Common Secondary Malignancies Research Articles

Final Analysis of the Randomized Phase II/III Study of Standard R-CHOP Versus CHOP Combined with Dose-Dense Weekly Rituximab for DLBCL: JCOG0601

Background: Despite several attempts of randomized phase III trial to overcome R-CHOP in overall survival (OS), R-CHOP has been continued to be a standard of care in previously untreated DLBCL. We conducted a randomized phase II/III study (JCOG0601, jRCTs031180139) that investigated the efficacy of dose-dense weekly rituximab combined with standard CHOP regimen (RW-CHOP) during the early treatment period for previously untreated DLBCL and published the results (Ohmachi K, et al. Blood Adv. 2021). Here in, we report the long-term efficacy and safety of the JCOG 0601 trial after 8 years follow-up from the end of accrual. Methods: Patients aged 20-79 years with previously untreated CD20-positive DLBCL (stage I-IV, performance status 0-2) were randomized to standard R-CHOP (CHOP-21 with eight doses of rituximab, once every 3 weeks) or RW-CHOP (CHOP-21 with eight doses of weekly rituximab). The primary endpoint of phase III part was progression-free survival (PFS). Required sample size was 422 patients, an accrual period of 7 years, and a follow-up period of 3 years with the primary analysis. An additional follow-up period was added to assess long-term outcomes, for a total of 8 years of follow-up. Results: Between December 2007 and December 2014, 422 patients were enrolled, but primary analysis was performed on 421 patients after one patient withdrew consent: 213 in the R-CHOP arm and 208 in the RW-CHOP arm. The baseline characteristics were as follows (R-CHOP arm vs. RW-CHOP arm): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and International Prognostic Index score ≤2, 77.0% vs. 87.5%. At a primary analysis, there was no significant difference in PFS between the arms. At the time of final analysis with a median follow-up of 9.6 years (range: 0.3-14.9) among all patients, meaningful differences were not found in PFS and OS as well as the primary analysist (hazard ratio [HR] in PFS of RW-CHOP against R-CHOP, 0.94; 95% confidence interval [CI], 0.67 to 1.32, one-sided log-rank, P = 0.36 and HR in OS, 0.94; 95% CI, 0.63 to 1.41). Median PFS and OS were not estimable in both arms. Estimated 10 years PFS and OS of all patients was 66.9% (95% CI, 62.1 to 71.3) and 78.0% (95% CI, 73.6 to 81.7). After the first relapse or refractoriness, 126 patients received post-protocol salvage therapy: 66 in the R-CHOP arm and 60 in the RW-CHOP arm. In each arm, 3 patients received high-dose chemotherapy followed by autologous stem cell transplantation. One patient in the R-CHOP arm proceeded to allogeneic stem cell transplantation from a sibling donor. Ann Arbor stage I to II disease tended to have more favor prognosis than Ann Arbor stage III to IV disease, and no sustained relapse was observed in either stage. Of the 401 patients who underwent central pathological review, 125 were diagnosed with germinal center B-cell-like (GCB) type and 216 with non-GCB type by immunohistochemistry analysis. There was no remarkable difference in PFS between the arms for GCB type and non-GCB type. Death occurred in 95 patients: 56 from DLBCL, 2 from treatment-related cardiac toxicity, 9 from treatment-related mortality caused by salvage treatment, 14 from secondary malignancies, and 11 from other diseases or reasons. There were 34 secondary malignancies in 31 patients (14.6%) in the R-CHOP arm, and 39 cases in 35 patients (16.8%) in the RW-CHOP arm. The most common secondary malignancies were lung cancer (2.6%), colon cancer (1.9%), prostate cancer (1.7%) and gastric cancer (1.9%). Three cases of acute myeloid leukemia (0.7%) and three of myelodysplastic syndromes (0.7%) were observed. The median age of patients who developed secondary malignancy was 72 years (range: 49-84) at the onset. The median time from study enrollment to the onset of secondary malignancy was 4.5 (range: 0.1-13.1) years and the incidence was time dependent. There were no unexpected adverse events, including late opportunistic infections. Conclusion: This final-follow up data demonstrated again no superiority of RW-CHOP in PFS and OS. Standard R-CHOP remains a standard of care for untreated DLBCL.

Long-Term Toxicity after Total Body Irradiation-Based Conditioning Regimens for Allogeneic Stem Cell Transplantation

