Meiko Nishimura

Large cell neuroendocrine carcinoma originating from the uterine endometrium: a report on magnetic resonance features of 2 cases with very rare and aggressive tumor.

Neuroendocrine carcinomas (NEC) of the female genital tract are aggressive and uncommon tumors, which usually involve the uterine cervix and ovary, and are seen very rarely in the endometrium. Only less than 10 cases of large cell NEC (LCNEC) of the endometrium have been reported in the literature and their radiological findings are not well described. We report here two cases of pathologically proven LCNEC of the uterine endometrium. In both cases, the uterine body was enlarged and the tumor occupied part of the uterine cavity. Endometrial mass exhibited heterogeneous high intensity on T2-weighted magnetic resonance (MR) images, and diffusion-weighted MR images revealed high intensity throughout the tumor, consistent with malignancy. LCNEC is a highly malignant neoplasm without particular findings in terms of diagnostic imaging and pathology, so its preoperative definitive diagnosis is very difficult. However, when laboratory test, pathologic diagnosis and MR imaging suggest a poorly differentiated uterine malignancy, positron emission tomography-computed tomography scan should be performed as a general assessment to help with diagnosis.

Malignant melanoma with bone marrow involvement diagnosed from hypercalcemia: Development of a neural cell adhesion molecule stain.

Dear Editor, Hypercalcemia is a life-threatening complication in patients with cancer, but rarely in patients with malignant melanoma. We report a case of a malignant melanoma associated with bone marrow involvement, which was referred to us because of hypercalcemia. Neural cell adhesion molecule (NCAM) is a protein expressed in malignant melanoma. Some reports suggested that NCAM potentiates cellular invasion and metastasis of melanoma cells, although its function in melanoma progression remains unclear. In this case, immunohistochemical observation revealed dynamic changes in NCAM expression with strong expression in bone marrow metastases. A 29-year-old man presented with back pain. He had no relevant medical history. A physical skin examination revealed a black nodule on his right abdomen that had persisted for 1 year (Fig. 1a). Laboratory findings revealed mild leukocytosis, lactate dehydrogenase level of 357 IU/L (normal, 115–217), calcium level of 4.01 mmol/L (normal, 2.2–2.5) and phosphorus level of 0.326 mmol/L (normal, 0.77–1.5). His parathyroid hormone (PTH) level was in the low-normal range at 6 ng/L (normal, 15–65); his PTH-related peptide (PTH-rP) level was lower than normal. Other hormone levels were normal. Computed tomography showed multiple spinal fractures. Magnetic resonance imaging showed osteolysis with non-traumatic

L-Asparaginase-induced fulminating liver dysfunction

A 40-year-old woman with no past medical history was diagnosed with B lymphoblastic leukemia (ALL), and received induction chemotherapy with L-asparaginase (Lasp), cyclophosphamide, doxorubicin, vincristine, and prednisolone. On day 20 of treatment, 2 days after the fifth administration of L-asp at a dose of 3000 KU/m/day, laboratory tests showed deranged liver function with elevated total bilirubin (2.2 mg/dL, normal 0.3–1.0), AST (70 U/L, normal 8–34), and ALT (43 U/L, normal 13–31). A computed tomography (CT) scan on day 26 revealed severely diffuse low-density of the liver (Fig. 1b), which was not observed at the onset of ALL (Fig. 1a). Furthermore, total bilirubin, AST, and ALT increased to 4.1 mg/ dL, 640 U/L, and 693 U/L, respectively. Because L-asp was suspected to have induced the fulminating liver dysfunction, the next dose of L-asp was discontinued, and ursodeoxycholic acid was administered for liver protection. While CT on day 40 showed similar results (Fig. 1c), on day 100 liver density had nearly recovered to its pre-chemotherapy state, followed by normalization of laboratory findings (Fig. 1d). Thereafter, she achieved and maintained a complete remission after the post-remission therapy, which included allogeneic hematopoietic stem cell transplantation. Although liver injury due to L-asp seems to be a wellknown adverse effect, impressive CT images such as in this case, possibly due to severe fatty liver, have rarely been reported. The mechanism of liver steatosis remains to be elucidated, but asparaginase may cause abnormalities in lipid metabolism by inhibiting protein synthesis. Such liver dysfunction may occasionally develop into fatal liver failure. This case suggests the importance of evaluating periodic CT scans for liver dysfunction after treatment with L-asp. CT images may be useful not only for early

