Seyoung Seo

Differential protein stability and clinical responses of EML4-ALKfusion variants to various ALK inhibitors in advanced ALK-rearranged non–small cell lung cancer

Background Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8–100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5–66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9–95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6–68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Conclusion Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.

Clinical features and outcomes in patients with human immunodeficiency virus-negative, multicentric Castleman's disease: a single medical center experience

Background Multicentric Castlemans disease (CD) is commonly associated with poor prognosis, and well-known prognostic factors are scarce. We performed a retrospective analysis to define the clinical features and prognostic factors for patients with multicentric CD. Methods Between 1990 and 2013, 32 patients with multicentric CD were identified from the database of the Asan Medical Center, Seoul, Korea. Clinicopathologic data were collected by reviewing the medical records. With the exclusion of 4 patients because of unknown human immunodeficiency virus infection status, 28 human immunodeficiency virus-negative patients with multicentric CD were included in this analysis. Results Most of the patients were male (76%) and had a median age of 54 years. Hyaline vascular variant was the most common subtype (N=11, 39%). Hepatosplenomegaly (61%), fever (39%), edema (29%), and ascites (18%) were the most frequently reported symptoms and signs at diagnosis. With a median follow-up of 67 months, the 5-year overall survival (OS) was 77%. Patients with extravascular fluid accumulation (i.e., peripheral edema, ascites, and/or pleural effusions) were significantly associated with a poor survival rate (5-year OS, 94% vs. 56%; P=0.04). The extent of disease involvement was also a significant prognostic factor (5-year OS, 91% for involvement on a single side vs. 73% on both sides of the diaphragm; P=0.03). Other clinicopathologic factors were not significantly associated with patient survival. Conclusion Our findings suggest that the hyaline vascular variant is not a rare subtype of multicentric CD. Extravascular fluid accumulation and disseminated disease involvement seem to be significant prognostic factors.

Prognostic impact of fibroblast growth factor receptor 2 gene amplification in patients receiving fluoropyrimidine and platinum chemotherapy for metastatic and locally advanced unresectable gastric cancers

Although Fibroblast growth factor receptor (FGFR) 2 gene amplification and its prognostic significance have been reported in resectable gastric cancers, information on these features remains limited in the metastatic setting. The presence of FGFR2 amplification was assessed in formalin-fixed, paraffin-embedded tissues using a quantitative PCR-based gene copy number assay with advanced gastric cancer cohorts. A total of 327 patients with tumor portion of ≥70% were analyzed for clinical features. Among these patients, 260 who received first-line fluoropyrimidine and platinum chemotherapy were analyzed for survival. Sixteen of 327 patients (4.9%) exhibited FGFR2 amplification. The amplification group showed associations with age <65 years, Borrmann type 4 disease, poor performance status, poorly differentiated histology, extra-abdominal lymph node metastases, and bone metastases. The median overall survival (OS) and progression-free survival (PFS) were found to be 12.7 and 5.8 months, respectively. In univariate analysis, PFS did not differ between amplification and no amplification groups (hazard ratio [HR]=1.34, 95% confidence interval [CI]: 0.78-2.31, p=0.290), although the OS was significantly shorter in the amplification group (HR=1.92, 95% CI: 1.13-3.26, p=0.015). However, multivariate analysis indicated that FGFR2 amplification was not an independent prognostic factor for OS (HR=1.42, 95% CI: 0.77-2.61, p=0.261). Although FGFR2 amplification is associated with poorer OS, it does not appear to be an independent prognostic predictor in patients with advanced gastric cancer treated with palliative fluoropyrimidine and platinum chemotherapy.

Prognostic significance of serum beta-2 microglobulin in patients with diffuse large B-cell lymphoma in the rituximab era

The prognostic value of serum beta-2 microglobulin for diffuse large B-cell lymphoma (DLBCL) is not well known in the rituximab era. A retrospective registry data analysis of 833 patients with de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was conducted to establish the prognostic significance of serum beta-2 microglobulin at a ≥2.5 mg/L cutoff. Five-year progression-free survival (PFS, 76.1% vs. 41.0%; p < 0.001) and overall survival (OS, 83.8% vs. 49.2%; p < 0.001) were significantly worse in patients with elevated serum beta-2 microglobulin (n = 290, 34.8%). Furthermore, the five parameters of the International Prognostic Index, accompanying B symptoms, bone marrow involvement and impaired renal function were associated with worse PFS and OS. In multivariate analysis, elevated beta-2 microglobulin was a significant poor prognostic factor for PFS (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.29–2.24; p < 0.001) and OS (HR, 2.0; 95% CI, 1.47–2.75; p < 0.001). In an independent validation cohort of 258 R-CHOP treated patients with de novo DLBCL, elevated beta-2 microglobulin levels remained a significant poor prognostic factor for PFS (HR, 2.03; 95% CI, 1.23–3.32; p = 0.005) and exhibited a strong trend of association with worse OS (HR, 1.64; 95% CI, 0.98–2.75; p = 0.062). The significance of serum beta-2 microglobulin levels as an independent prognostic factor for patients with DLBCL receiving R-CHOP is confirmed.