Total body irradiation (TBI) is an integral component of many conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT). Few studies have investigated long-term sequelae. A large series of patients undergoing myeloablative and non-myeloablative regimens was studied. Adult patients undergoing allogeneic HSCT utilizing TBI-based conditioning regimens from 1995-2020 at our institution were included. Baseline treatment-related factors and long-term toxicities (developing, or persisting beyond, 6 months after HSCT) were collected. The cumulative incidence of long-term toxicities and overall survival (OS) were calculated. Cox regression was used to assess for predictors of toxicity. Five hundred fifty-two patients were analyzed: 378 myeloablative (typically 13.5 Gy/9fx) and 174 non-myeloablative (typically 2 Gy/1fx) TBI recipients. Median follow-up was 7.4 years for surviving patients. Cumulative incidences of long-term toxicities at 5 and 10 years are included in the Table. The most common toxicities were: pulmonary- infectious pneumonia and respiratory failure NOS; cardiac- heart failure and myocardial infarction; other endocrine- adrenal insufficiency and testosterone deficiency. The most common secondary malignancy was non-melanoma skin cancer. The proportion of all toxicities that were high-grade (3-5) for myeloablative and non-myeloablative regimens, respectively, were: pulmonary (65%, 52%), cardiac (66%, 39%), renal (23%, 27%), and other endocrine (3%, 18%). Increasing number of chemotherapy regimens (p = 0.05) and umbilical cord donor (p = 0.02) were associated with long-term pulmonary toxicity. Male sex (p = 0.03), increasing number of chemotherapy regimens (p<0.01), and elevated creatinine after transplant (p<0.01) were associated with long-term renal toxicity. Cataract development was associated with increasing age at transplant (p = 0.02). OS (5 years) was 40% (42% -myeloablative; 33%-non-myeloablative). Allogeneic HSCT, often preceded by TBI-based conditioning regimens, has significant survivorship challenges. Recipients of non-myeloablative regimens are still at risk of significant long-term multisystem toxicity despite much lower doses of TBI and chemotherapy. Pre-transplant factors such as cumulative chemotherapy exposure and age at transplant were associated with some toxicities.

Role of brentuximab vedotin plus sirolimus in the treatment of classical Hodgkin lymphoma type post-transplant lymphoproliferative disorder: a case-based review.

Post-transplant lymphoproliferative disorder (PTLD) is a common secondary malignancy after transplantation, which has been recognized as a life-threatening complication. Hodgkin lymphoma (HL)-type PTLD is the rarest of four subtypes of PTLD, which has no treatment guideline due to its rarity. HL-type PTLD includes classical HL-type PTLD (cHL-PTLD) and HL-like PTLD. In our study, we reported the case of successful treatment using brentuximab vedotin (BV) plus sirolimus for a patient with classical HL-type PTLD in detail. Lymph node biopsy showed a picture of classical HL with mixed cellularity subtype, and immunophenotyping suggested CD30 strong positivity. Due to his impaired physical condition, we decided against intensive chemotherapy and started BV treatment with immunosuppressive agents switched to sirolimus. The 66-year-old patient with cHL-PTLD had achieved a durable complete remission for over a 1-year follow-up period. Additionally, we analyzed the clinical profile and outcomes in PTLD patients who used BV monotherapy or combined therapy by literature review. In summary, this case-based review might provide clues that treatment of cHL-PTLD with new modalities such as BV monotherapy or combination therapy, together with improvements in the immunosuppressive regimens like sirolimus, might be a feasible and chemotherapy-free approach, but warrants further evaluation in a larger patient cohort.

FINE NEEDLE ASPIRATION CYTOLOGY OF LYMPH NODES - IS IT A BOON?

Fine needle aspiration cytology (FNAC) is a simple and rapid diagnostic procedure to identify etiology in an enlarged lymph node. We studied malignant lymph nodes .Most common site aspirated, age &amp; sex distribution an Aim: d spectrum of diagnosis was presented in our result. We retrospectively reviewed malignant lymph node Methods: aspirates over a period of three years from June 2019 to May 2022 in Department of Pathology, Gajraraja Medical College, Gwalior, India .We excluded tubercular and reactive lymph nodes. A total of1026 lymph node aspirate Results: s were identified during this period. 198 cases (12.1%) were identified as malignant. Age distribution was 5 to 88 years. Male to female ratio was 5.8:1.In metastatic lymph nodes Cervical lymph nodes (174/201; 86.56%) were the main group.173 cases ( 86 %) showed metastatic deposits which was more common compared to 28 cases ( 13.9%) of primary lymphomas.Malignancies, included 143 cases (71.1%) of SCC (metastasis) and 22 cases (78.5%) of Non Hodgkins lymhoma. Cervical lymph node was the most common malignant lymph node aspirated. Squamous cell Conclusion: carcinoma and Non Hodgkins lymphoma were the most common primary and secondary malignancies. We can conclude FNAC as a one-step routine OPD procedure as mostly lymph nodes are easily accessible and can be reported within 5 days thus saving time and reducing discomfort of biopsy. Majority of benign etiologies can be triaged, thereby focusing more on malignant cases. FNAC thus proves to be a boon for diagnosing lymph node malignancies

Prevalence and correlates of skin examination among ethnically diverse young adult survivors of childhood cancer.

Skin cancer is the most common secondary malignancy among young adult childhood cancer survivors (YA-CCS). Skin examination to detect skin cancer early (including melanoma as well as basal or squamous cell skin cancers), both physician-based (PSE) and self-skin exam (SSE), is recommended, particularly for radiotherapy-exposed YA-CCS who are at high risk of developing skin cancer. Awareness and prevalence of skin examination and demographic, clinical, and healthcare correlates were examined in a population-based sample of YA-CCS with diverse cancer types excluding melanoma. Descriptive frequencies and logistic regression models were conducted using sample weights to correct for non-response bias with PSE, SSE and adherence to both as outcomes. The sample comprised 1064 participants with 53% Latino. Eight percent of participants were aware of the need for skin examination; 9% reported receipt of PSE within past 2 years; 35% reported regular SSE; and 6% were adherent to both. Among the radiotherapy-treated, 10% were aware of the need for skin examination, 10% reported recent PSE; 38% reported regular SSE; and 8% were adherent to both. Healthcare and clinical factors including healthcare self-efficacy, engagement in cancer-related follow-up care, greater treatment intensity and greater number of treatment-related late effects were positively associated with PSE and SSE. Latino YA-CCS were less likely to engage in PSE and SSE. Adherence to recommended screening for skin cancer was low in this at-risk population, notably for YA-CCS exposed to radiotherapy. The development of effective strategies to expand skin cancer screening is needed in this at-risk population.

CML-357 Jumping Out of the Frying Pan, Into the Fire: Case Report of Secondary Non-Hodgkin Lymphoma (NHL) in a Case of Chronic Myeloid Leukemia (CML)

The introduction of TKIs at the start of the second millennium has dramatically changed CML treatment. Now, two decades later, we are observing and trying to assess the long-term side effects of prolonged TKI use. To report a secondary malignancy in a CML patient on TKI and its impact on her CML course. This is a case report of a chronic-phase CML patient who developed NHL. OCMU is an academic institutional practice acting as a referral center that provides multidisciplinary tertiary care for hematology patients in the Egyptian delta region. A 58-year-old female resident of Damietta was referred to OCMU in January 2020 after discovering leukocytosis. She was diagnosed as CML based on blood film, bone marrow aspiration, and biopsy results and was confirmed by the detection of Philadelphia chromosome P210 in 46% of cells. The patient was started on 100 mg dasatinib, but she developed a diffuse skin rash with recurring anemia requiring transfusion and dasatinib interruptions. She was shifted to nilotinib with the absence of the previous toxicities and QPCR reduction. She was referred back to us in November 2021 with left submandibular swelling measuring 3.8×3.5 cm, with submandibular LNs as large as 1.8×1.1 cm with faint hilum. QPCR was undetectable, but bone marrow aspiration and both free-hand and tru-cut biopsies revealed DLBCNHL positive for CD20 and negative for CD3 and CD23, with Ki67 detected in 85%. CD34, CD117, and TdT were negative, excluding chloroma. PET-CT showed active uptake only in the submandibular mass (4 × 3 cm; SUV=7). She started the R-CHOP regimen and continued nilotinib. The response was assessed by PET-CT and QPCR. PET- CT was negative after four cycles, and QPCR remained undetectable. Therefore, the patient is continuing nilotinib with regular monthly follow-up for lymph node ultrasonography. Secondary malignancies with CML are increasingly common, but the literature reports contradictory data, with NHL ranked as the fourth most common secondary malignancy. The roles of TKIs in disease evolution and increased life expectancy require more research to assess the genetic bases and incidences of secondary malignancies.

Skull metastases and osseous venous malformations: The role of diffusion-weighted and dynamic contrast-enhanced MRI.

Skull metastasis (SM) is a common secondary malignancy. We evaluated the diagnostic performance of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (MRI) in differentiating SM from osseous venous malformations and SM of various origins. This study included 31 patients with SM (median age, 64years; range, 41-87years; 29 women; 24 and 7 patients with breast and non-small cell lung cancer, respectively) and 16 with osseous venous malformations (median age, 68years; range, 20-81years; 10 women) who underwent both DWI and dynamic contrast-enhanced MRI between January 2015 and October 2021. Normalized mean apparent diffusion coefficients (ADCs) and dynamic contrast-enhanced MRI parameters were compared between SM and osseous venous malformations, and between breast cancer and non-small cell lung cancer. Multivariate stepwise logistic regression analyses were performed to identify statistically significant parameters. Plasma volume and time-to-maximum enhancement were the most statistically significant parameters for differentiating SM from osseous venous malformations, with an area under the receiver operating characteristic curve of 0.962. The normalized mean ADC and peak enhancement values were the most statistically significant parameters for differentiating breast cancer from non-small cell lung cancer, with an area under the curve of 0.924. Our results highlight the efficacious diagnostic performance of DWI and dynamic contrast-enhanced MRI in distinguishing SM from osseous venous malformations and differentiating SM of various origins.

Thyroid Hormones Enhance the Growth of Estrogen Receptor-Positive Breast Cancers.