Effectiveness of Pertuzumab, Trastuzumab, and Docetaxel Combination Neoadjuvant Chemotherapy for HER2-Positive Inflammatory Breast Cancer: A Case Report

Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer. Case Report: A 40-year-old woman was referred to our hospital for evaluation of an induration in the right breast, suspected to be breast cancer. The tumor was diagnosed as estrogen receptor-negative, progesterone receptor-negative, HER2-positive, T4dN3cM0 stage IIIc IBC with axillary lymph node metastasis. Rather than surgical intervention, we chose a systemic treatment approach with pertuzumab, trastuzumab, and docetaxel (PTD) combination therapy which was shown to be effective for HER2-positive IBC in the NeoSphere trial. After 4 cycles of treatment, the patient had a partial response, allowing mastectomy of the right breast and axillary lymph node dissection to achieve local control. We review this case because of the success of PTD combination neoadjuvant chemotherapy for HER2-positive IBC. Conclusion: To improve the poor prognosis of IBC, combined modality therapy is required, including chemotherapy and local treatment such as surgery and/or radiation therapy. In this case, combination neoadjuvant chemotherapy with PTD for HER2-positive IBC was effective, and this regimen may contribute to further improvements in the cure rate for this malignancy.

Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging

Background The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Results Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 ± 192 vs. 120 ± 103 ions/mm2; P = 0.009 in paired t-test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 ± 1258 vs. 1174 ± 662 ng/cm3; P = 0.028 in paired t-test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Conclusions Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. Methods We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC–MS/MS) with laser microdissection.

Abstract 2872: Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib

Background The development of rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib. A significant relationship exists between the severity of a rash and survival in various cancers. However, whether erlotinib becomes distributed to the skin and whether its concentration is higher in a rash than in normal skin of treated cancer patients remains unknown. Here, using quantitative mass spectrometry imaging (qMSI), we successfully visualized the distribution of erlotinib in rashes and normal skin of patients with advanced pancreatic cancer receiving this drug. Methods We studied five patients with advanced pancreatic cancer who developed rashes after treatment with gemcitabine (1000 mg/m² by intravenous infusion for 30 minutes on days 1, 8, and 15 every 4 weeks) and erlotinib (given orally at 100 mg/day). We biopsied both rashes and normal skin, and compared the distribution of erlotinib using matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). The plasma concentration of erlotinib was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results Erlotinib concentrations in five patients were 2.55 ± 1.46 ng/mm3 in normal skin and 3.18 ± 1.53 ng/mm3 (mean ± SD) in rashes (p=0.123). In four out of five patients, the erlotinib concentration in rashes was higher than that in normal skin. The epidermis showed the strongest expression of EGFR in skin as judged by immunohistological staining. Erlotinib showed a greater tendency for distribution to the epidermis than subcutaneous tissue. There was no correlation between erlotinib plasma concentrations vs. concentrations in rashes or normal skin. Conclusions Using qMSI, we, for the first time, visualized the distribution of erlotinib in skin tissue of pancreatic cancer patients receiving erlotinib. We found a tendency for a higher concentration of erlotinib in rashes than in normal skin. A greater distribution of erlotinib to the epidermis than subcutaneous tissue suggests erlotinib may directly bind EGFR expressed in the epidermis. Citation Format: Meiko Nishimura, Hiroaki Aikawa, Mitsuhiro Hayashi, Yu Mizutani, Kei Takenaka, Yoshinori Imamura, Naoko Chayahara, Masanori Toyoda, Naomi Kiyota, Toru Mukohara, Akinobu Hamada, Hironobu Minami. Quantitative mass spectrometry imaging of erlotinib in skin rashes of cancer patients receiving erlotinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2872. doi:10.1158/1538-7445.AM2017-2872

A mimicking "multiple liver metastasis" of breast cancer by recurrent B lymphoblastic leukemia.