Sequential heart and autologous stem cell transplantation for light-chain cardiac amyloidosis

REFERENCES 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29. 2. Hong J, Lee JH. Recent advances in multiple myeloma: a Korean perspective. Korean J Intern Med 2016;31:820-34. 3. Au WY, Caguioa PB, Chuah C, et al. Chronic myeloid leukemia in Asia. Int J Hematol 2009;89:14-23. 4. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol 2005;23:3412-20. 5. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984; 63:789-99. 6. Ide M, Kuwahara N, Matsuishi E, Kimura S, Gondo H. Uncommon case of chronic myeloid leukemia with multiple myeloma. Int J Hematol 2010;91:699-704. 7. Alsidawi S, Ghose A, Qualtieri J, Radhakrishnan N. A case of multiple myeloma with metachronous chronic myeloid leukemia treated successfully with bortezomib, dexamethasone, and dasatinib. Case Rep Oncol Med 2014;2014:962526. 8. Offiah C, Quinn JP, Thornton P, Murphy PT. Co-existing chronic myeloid leukaemia and multiple myeloma: rapid response to lenalidomide during imatinib treatment. Int J Hematol 2012; 95:451-2. 9. Monroy RH, Vargas-Viveros P, Ceballos EC, Velazquez JC, Munos SC. Imatinib (IM) plus thalidomide (Thali), a effective combination for the treatment of chronic myeloid leukemia (CML) Philadelphia chromosomepositive (Ph +) in IM-resistant disease. Report of 14 new cases from a single center in Mexico. Blood 2013;122:5172. Sequential heart and autologous stem cell transplantation for light-chain cardiac amyloidosis

Multiple Myeloma in a Patient with Acromegaly

Acromegaly is a slowly progressing condition resulting from excess growth hormone (GH), generally caused by a GH-secreting pituitary adenoma. Cancer is the third most common cause of mortality in patients with acromegaly, and insulin-like growth factor 1 (IGF-1) is known to influence tumor formation by increasing cell proliferation and inhibiting apoptosis. Multiple myeloma (MM) is a plasma cell neoplasm, and previous studies have suggested the possible role of IGF-1 in its development of MM. However, no cases of acromegaly accompanied with MM have been reported in Asia to date. We here report the case of a 58-year-old woman with acromegaly accompanied with MM who presented with longstanding acromegalic manifestations resulting from a GH-secreting pituitary adenoma and also exhibited anemia, a reversed albumin/globulin ratio, and plasmacytosis on bone marrow examination. Because IGF-1 has been suggested to play an important role in the development and progression of MM, the patient promptly underwent surgical removal of the pituitary adenoma via a transsphenoidal approach. Since there is currently no consensus on therapeutic guidelines and suggested prognosis for MM with acromegaly, long-term follow-up of such cases is needed.

Clinical outcomes of patients with resectable pancreatic acinar cell carcinoma

Given the rarity of the disease, the post‐resection clinical course of localized pancreatic acinar cell carcinoma (ACC) is largely unknown. Therefore, we aimed to analyze the outcomes of patients with localized pancreatic ACC who underwent curative surgical resection.

The HSP90 inhibitor, NVP-AUY922, attenuates intrinsic PI3K inhibitor resistance in KRAS-mutant non-small cell lung cancer

More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway. The HSP90 inhibitor AUY922 suppressed both PI3K/AKT/mTOR and RAF/MEK/ERK signaling, rendering cells sensitive to a PI3K inhibitor (omipalisib, GSK458). Combining these two drugs achieved a synergistic effect, even using only sub-therapeutic concentrations. Dual inhibition of the HSP90 and PI3K signaling pathways with sub-therapeutic doses of these combined anticancer drugs may represent a potent treatment strategy for KRAS-mutant NSCLC with intrinsic resistance to PI3K inhibition.

The clinical impact of an EML4-ALK variant on survival following crizotinib treatment in patients with advanced ALK-rearranged non-small-cell lung cancer

We received valid questions from Duruisseaux et al. [1] regarding our previous report of differential efficacy among ALK tyrosine kinase inhibitors (TKIs) in patients with ALK-rearranged non-small cell lung cancer (NSCLC) according to EML4-ALK fusion variants [2]. We agree that the benefits of local ablation therapy (LAT) and/or continuing crizotinib beyond progressive disease (CBPD) are considerable. The treatment line with crizotinib as well as subsequent second-generation ALK inhibitor treatment may affect overall survival (OS) in NSCLC patients. To address these questions, we analyzed the survival, progression profile, and subsequent treatment of 44 crizotinib-treated patients from our prior analysis. Over a median follow-up period of 26.5 months, the median OS of the surviving patients was 36.3 months, while the systemic time to progression (TTP), defined from the first dose to the first documented objective progression, was 17.9 months. Similar to our previous data, the 2year systemic TTP rate was significantly better for patients with variants 1/2/others (V1/2/others) than for those with variants 3a/b (V3a/b): 42.9% versus 10.6%, respectively (P1⁄4 0.04). However, the 2-year OS rate was not significantly different between the V1/2/others (74.2%) and V3a/b (56.4%) groups (P1⁄4 0.797). Table 1 summarizes the following patient information: progression profile, LAT usage, CBPD, crizotinib treatment line, brain metastasis at baseline, and subsequent second-generation ALK inhibitor treatment. The progression profile and proportion of patients receiving CBPD were not significantly different between the groups. Continuing CBPD was dependent on the clinician’s decision about whether oligoprogression had occurred. As mentioned in our previous report, the proportions of heavily treated (secondline or higher) patients and those with brain metastasis at baseline were higher (75.0% versus 45.0%; P1⁄4 0.042 and 37.5% versus 25.0%; P1⁄4 0.375, respectively), and the proportion of patients receiving second-generation ALK inhibitors lower (29.2% versus 55.0%; P1⁄4 0.083), in the V1/2/others group than in the V3a/b group. These factors could have affected the discrepancies in systemic TTP and OS between the groups. Most LATs used were brain or bone radiosurgery or radiotherapy; therefore, we assume that the higher proportion of LAT usage was associated with the higher frequency of brain metastases in the V1/2/others group. All patients were confirmed to harbor the ALK translocation by FISH and were genotyped for EML4-ALK fusion variants by quantitative PCR, which can detect 28 known ALK rearrangement types, as indicated by Duruisseaux et al. [1]. In two patients in whom we could not identify the variant type, we sequenced the PCR products directly to identify EML-ALK fusion events. In conclusion, we agree with Duruisseaux et al. [1] that our study is a small, single-institute, retrospective analysis of crizotinib sensitivity, and that larger comprehensive studies of EMLALK-rearranged NSCLC cases are needed to determine the potential impact of ALK variants. However, we emphasize that the 2year systemic TTP rate remained significantly different between the two groups after additional follow-up. The biological mechanisms underlying the heterogeneity of the outcomes following ALK TKI therapy are important but not understood [3, 4]. We hope our study can provide a basis for more precise stratification of ALK-driven lung cancers. S. Seo, C. G. Woo, D. H. Lee & J. Choi Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul; Department of Pathology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju; Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea (*E-mail: jenec@amc.seoul.kr)

971PCLINICAL FEATURES AND OUTCOMES OF HUMAN IMMUNODEFICIENCY VIRUS (HIV)-NEGATIVE PATIENTS WITH MULTICENTRIC CASTLEMAN'S DISEASE

ABSTRACT Aim: Castlemans disese (CD) is a rare polyclonal lymphoproliferative disease that presents a variety of symptoms and clinical courses. Multicentric Castlemans disese (MCD) is defined by the involvement of at least two non-contiguous lymph node areas and commonly associated with poor clinical outcomes. We performed a retrospective analysis to reveal the clinical features and prognostic factors for patients with MCD. Methods: Between 1990 and 2013, 80 patients of biopsy proven CD were identified from the database of Asan Medical Center, Seoul, Korea. The data were collected retrospectively by reviewing medical records. Among them, 32 patients were classified into MCD. With the exclusion of 4 patients with unknown HIV infection status, a total of 28 HIV-negative patients with MCD were included in this analysis. Results: Most patients were male (76%) and median age was 54 years (range, 13-75) at diagnosis. Hyaline vascular variant was the most common subtype (39%) and followed by plasma cell variant (36%) and mixed cell variant (25%). Frequently reported symptoms and signs at diagnosis were hepatomegaly or splenomegaly (57%), fever (39%), edema (29%) and ascites (18%). As an initial therapy, cytotoxic chemotherapy, glucocorticoid alone, and interferon-a were given in 11 (39%), 6 (21%), and 1 (0.4%) patients, respectively. Remaining 10 (36%) patients were managed with ‘watch and wait’ strategy. With median follow-up of 67 months (range, 1-162), 10 (36%) patients died and 5-year overall survival rate was 77% (95% CI, 61%-93%). Patients who showed extravascular fluid accumulation (peripheral edema, ascites, pleural effusions) were significantly associated with poorer survival than those without those signs (5-year survival rate, 94% vs 56%; p = 0.04). Extent of involvement (same side vs both sides of diaphragm) was marginally associated with survival (p = 0.11). However, other clinicopathologic factors, including gender, age, histopathologic types, hepatosplenomegaly, anemia, thrombocytopenia, serum albumin and lactate dehydrogenase were not associated with survival (p > 0.1 for all comparisons). Conclusions: Clinicopathologic features of MCD in our cohort were consistent with previous reports. Our analyses showed that the signs of extravascular fluid accumulation at diagnosis were associated with poor overall survival in patients with MCD. Disclosure: All authors have declared no conflicts of interest.