Thyroid disorders have been associated with breast cancer. In fact, breast cancer is the most common secondary malignancy in female patients with thyroid cancer (1). Moreover, hyperthyroidism is associated with an 11% increased risk of breast cancer in women (2). Importantly, up to 30% of patients with breast cancer are treated with thyroid hormone replacement therapy (THRT) for overt or subclinical hypothyroidism (3). These observations, coupled with the preclinical data showing growth stimulatory effects of thyroid hormones (THs) in various cancer models (4), formed the rationale for the study by Wahdan-Alaswad et al. aimed at investigating the role of THRT on the outcome of patients with nonmetastatic breast cancer (3). The authors conducted an observational study analyzing the association between THRT, disease-free survival (DFS), and disease-specific survival (DSS) in two cohorts of patients with nonmetastatic breast cancer. The first cohort consistent of 820 patients followed for a median of 10 years and treated for breast cancer between 1962 and1993, with THRT implemented in 69 patients. The second cohort included 160 patients treated more recently (between 2006 and 2009) and followed for a median of 8.8 years, with 50 patients exposed to THRT. The data on the age, tumor size, presence or absence of steroid (estrogen and/or progesterone) receptors (SR+/SR-), and treatment regimen were incorporated in the multivariate model analyzing the association between DFS/DSS and THRT at 5 and 10 years. To better understand the results of the observational cohort study, the authors performed functional in vitro and in vivo experiments to investigate the molecular mechanisms underlying TH effects on breast cancer cells and to test the interactions between estrogen receptors (ERs) and TH receptors (THRs). In patients with SR+ breast cancer, THRT was associated with a significantly increased risk of recurrence (DFS RR, 2.9; P<0.001) and death (DSS RR, 3.4; P<0.001), independent of age, tumor size and grade, while THRT in patients with SR- breast cancer was not associated with worse outcomes. Moreover, patients with SR+ breast cancer undergoing therapy with aromatase inhibitor combined with THRT were characterized by a shorter DFS (P<0.042) and a higher 10-year recurrence rate of 14%, as compared with 2% in patient treated with the aromatase inhibitor alone.The functional in vitro and in vivo studies revealed growth stimulatory effects of monotherapy with TH or estrogens that were further potentiated with combination therapy in ER+ breast cancer cell lines and mice xenografts. The RNA-Seq analysis revealed that combination therapy was associated with a significant activation of the cell cycle, mismatch repair, homologous recombination, and DNA replication signaling, as well as induced thyroid-specific genes and estrogen-mediated signatures. These effects were abrogated by the knockdown or inhibition of ER and/or THRa, suggesting that cross-talk and nuclear colocalization of ERs and THRs are major drivers of pro-oncogenic signaling in the ER+ breast cancer model. The study reveals clinically significant associations between THRT and worse outcomes in patients with nonmetastatic SR+ breast cancer that are likely driven by interactions between the nuclear ERs and THRs, leading to upregulation of pro-oncogenic signaling. These results suggest that overuse of THRT in patients with hypothyroidism and concurrent breast cancer should be avoided.

Metastatic Clear Cell Renal Cell Carcinoma Involving the Thyroid Gland: A Clinicopathologic Study of 17 Patients.

Background. Metastatic clear cell renal cell carcinoma (RCC) is one of the most common secondary thyroid malignancies. Diagnosis can be challenging, particularly if presenting many years after initial diagnosis. We reviewed clinicopathologic features and immunoprofile of metastatic clear cell RCC in thyroid. Design. We identified 17 patients from 2003-2021. Clinical data were obtained from medical records, and slides were retrieved and reviewed. Results. Seventeen patients (12 male and 5 female) included 12 thyroidectomies, 3 core biopsies, 1 excisional biopsy, and 1 fine-needle aspiration. The average patient age was 68.7 years (range, 45-88 years). Sixteen patients had history of clear cell RCC, and in 1 patient, the clear cell RCC was discovered after the thyroid metastasis was found. Thyroid gland metastases were on average diagnosed 90.7 months after the diagnosis of the renal primary (range, 24-240 months). Patients presented with a new palpable mass (n = 11) or dyspnea/stridor (n = 1). Five tumors were incidentally found via surveillance imaging. In 2 patients, metastases occurred within follicular thyroid neoplasms. All metastases showed conspicuous sinusoidal vasculature between the tumor nests and areas of myxoid degeneration. A prominent thick fibromuscular pseudocapsule was evident in 10 resections. Immunohistochemistry (n = 5) showed that the metastases were positive for PAX8, CA9, and CD10, while negative for keratin 7, thyroglobulin, and TTF1. Conclusions. Metastatic clear cell RCC involving the thyroid gland is infrequent and typically occurs remotely after the initial diagnosis. Cytologic and histologic features may show significant overlap with primary thyroid lesions. Immunohistochemistry can help reliably distinguish metastases from primary thyroid neoplasms.

Treatment of Radiation-Induced Meningiomas With Non-Invasive Stereotactic Radiosurgery

Radiation-Induced Meningiomas (RIMs) are one of the most common secondary malignancies from prior brain irradiation and are known to be recurrent. While Gamma Knife (GK) radiosurgery is routinely employed for the treatment of sporadic meningiomas, data on its use for RIMs are limited. Here, we assessed whether the use of GK radiosurgery for RIMs can achieve > 80% local control at 1 year.We retrospectively reviewed our institution's GK database from 08/31/99 - 10/08/20. Meningiomas were considered radiation-induced if they met Cahan's criteria: (1) occurred after brain radiation for a previous neoplasm, (2) were within the previous radiation field, and (3) had a distinct histology or radiographic appearance from previously treated neoplasm. Patients with a genetic predisposition for tumor formation were excluded. Endpoints included overall survival (OS), progression free survival (PFS), local failure (within 2cm of GK field), and distant failure. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.A total of 29 patients with 86 RIM lesions were identified from 1999 to 2020 and followed for a median of 59 months. Of these patients, 20 had WHO grade I (n = 4) or presumed grade I (n = 20) RIMs and 5 had WHO grade II RIMs. The median latency time from previous brain irradiation to initial SRS was 26 years. The median dose prescribed to the 50% isodose line was 14 Gy (range 12-20 Gy) with a median lesion volume of 2 cm3. The actuarial 5-yr OS and 5-yr PFS were 95% and 70%, respectively. Patients who were treated for recurrent RIMs after previous surgery had a significantly lower 5-yr OS (88% vs 100%; log-rank, P < 0.0046) and 5-yr PFS (39% vs 81%; log-rank, P < 0.005) than patients who were treated in the upfront setting. On a per-lesion basis, local control at 1-, 3-, and 5-yrs was 82%, 76%, 74%, respectively. Presumed or WHO grade I RIMs had a significantly greater 5-yr local control than WHO grade II RIMs (100% vs 56%, log-rank, P < 0.001). The rate of distant failure at 1-, 3-, and 5-yrs was 3.5%, 18%, and 32%, respectively. At time of progression, 5 patients had distant failures, while 3 patients had local and distant failures. Failures were salvaged through additional GK (n = 8), surgery (n = 2), or chemotherapy (n = 1). The crude incidence of grade 1-3 toxicity from GK was 10% (n = 3). No grade 4 or 5 adverse events were recorded. Only 1 patient developed grade 3 toxicity (cranial nerve neuropathy), which resolved with steroids.This is the largest series of RIM lesions treated with GK radiosurgery. RIMs are associated with a high OS and GK radiosurgery provides satisfactory PFS and local control. Recurrent and WHO grade II lesions are associated with lower PFS and local control after radiosurgery than upfront and WHO grade I lesions. The majority of failures after GK are distant. Treatment using GK radiosurgery has minimal morbidity. It should be considered for patients or tumors that are not candidates for surgical resection.N.Razavian: None. C.A.Helis: None. A.Laxton: None. S.B. Tatter: None. J.Bourland: None. R.T. Mott: None. G.J. Lesser: None. R.Strowd: None. M.D. Chan: None. C.K. Cramer: None.

Secondary pulmonary malignancies requiring interventional bronchoscopic procedures.

Background In this study, we aimed to share our singlecenter experience and to investigate the effect of interventional bronchoscopic procedures on secondary pulmonary malignancies in terms of complications, success, and survival rates. Methods A total of 83 patients (42 males, 41 females; mean age: 57.8±15.2 years; range, 18 to 94 years) with secondary pulmonary malignancies who underwent interventional bronchoscopic procedures between January 2009 and December 2019 were retrospectively reviewed. Data including demographic and clinical characteristics of the patients, complications, and success and survival rates were recorded. Results The most common secondary pulmonary malignancies were kidney and thyroid tumors with the complaints of cough, shortness of breath, and hemoptysis. The mean duration before the diagnosis was 34.7±52.8 (range, 0.1 to 219.3) months, and the mean survival after the diagnosis were 10±13.1 (range, 0.2 to 44.4) months. A total of 92% of the patients had an airway obstruction of >50% and the interventional bronchoscopic procedures such as argon plasma coagulation, laser, cryo, and mechanical resection were successful in achieving airway patency. Laser application was found to significantly improve survival (p=0.015). Acute complication rate was 8.4% and mortality rate was 0%. Conclusion In patients with tracheobronchial lesions due to secondary pulmonary malignancies, interventional bronchoscopic procedures, regardless of the stage of the disease, provide rapid palliation in life-threatening symptoms such as dyspnea and hemoptysis due to airway obstruction, prolonging patient"s survival and gain time for additional treatments to take effect for primary disease.

Incidence of Secondary Malignancies in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) in the Era of Tyrosine Kinase Inhibitors (TKI)

IntroductionWith TKI therapy the survival of patients with CML-CP is approaching to that of general population. Data on the incidence of secondary malignancies in CML is conflicting given the rarity of CML and the low incidence of secondary malignancies. The aim of this study is to evaluate the incidence of secondary malignancies in patients with CML-CP in a large US-based database.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database identified 13,276 patients with newly diagnosed CML-CP during the period from 2001 to 2014. Patients who had prior history of cancer, concurrent diagnosis of other malignancies at the same diagnostic year, and patients who developed secondary leukemia after the diagnosis of CML were excluded. Cumulative incidence of secondary malignancies were estimated with the presence of competing risk of death. Standard incidence ratio (SIR) was calculated from person-years at risk divided by expected cases based on the age-adjusted incidence ratio of the 2000 U.S. standard population.ResultsOf 13,276 patients, secondary malignancies were observed in 597 patients (4%) with a median follow-up of 69 months (Table 1). The three most common secondary malignancies were male genital system 130 (22%), digestive system 124 (21%) and respiratory system, 92 (15%). The 5-year and 10-year cumulative incidence of death for all patients was 30.5% (95% confidence interval [CI], 29.6-31.4), and 41.8% (95% CI, 40.7-43.0). The 5-year and 10-year cumulative incidence of secondary malignancies were 4.4% (95% CI, 4.0-4.8), and 7.2% (95% CI, 6.6-7.9), respectively (Figure 1). Overall SIR was 1.204 (95% CI, 1.108-1.301). The increased SIRs were observed in male genital system of 1.593 (95% CI, 1.319-1.866); digestive system, 1.291 (95% CI, 1.064-1.519); skin, 1.588 (95% CI, 1.083-2.093); urinary system, 1.366 (95% CI, 1.008-1.724); and miscellaneous, 1.877 (1.033-2.721) (Figure 2). The decreased SIR was observed in breast cancer of 0.665 (95% CI, 0.479-0.852). Overall excess absolute risk was 1.714 per 1,000 person years at risk (95% CI, 0.622-2.805).ConclusionRelative incidence of overall secondary malignancies in CML-CP is slightly higher than that of general population with minimal increase in the excess absolute risk. Given the limitation of registry data, the uncertainty of use and type of TKI, and response status at the diagnosis of secondary malignancies, conclusions regarding actual risk should be cautiously interpreted. It is also at this stage not possible to determine whether any possible increased risk is associated with the diagnosis of CML-CP per se or the use of TKIs. Further analysis is needed. [Display omitted] DisclosuresKantarjian:Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding. O'Brien:Amgen: Consultancy; Alexion: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Vaniam Group LLC: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; GSK: Consultancy; Acerta: Other: Research Support: Honorarium, Research Funding; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding; Regeneron: Other: Research Support: Honorarium, Research Funding; Aptose Biosciences, Inc.: Consultancy; ProNAI: Other: Research Support: Honorarium, Research Funding; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy. Wierda:Emergent: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding; Kite: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Juno: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Daver:Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Incyte Corporation: Honoraria, Research Funding; Jazz: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Karyopharm: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Pfizer Inc.: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Sun Pharma: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding.

Secondary Malignancies: The Cost of Progress.

With advances in treatment of cancer, patients who survive their first malignancy are at risk of developing additional malignancies. Data on the risks of secondary malignancies after treatment of some of the more common cancers are lacking. Our prospectively maintained database was queried from 1996 to 2016 to identify patients with breast cancer, colorectal cancer, melanoma, sarcoma, gastric, and pancreatic adenocarcinoma who developed additional malignancies. Predisposing clinical factors were included in our analysis. We identified 756 patients diagnosed with a solid malignancy who developed a second malignancy, of which 606 (80.1%) had one of the most common treated cancers. 59.5% of patients were women. 810 additional malignancies were identified in the 606 patients with breast and colon cancer being the most common secondary malignancies. Of these 606 patients, 460 (76%) patients had two malignancies; 145 (23.9%) had 3 or more malignancies. 15.2% of patients were diagnosed under the age of 40.63years. 8.3% patients had a known genetic mutation, with BReast CAncer gene, and Lynch mutations being the most common. Advances in cancer treatment have led to higher cure rates. These patients should continue surveillance and undergo screening as they may be at risk of developing additional malignancies.

Long-term Testis Cancer Survivors in Canada—Mortality Risks in a Large Population-based Cohort

BackgroundTestis cancer (TC) patients are young with excellent cancer prognosis. Hence, the risk of late-onset treatment-related morbidity and mortality is of concern due to longer survival after treatment. ObjectiveWe set to characterize long-term survival of TC patients through a Canadian population dataset. Design, setting, and participantsWe used a population-based dataset, the Canadian Census Health and Environment Cohort (CanCHEC), to identify individuals diagnosed with TC between 1991 and 2010. We compared them with all other male individuals without TC. Outcome measurements and statistical analysisThe primary outcome was mortality due to cardiovascular disease (CVD) or nontesticular malignancy. Mann-Whitney or chi-square test was used where applicable. Data were analyzed using a Cox proportional hazard model with and without matching. Results and limitationsWe identified 1950 individuals with TC. We compared them with 1 300 295 men with no TC. There were 335 deaths in the study group during the study period (17.2%) with a mean follow-up of 19.6 yr. TC patients were at increased risk of death from secondary malignancies (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.39–1.91; p < 0.0001) with specific risks for hematologic neoplasms (HR 3.86, 95% CI 2.78–5.37; p < 0.001) and other malignancies (HR 2.41, 95% CI 1.76–3.29; p < 0.001). Gastrointestinal, hematologic, and respiratory toxicities were the most common secondary malignancies leading to death. When stratified according to histology, nonseminoma (NS) patients were at significantly increased risk of death from CVD (HR 2.03, 95% CI 1.27–3.25; p = 0.0032). Individuals with seminoma were at increased risk of death from other nontestis neoplasms (HR 1.46, 95% CI 1.17–1.82; p = 0.0007), specifically hematologic neoplasms (HR 2.09, 95% CI 1.18–3.72; p = 0.0118). ConclusionsNS patients are at increased risk of CVD-related death, whereas seminoma patients are at increased risk of death from non–testis-related malignancies. Patient summaryWe report long-term mortality following diagnosis of testis cancer. Nonseminoma patients have an increased risk of death from cardiovascular disease, while seminoma patients have an increased risk of death from secondary malignancies.

Long-Term Effect of Ruxolitinib (RUX) in Inadequately Controlled Polycythemia Vera (PV) without Splenomegaly: 5-Year Results from the Phase 3 Response-2 Study

Long-Term Effect of Ruxolitinib (RUX) in Inadequately Controlled Polycythemia Vera (PV) without Splenomegaly: 5-Year Results from the Phase 3 Response-2 Study

Oral Dysplastic Complications after HSCT: Single Case Series of Multidisciplinary Evaluation of 80 Patients.

Oral squamous cell carcinoma (OSCC) is the most common secondary solid malignancy after hematopoietic stem-cell transplantation (HSCT). OSCC following HSCT is frequently preceded by chronic graft-versus-host disease (cGVHD). The aim of this study was to describe a cohort of post-HSCT patients and to evaluate the onset of oral epithelial dysplasia and/or OSCC over time. In this retrospective cohort study, we present a cohort of hematological patients that underwent HSCT. Demographic variables, clinical hematological data, data regarding acute graft-versus-host disease (aGVHD) and cGVHD, and oral clinical features were analyzed. We focused on clinicopathological features of a subgroup of 22 patients with oral cGVHD and OSCC after HSCT. Among 80 included patients, 46 patients (57.5%) developed aGVHD and 39 patients (48.7%) developed cGVHD. Oral mucosa was involved in 17 patients with aGVHD (36.9%) and in 22 patients (56.4%) with cGVHD. Out of a total of 22 oral biopsies, roughly 40% revealed mild to moderate dysplasia, and 32% were OSCC. In the absence of international agreement on the best timing of oral follow-up after HSCT, it is mandatory to establish a close multidisciplinary evaluation in order to prevent the onset of HSCT-related OSCC and to reduce post-transplant mortality due to secondary tumors.

Neuro-Ophthalmic Manifestations of Intracranial Malignancies.

To describe the various neuro-ophthalmic presentations, key exam features, and clinical findings associated with 5 common primary and secondary intracranial malignancies. Retrospective PubMed search and review of published case reports, case series, observational studies, book chapters, and review articles examining the neuro-ophthalmic features of intracranial malignancies including primary glial neoplasms (e.g., glioblastoma multiforme), primary and secondary lymphoma, intracranial metastases, carcinomatous/lymphomatous meningitis, and intracranial germ cell tumors. The search strategy used to perform the retrospective review included the aforementioned tumor type (e.g., glioblastoma multiforme) and the following terms and Boolean operators: AND ("visual loss" OR "papilledema" OR "diplopia" OR "ophthalmoplegia" or "neuro-ophthalmology" OR "proptosis"). The rate of growth and the location of an intracranial tumor are essential factors in determining the neuro-ophthalmic presentation of certain intracranial malignancies. Primary malignant brain glial neoplasms commonly present with visual afferent complaints (e.g., unilateral or bilateral visual acuity or visual field defects, bitemporal or homonymous hemianopsia), pupil abnormalities (relative afferent pupillary defect), and optic atrophy or papilledema. Primary intraocular lymphoma (with or without central nervous system lymphoma) typically presents as a painless bilateral vitritis. Secondary intracranial malignancies have variable afferent and efferent visual pathway presentations. Carcinomatous/lymphomatous meningitis is associated with diplopia (e.g., multiple ocular motor cranial neuropathies with or without vision loss from papilledema or compressive/infiltrative optic neuropathy). Intracranial germ cell tumors can present with a chiasmal syndrome or dorsal midbrain syndrome. Intracranial malignancies can present with neuro-ophthalmic symptoms or signs depending on topographical localization. Specific neuro-ophthalmic presentations are associated with different malignant intracranial tumors. Clinicians should be aware of the common malignant intracranial tumors and their associated clinical presentations in neuro-ophthalmology.

Family History of Breast Cancer Associated with Breast Cancer in Survivors of Hodgkin Lymphoma.