Dear Editor, A 60-year-old female presented with progressive headache and fatigue. Twelve years ago, she had suffered from estrogen receptor (ER)-positive breast cancer and received radical excision followed by radiotherapy and endocrine therapy. Complete blood cell analysis showed a white blood cell count of 4.6× 10/L with 11 % of blasts and a hemoglobin concentration of 7.9 g/dL. Bonemarrowwas hypercellular with 83.8% of blasts, which were positive for CD10, CD19, and HLA-DR, and were negative for membrane-bound light chains by flow cytometric analysis. Cytogenetic abnormalities were not found. She was diagnosed with B lymphoblastic leukemia, not otherwise specified (pre-B-ALL), in accordance with the WHO classification (fourth edition) [1]. She received induction chemotherapy and eventually achieved complete remission. During the postremission therapy and the outpatient follow-up period, there was no evidence of leukemic recurrence. Eleven months after completion of the chemotherapy, she underwent an abdominal computed tomography (CT) scan for a periodical follow-up of inveterate ureterolithiasis. A non-enhanced CT scan of the liver showed multiple low-density masses (Fig. 1a), which were not observed at the onset of pre-B-ALL 2 years before. After intravenous administration of contrast material, these hepatic masses appeared to be more attenuated compared with normal parenchyma (Fig. 1b). These radiographic characteristics seemed to be consistent with multiple liver metastasis of breast cancer in consideration of her medical history. However, laboratory tests showed normal liver function, except for a slightly elevated LDH (230 U/L; reference range, 118– 221 U/L), and serum levels of tumor-specific markers such as carcinoembryonic antigen, CA19-9, CA15-3, and Nation Cancer Center-Stomach-439 were not elevated. Furthermore, a liver biopsy revealed that small round cells with high N/C ratio occupied the hepatic lesions with relatively clear boundaries (Fig. 1c, d). Immunohistochemistry demonstrated that these abnormal cells were negative for cytokeratin AE1/AE3 (Fig. 1e), ER, and mammaglobin, suggesting that recurrence of breast cancer was negative. On the other hand, these cells were diffusely positive for CD79a (Fig. 1f) and partially positive for CD20 and TdT. These pathological findings were similar to those of the bone marrow at the initial diagnosis of pre-B-ALL. Finally, we made a correct diagnosis of pre-B-ALL recurrence, multi-focal infiltration of leukemic cells in the liver. Although there were more than 15 % of blasts in the bone marrow, blasts and cytopenia were not observed in the peripheral blood. Because hormone receptor-positive breast cancer is slowly progressive in general, a recurrence after a latency period of more than 10 years is not rare in long-term follow-up patients [2]. Thus, it is possible that multiple hepatic nodules in this case comprised of recurrent breast cancer cells. Leukemic cells often infiltrate into the liver diffusely, and to our knowledge, multi-focal lesions have not been reported in patients with leukemia relapse [3, 4]. However, by a liver biopsy, we could confirm that these lesions actually consisted of recurrent lymphoblasts. Lossos et al. emphasized that re-biopsy should be performed in every patient with follicular lymphoma to evaluate the presence of transformation [5]. In patients with breast cancer, re-biopsy is also recommended to assess the switches in biomarker status such M. Nishimura :A. Okamura :Y. Inui :Y. Imamura : K. Yakushijin :H. Matsuoka :K. Yamamoto :H. Minami Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan