid metastases. Long-term follow-up of retinoblastoma survivors is important to identify late effects associated with treatment and the occurrence of second malignancies.

A population-based study of hairy cell leukemia over a period of 20 years

There are limited population-based studies of hairy cell leukemia (HCL), a rare chronic lymphoproliferative disorder of B-cells. We conducted a population-based study that included all patients diagnosed with HCL between 1996 and 2016 in Western Normandy. Recorded data focused on medical history, clinical presentation, biological results, treatment modalities in the first line and in relapsed/refractory patients and the occurrence of secondary malignancies. One hundred and twenty-three HCL patients were registered in the database. HCL represented 0.7% of all malignant hematological disorders and 3.0% of all leukemia. The overall age-standardized incidence ratio (SIR) was 0.39/100,000 inhabitants in men and 0.09/100,000 in women, and it remained stable over the 20-year period analyzed. One hundred and seven patients (88%) received first-line treatment, 33 patients (27%) received at least 2 lines of treatment and 14 patients (11%) received more than 2 lines. Cladribine used as first-line treatment induced a high hematological complete response (HCR) rate of 92%. The median overall survival (OS) was over 15 years, with 5-year and 10-year survival rates of 84% and 70.5%. No significant differences in OS were observed between men and women, between the calendar periods studied or between patients who received a single line treatment with IFN-α or PNA. The risk of relapse was higher with IFN-α treatment, requiring subsequent treatments in that patients. The time to next treatment (TTN) tends to be longer for PNAs compared to IFN-α even if difference is not significant. Secondary cancers were observed in 9/123 patients (7.3%) with solid tumors in 8 patients and hematological malignancy in one patient. Our data confirm in real life that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are HCR. Relapses seem less frequent than with IFN-α and the administration schedule is less restrictive for the patients. The emergence of chemo-immunotherapy and the development of effective new drugs such as recombinant immunotoxins and BRAF targeting will offer new possibilities in the management of HCL patients.

Second lung malignancy and Richter syndrome in chronic lymphocytic leukemia: case report and literature review

Background: Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative disease. Transformation into Richter disease and occurrence of second malignancies involving the lungs are rare complications. The hallmarks of any thoracic involvement are still unknown. Case presentation: We report a case of a 56-year-old male patient, with history of tobacco smoking, who presented with recurrent hemoptysis, fatigue and weight loss. Physical examination was normal except a slightly enlarged supraclavicular lymph node. Chest x-ray revealed a mediastinal widening due to enlarged paratracheal nodes and a left parahilar infiltrate. Blood tests showed a hyperlymphocytosis and a biological inflammatory syndrome. CT scan showed bilateral mediastinal and axillary lymphadenopathy, as well as left supraclavicular lymphadenopathy, with a left upper lobe alveolar attenuation and a solitary contralateral pulmonary nodule. Examination of Virchow’s node and bone marrow biopsies confirmed metastasis of a pulmonary adenocarcinoma, as well as chronic lymphocytic leukemia with Richter’s transformation. The clinical course was unfavorable since the first days of therapy as the patient passed away in a matter of a few days. Conclusions: Steady surveillance of CLL patients and systematic screening for second solid tumors, particularly lung cancer, and Richter’s transformation seem to be relevant more than ever. Early diagnosis might help us understand the pathways leading to these complications and adapt therapy.

Second Cancers in Adults with Acute Promyelocytic Leukemia (APL) Treated with or without Arsenic Trioxide (ATO): A SEER-Medicare Analysis

Background: ATO was approved by the U.S. Food and Drug Administration in 2000 for treatment of patients with relapsed/refractory APL and in 2018 in combination with all-trans retinoic acid (ATRA) for adults with newly-diagnosed low-risk APL. ATRA and ATO combinations result in long-term remissions in most patients with APL (Lo-Coco et al. NEJM 2013, Burnett et al. Lancet Oncol 2015). However, epidemiologic studies have shown associations between exposure to inorganic arsenic and development of skin, lung, bladder, and potentially liver, kidney, and prostate cancers (IARC 2004). The prescribing information for ATO includes a warning for carcinogenesis, with advice to monitor patients for development of second primary malignancies. Retrospective cohort analyses of second cancers in APL patients treated with ATO have been performed, finding incidence rates of 1-5% (Eghtedar et al. Leuk Lymphoma 2015, Au et al. Leuk Res 2007, Zhu et al. Blood 2016). We sought to perform an exploratory population-based analysis of second cancers in adults with APL treated with ATO compared to those treated with other systemic APL therapies without ATO using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Methods: Using SEER-Medicare linked data, we identified APL patients diagnosed from January 1, 2006 to December 31, 2015. Patients whose first SEER cancer diagnosis was APL, who were continuously enrolled in Medicare Parts A, B, &amp; D from the month of their APL diagnosis, and who received treatment with ≥ 1 systemic APL therapy within 1 year of diagnosis were included. Patients were followed from their first month of treatment group-defining APL therapy (ATO or non-ATO containing) until disenrollment from Medicare Parts A, B, or D, end of study period, or death. We determined the cumulative incidence of SEER-confirmed second cancers and overall survival (OS) according to whether patients were treated with or without ATO using the Kaplan-Meier method. We used a multivariate Cox proportional hazards model to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of cumulative incidence of second cancers and OS adjusted for relevant covariates of age, sex, and year of diagnosis. Results: We identified 1,442 APL cases, with 1,179 having APL as their first cancer diagnosis, of which 246 were enrolled in Medicare Parts A, B, and D. Of these, 64 received ATO and 60 received systemic APL therapy without ATO within 1 year of diagnosis. Characteristics, follow-up, and second malignancies for these cohorts are presented in the Table. Absolute incidence rates of second cancer were 3.4 per 1000 person-months compared to 1.4 per 1000 person-months in patients treated with and without ATO, respectively, and cumulative incidence rates at 24 months were 9.9% and 6.0%, respectively (p=0.20) (Figure 1). Mortality rates were 1.9 per 1000 person-months compared to 5.1 per 1000 person-months in patients treated with and without ATO, respectively, and OS rates at 24 months were 90.8% and 81.5%, respectively (p=0.10) (Figure 2). After adjusting for relevant covariates, HR for cumulative incidence of second malignancies in patients treated with ATO was 1.27 (95% CI 0.29-5.49; p=0.75) and for OS was 0.46 (95% CI 0.16-1.29; p=0.14) compared to APL therapy without ATO. Conclusions: This exploratory analysis revealed a high incidence of second malignancies in APL patients treated with ATO, although the risk was not significantly increased compared to patients who received other APL therapies. Most second malignancies following ATO were solid tumors, in line with prior epidemiologic studies of inorganic arsenic exposures. Despite the occurrence of second malignancies, there was a tendency towards longer OS in patients treated with ATO. Given the small sample size, short follow-up, potential selection and immortal time bias, and unaccounted for differences between comparator groups, firm conclusions cannot be inferred. However, the nearly 10% cumulative incidence of second malignancies at 24 months follow-up in Medicare patients with APL treated with ATO suggests the need for close monitoring for second malignancies following ATO therapy. Further prospective research into second malignancies following ATO is needed. Disclosures No relevant conflicts of interest to declare.

Abstract 988: Synthesis and preclinical evaluation of dual-stimuli responsive doxorubicin prodrug activated by histone deacetylases and cathepsin L

Abstract Doxorubicin (DOX) an anthracycline is a leading anticancer drug with a broad spectrum of activity against numerous solid and hematologic malignancies. However, its clinical application is limited by lower efficacy, severe cardiotoxicity and occurrence of secondary malignancies. There is an urgent need for eliminating the Dox adverse effects while retaining its anticancer efficacy. One of the major goals of cancer therapy is the selective targeting of malignancies over normal tissues. One way to avoid these severe adverse reactions is to develop tumor-targeted prodrugs that are converted to active antitumor drugs at tumor sites in the presence of enzymes that are overexpressed human cancers. Among these, the histone deacetylases (HDACs) and cathepsin L (CTSL) are highly expressed in cancer cells and are considered as potential cancer-specific targets. HDACs are critical enzymes involved in the regulation of histone and non-histone proteins and elevated HDACs in tumor cells are known to be closely associated with tumor initiation, progression, and metastasis. Similarly, the lysosomal cysteine protease CTSL plays key roles at multiple stages of tumor progression and metastasis. In the present study, we developed a new prodrug by coupling an acetylated lysine group to doxorubicin (Lys(Ac)-Dox), a masked cytotoxic agent, which is consecutively activated by HDACs and a CTSL to liberate doxorubicin. We first verified whether Lys(Ac)-Dox could be specifically cleaved by HDACs and CTSL in vitro. The results showed that after incubating with HDACs and CTSL at 37 °C for 20 h, the hydrolysis of Lys(Ac)-Dox reached 99%, suggesting that Lys(Ac)-Dox could be successfully cleaved by the target enzymes. To prove that the Lys(Ac)-Dox would have a much improved growth-inhibitory effect against cancer cells, the cytotoxicity of free DOX and Lys(Ac)-Dox against lung cancer cell lines normal human lung epithelial cell line was determined. The dose-response curves obtained from the cell lines tested indicated that Dox was equally cytotoxic against both cancer and normal cells. In contrast, Lys(Ac)-Dox highly cytotoxic against cancer cells and non-toxic to the normal counterparts. To measure the in vivo anticancer efficacy of Lys(Ac)-Dox vis-vis Dox, we developed subcutaneous xenografts by injecting human lung cancer A549 and H460 cells in nude mice. Lys (Ac)-Dox and Dox were administered daily i.p. at 5 mg/kg. The prodrug showed a significantly higher (&amp;gt;2-fold) tumor regression than Dox. A diminished circulating reticulocyte counts from whole blood after Dox treatment is known to reflect the hematological toxicity caused by the drug. Only Dox caused significant reticulocyte ablation while the prodrug did not, validating our drug design. Biochemical tests involving topo II inhibition and ROS production by the prodrug are in progress (supported by CPRIT grant RP 170207 to KSS). Note: This abstract was not presented at the meeting. Citation Format: Surendra R. Punganuru, Hanumantha Rao Madala, Viswanath Arutla, Kalkunte S. Srivenugopal. Synthesis and preclinical evaluation of dual-stimuli responsive doxorubicin prodrug activated by histone deacetylases and cathepsin L [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 988.

A Rare Case of Synchronous Presentation of Acute Myeloid Leukemia and Lung Cancer

Background: There are very few publications on synchronous presentation of dual malignancies in the literature. Occurrence of second malignancy in a patient with a known malignant tumor is not uncommon, though synchronous primary malignancies are unusual. Case Presentation: A 77-year-old man was diagnosed elsewhere as squamous cell carcinoma of lung came to our oncology department for further management. He underwent bone marrow evaluation with the suspicious of metastasis in view of pancytopenia. On bone marrow evaluation, found to have prominence of blasts more than 20%, which were CD34 positive and CD117 positive and. Conclusion: Here we describe an unusual rare combination of synchronous presentation of acute myeloid leukemia and squamous cell carcinoma of lung.

Long-Term Follow-up of Patients Treated at a Single Institution Using a Passively Scattered Proton Beam; Observations Around the Occurrence of Second Malignancies

To investigate the occurrence of second malignancies resulting from the secondary radiation from a passively scattered proton beam. A cohort of patients with long-term follow-up was defined. All were treated at the same institution with the same proton delivery system, consisting of a 200MeV fixed, horizontal, passively scattered beam combined with a robotic chair. This setup allows for stereotactic positioning and permits fractionated treatments. The majority of patients underwent cranial or intracranial stereotactic radiation therapy. Patients with previous photon therapy or a follow-up of 24months or less were excluded. For out-of-field secondary malignancies (SMs), the observed incidence in the study population was compared to the risk of developing a malignancy in the general population, taking patient sex into account. From September 1993 to May 2016, a total of 524 patients received proton beam therapy, and 322 patients could be evaluated for this study (164 female and 158 male). Age ranged from 2 to 85years, with a median of 40years. Follow-up ranged from 25 to 276months, with a median of 150months (12.5years). During the study observation period, 7 patients had out-of-field new malignant disease. Three female patients developed a malignancy, compared with an expected incidence of 4.09 (standardized incidence ratio, 0.73 [95% confidence interval, 0.24-2.27]); 4 male patients developed a malignancy, versus an expected incidence of 3.99 (standardized incidence ratio, 1.00 [95% confidence interval, 0.38-2.67]). New intracranial disease developed in 9 patients: 8 meningiomas and 1 carcinoma. For out-of-field SMs, no increased risk of developing a variety of malignancies was observed. For in-field SMs, only 1 malignant histology was noted 15years after the original proton therapy. No SM was observed in children and young adults.

Long Term Follow Up of Patients Treated at a Single Institution using a Passively Scattered Proton Beam; Observations Around the Occurrence of Second Malignancies

To report our observations around whether any patterns of secondary malignancies occurred in patients treated at a single institution, all with the same passively scattered proton beam delivery system. We examined case records from a single national particle therapy facility offering proton and neutron therapy over a 23 year period. Proton beam treatment at the institution started in October 1993 and uses a 200 MeV fixed horizontal beam line combined with a robotic chair. The vast majority of patients was treated for intracranial and cranial lesions and positioned using the stereophotogrammetric positioning system (SPG). Follow up was achieved by way of medical records, telephone calls to patients, and home visits by social workers or community nurses. All patients with 24 or fewer months of follow up were excluded, as well as patients who had previous photon therapy. Rates of observed malignancies in the patient population were compared with expected rates, which were obtained from the national cancer statistics. We analyzed the group as a whole, and also particular sub-populations, including children who were treated with the proton therapy. From October 1993 to May 2016 a total of 524 patients received proton beam therapy, with 322 patients evaluable (164 females & 158 males). Age ranged from 2 – 85 years, with a median of 40 years. Their follow up ranged from 25 to 276 months, with a median of 150 months (12.5 years). 9 patients developed new intracranial lesions consisting of 8 meningiomas and 1 carcinoma. Eight patients had new extracranial primary malignancies. No significant increased risk was observed in the patients who received proton therapy when compared with the expected risk in the general population. 37 pediatric patients (<20 years of age) were treated. No observed second malignancies were seen in this subgroup after a median follow-up of 15 years. No patient developed a second in field malignancy, and no apparent increased risk for a second out of field malignancy was observed. This is reassuring, especially in children and young adults. A solitary patient developed an intracranial carcinoma but this followed combined modality treatment with neutrons plus a proton boost. All other observed intracranial lesions were meningiomas. The findings of this study bode well for patients treated with pencil beam scanning systems, given the lower secondary neutron dose associated with that technique.

Second Malignant Neoplasms in Children and Adolescents Treated for Blood Malignancies and Solid Tumors: A Single-Center Experience of 15 Years

Abstract Context: The occurrence of second malignancies is not rare in children treated for primary tumors. Objectives: The aim of this study was to investigate the occurrence and the outcomes of second malignancies in children and adolescents from a large tertiary pediatric hematology-oncology center. Materials and Methods: A retrospective study was performed looking into the characteristics and outcomes of second malignant neoplasms in children and adolescents treated for primary malignancies in a single center over a 15-year period. Results: Among 270 children and adolescents treated for hematological malignancies and solid tumors from 2000 to 2015, five cases of second malignancy were diagnosed including cancer of the parotid gland, renal cell carcinoma, Hodgkin’s lymphoma, thyroid carcinoma, and transitional liver cell carcinoma in patients previously treated for acute myeloid leukemia, glioblastoma multiforme, B-acute lymphoblastic leukemia, Langerhans cell histiocytosis, and medulloblastoma, respectively. Primary malignancies were treated with chemotherapy in all cases and four out of five patients had also received radiotherapy. Mean age at diagnosis of second malignancy was 10 years and 4 months. Overall survival after diagnosis of second malignancy was 80% at 12 months and 75% at 5 years. Conclusions: Close surveillance and long-term follow-up are mandatory for the identification of late effects in children treated for malignancy.

Risk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients.

PurposeDexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients.Materials and MethodsData was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected.ResultsData of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis.ConclusionDexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.

Comparison Long-term Outcome of Definitive Radiotherapy plus Different Chemotherapy Schedules in Patients with Advanced Nasopharyngeal Carcinoma

Concurrent chemoradiotherapy (CCRT) is the current standard of care for advanced nasopharyngeal carcinoma (NPC). We hypothesize that shifting CCRT to neoadjuvant chemotherapy followed by radiotherapy (NeoCT-RT) is an alternative option. From December 2004 to January 2009, 256 NPC patients with stage II-IVB were treated by either CCRT or NeoCT-RT. All patients received the same dosage and fractionation schedule of RT. After long-term follow-up, 26.8% (34/127) and 23.3% (30/129) of patients who received CCRT and NeoCT-RT respectively, developed a tumor relapse (P = 0.6134). Overall survival (HR = 1.52, 95%CI = 0.91–2.55, P = 0.1532) and progression-free survival (HR = 1.22, 95%CI = 0.75–1.99, P = 0.4215) were similar in both groups. However, acute toxicities during RT period revealed a significant reduction of grade 3/4 vomiting (23% vs. 0%, P < 0.0001), mucositis (55% vs. 16%, P < 0.0001), and neck dermatitis (31% vs. 16%, P = 0.0041) in the NeoCT-RT group, resulting in fewer emergency room visits (10.2% vs. 1.6%, P = 0.0071). Severe treatment-related late toxicity (15% vs. 14%, P = 0.9590) and the occurrence of second malignancy (3.9% vs. 5.4%, P = 0.7887) also showed no differences. We concluded that NeoCT-RT could be an attractive alternative option of CCRT for advanced NPC.