Advances in treatments for Hodgkin Lymphoma (HL) have significantly increased survival of childhood and adult patients; however, the leading cause of death in HL survivors is due to secondary malignancy following HL treatment [1,2]. Among women treated for HL, breast cancer (BC) is the most common secondary malignancy [3]. We explored if an association exists between HL and BC exists within families. Utilizing the Utah Population Database and the Utah Cancer Registry, we identified 988 women with HL, and no history of BC prior to HL, diagnosed in Utah from 1966-2014. We examined if women with HL were at greater risk of developing BC based on the presence or absence of family history of BC. We also examined the familial recurrence risk of BC among female FDRs of women with HL and BC using Cox regression methods. Among 988 female HL patients, 42 (4.3%) were diagnosed with subsequent BC while among 9,876 matched controls, 280 controls (2.8%) were diagnosed with BC from 1966-2014 (P < 0.05). We observed a significant 3-fold increased risk of BC in the first-degree relatives (parent, full sibling, or child of patient) of female HL patients with subsequent BC, compared to FDR in controls (HR = 2.8, 95%CI 1.4-5.6; P = 0.005). Female HL patients who had a family history of BC were significantly more likely to develop BC, compared to HL patients with no history of BC among relatives (HR = 3.3, 95%CI 1.6-7.1; P = 0.002). Women with HL and a family history of BC are at even higher than anticipated risk of BC, as are their female relatives. Obtaining a thorough family history for a woman preparing to undergo therapy for HL is important for treatment decisions for HL and maintaining an up to date family history over time is also important for the management of a woman's ongoing cancer risks and her surveillance strategy following survival of HL.

Ultrasound versus physical exam to screen for secondary thyroid cancer among high-risk childhood cancer survivors.

e21528 Background: Thyroid cancer is a common secondary malignancy among childhood cancer survivors who have received radiation to the head, neck and/or upper thorax. The optimal strategy for surveillance for thyroid carcinoma in childhood cancer survivors remains controversial. Current Children’s Oncology Group recommendations are limited to physical exam. The objective of this study was to determine the sensitivity and specificity of thyroid ultrasound versus neck exam by a pediatric endocrinologist in the diagnoses of thyroid cancer in a cohort of high-risk childhood cancer survivors. Methods: Medical records of childhood cancer survivors who received radiotherapy to the head, neck and/or upper thorax were reviewed. These patients were seen in a comprehensive childhood cancer survivorship clinic from 01/01/2010 to 12/31/2017. Patient populations included oncology, bone marrow transplant and brain tumor patients. Results: 226 patients received radiation to the head, neck and/or upper thorax. Of those, 129 patients were male (57%). Sixteen (7.1%) of patients developed a secondary thyroid malignancy including 4 patients previously treated for an oncological malignancy, 9 patients treated with bone marrow transplantation, and 3 patients with a CNS malignancy. Median radiation dose was 1800 cGy (range 400-5940 cGy). Time to thyroid carcinoma diagnosis occurred at a median of 12 years (range 4-19 years) from treatment with radiation. Screening ultrasounds were obtained in 146 (65%) patients while 226 (100%) had a physical exam. Two cases were identified by abnormalities on physical exam. The sensitivity of US was 100% (CI 80.6-100) compared to a sensitivity of 12.5% (CI 3.5-36) using physical exam (P &lt; 0.0001). Screening ultrasound had a specificity of 73% (CI 65.1-80.1) while physical exam yielded a specificity of 100% (CI 98.2-100). Conclusions: Regular screening with ultrasounds provide the greatest sensitivity for detection of secondary thyroid carcinomas after head, neck and upper thorax radiation in childhood cancer survivors. If screening ultrasounds were not routinely utilized in our clinic, 14 of the 16 patients (87.5%) would have had a delay in their diagnosis of a secondary thyroid malignancy. Screening ultrasounds may lead to earlier detection of thyroid carcinomas, with the potential to decrease the need for aggressive surgery, radioiodine therapy and, ultimately, to decrease recurrence risk.

A Clinical Study of Surgical Resection for Metastatic Tumors of Pancreas

Introduction: Metastasis to the pancreas is rare condition and it is reported that it accounts for less than 5 percent of all malignancies affecting the pancreas. Method: We performed 7 cases surgical resection for metastatic tumors of pancreas out of 262 cases of pancreas surgery from 2008 to 2018 in our hospital We evaluated the clinical characteristics and patient outcomes. Result: Primary malignancies were renal cell carcinoma (RCC, 6 cases) and thymic carcinoma (1 case). All cases had no extra-pancreatic metastasis. The median age at diagnosis of metastatic tumors of pancreas from RCC was 63 years old (58-77). The median interval time after nephrectomy was 104 months (39-189). A case with metastatic tumors of pancreas from thymic carcinoma was diagnosed simultaneously with its primary malignancy. 4 of 6 cases from RCC had multiple metastatic focuses in pancreas. The rest including the case from thymic carcinoma had single metastatic focus. Operative procedures were distal pancreatectomy (4 cases, one of these cases had recurrence in the remnant pancreas and underwent total pancreatectomy 12 months after distal pancreatectomy), total pancreatectomy (2 cases) and pancreaticoduodenectomy (1 case). The median survival time after pancreas surgery of cases from RCC is 87 months (8-111). 3 cases from RCC had recurrence 3, 6 and 10 months after pancreas surgery respectively. But they are receiving chemotherapy and still surviving for 98, 8 and 56 months. Thymic carcinoma case had recurrence 2 months after pancreas surgery. Conclusion: It is known that most common secondary malignancy of pancreas is RCC. Since the prognosis of metastatic tumors of pancreas from RCC without extra-pancreatic metastasis is relatively good, surgical resection is recommended. But when it occurs from other primary malignancy, surgical indication should be determined considering its pathological and clinical character.