Cardiac metastasis after esophagogastrectomy for esophageal adenocarcinoma with an antemortem diagnosis.

Cardiac metastasis is uncommon and rarely diagnosed antemortem. Here, we describe a case of symptomatic cardiac metastasis from esophageal adenocarcinoma. A 64-year-old man developed chest symptoms 26 months after curative esophagogastrectomy for esophageal adenocarcinoma. Initially, ischemic cardiac disease was suspected based on electrocardiography findings, but an infiltrative tumor was seen morphologically in the wall of the interventricular septum and apex. No other lesions were detected. Histological examination of a transcatheter biopsy specimen indicated that the cardiac tumor was metastasis from esophageal adenocarcinoma. Chemoradiotherapy with cisplatin relieved his symptoms, and he had resumed normal activities. However, he opted not to undergo further aggressive treatment due to severe adverse effects from cisplatin. Seventeen months after completion of chemoradiotherapy, metastases to the right ventricle and the left thighbone were detected and he died 27 and 24 months after the diagnosis of cardiac metastasis and completion of chemoradiotherapy, respectively.

Improvement of QOL and Immunological Function With Lentinula Edodes Mycelia in Patients Undergoing Cancer Immunotherapy: An Open Pilot Study.

Context • Combined treatment with an extract of Lentinula edodes mycelia (LEM) and chemotherapy has been reported to improve quality of life (QOL) and immunological function in cancer patients. However, those effects have not been elucidated for patients receiving cancer immunotherapy. Objective • The present study intended to investigate the effects of oral LEM on QOL and immunological function in cancer patients receiving immunotherapy. Design • The research team designed an open-label, single-armed pilot study. Setting • The study took place at Bio-Thera Clinic, a facility associated with Tokyo Women's Medical University in Tokyo, Japan. Participants • The participants were 10 cancer patients undergoing cancer immunotherapy at Bio-Thera Clinic. Intervention • The participants received either dendritic cell (DC)-based cancer vaccine therapy or CD3-activated T-lymphocyte (CAT) therapy as immunotherapy. They received the immunotherapy only for the first 4 wk of the study, and then oral LEM (1800 mg/d) was added for the next 4 wk. Outcome Measures • Preintervention and at 4 and 8 wk after the start of the study, participants completed a QOL survey, and immunological parameters were measured. Results • Participants' QOL symptom scores increased (ie, worsened) by 5.1 ± 1.7 during the first 4 wk of treatment when they were receiving immunotherapy only, but it decreased (ie, improved) by -2.5 ± 1.6 during the next 4 wk when the immunotherapy was combined with the LEM, P < .05. The measurement of the immunological parameters during the 4 wk of immunotherapy combined with LEM showed that the amount of interferon-γ (IFN-γ) produced in the peripheral blood tended to increase as compared with that during the first 4 wk of immunotherapy only. The rise in IFN-γ was correlated with changes in several regulatory T cells (Tregs) (ie, forkhead box P3 [FOXP3]+/cluster of differentiation 4 [CD4]+ and transforming growth factor beta [TGF-ß]). Conclusions • The findings suggest that a combined treatment of LEM and immunotherapy might improve QOL and immunological function in cancer patients.

Fever-range whole-body heat treatment stimulates antigen-specific T-cell responses in humans.

Increase in body temperature has been thought to play an important role in the regulation of immune responses, although its precise mechanisms are still under investigation. Here, we examined the effects of physiologically relevant thermal stress on the cytokine production from human peripheral T cells. Volunteers were heated using a whole-body hyperthermia device, the rectal temperature was maintained above 38.5 °C for more than 60 min, and peripheral blood mononuclear cells (PBMCs) were obtained before and after the treatment. When T cells were stimulated with anti-CD3/CD28 antibodies, marked increases in the production of interferon-γ (IFN-γ) and interleukin-2 were observed in PBMCs prepared immediately after and 24h after the treatment. Similarly, enhanced production of IFN-γ in response to the tuberculin purified protein derivative or antigenic viral peptides was also observed immediately after and 24h after the treatment. Fluorescence photo-bleaching analyses showed heat-induced increase of membrane fluidity in T cells, which probably enables them to induce rapid and efficient cluster formation of molecules involved in antigen recognition and signal transduction for T-cell stimulation. We concluded that physiologically relevant thermal stress could efficiently modify T-cell responsiveness to various stimuli, including enhanced responses to specific antigens.

[Evaluation of quality of life and immune function in cancer patients receiving combined immunotherapy and oral administration of lentinula edodes mycelia extract].

UNLABELLED: Lentinula edodes mycelia extract(LEM) may mitigate the immunosuppression caused by regulatory T cells(Tregs), and it is therefore expected that LEM will be useful with cancer immunotherapy. In this study, we evaluated the quality of life (QOL) and immune function in cancer patients receiving a combination of immunotherapy and oral administration of LEM. METHODS: Ten patients who had received cancer immunotherapy were enrolled. They received cancer immunotherapy alone for the first 4 weeks, and were then administered LEM (1,800 mg/day) with cancer immunotherapy for the next 4 weeks. QOL scores and immune parameters were evaluated at weeks 0, 4, and 8. RESULTS: The total score for QOL was improved during the period with LEM administration compared to the period with immunotherapy alone. Interferon (IFN)-γ secretion from peripheral blood cells was increased during the period with LEM administration. The change in IFN-γ secretion in the LEM administration period possibly correlated with changes in the Treg population. CONCLUSION: Oral administration of LEM may improve QOL and immunity in patients receiving cancer immunotherapy.

[Examination of the quality of life in the cancer patients under immunotherapy].

In recent years, quality of life(QOL) has received much attention as a subjective health outcome by which to measure and adopt patient treatment. Few studies, however, have examined how the QOL of cancer patients differs depending on treatment methods, or the effects of immunotherapy on patients' QOL. Thus, this study aimed to reveal: 1) the differences in QOL between patients treated with immunotherapy and other methods, and 2) whether the QOL of cancer patients treated with immunotherapy improves in accordance with the duration of immunotherapy. Thirty-nine cancer patients receiving immunotherapy who completed a Quality of Life Questionnaire for Cancer Patients Treated with Anti-Cancer Drugs(QOL-ACD) were the subjects for statistical analyses. The result indicated that patients treated with immunotherapy exhibited a higher physical conditions score than did patients receiving chemotherapy (p<0.01). Given that the side effects of immunotherapy are fewer than those of chemotherapy, the results suggested that the presence of side effects during cancer treatment plays an important role in determining patients' QOL.

[Examination of the patient serum presenting a CEA false high value after cancer immuno-cell therapy].

False positive elevation of carcinoembryonic antigen (CEA) was observed in a 65-year-old woman who was treated with dendritic cell therapy (DCT) and activated lymphocyte therapy (ALT) for intrahepatic cholangiocarcinoma. Three months after the initiation of these therapies, her CEA value measured by AIA (TOSOH) began to increase without any evidence of worsening of cholangiocarcinoma. CEA was measured by several different methods, and only the result measured by AIA was high, indicating the presence of a false positive phenomenon. To clarify this phenomenon, we evaluated the patient's serum precisely. Gel filtration chromatography of her serum showed that CEA was detected in the elution fraction of IgG, which was different from the reference samples. Furthermore, this peak disappeared after incubation of patient's CEA and HBR-1. The immunoglobulin absorption test revealed that CEA value was decreased only after absorption of IgG and absorption tests using HBR-1 and MAK-absorbents showed a dramatic decrease in CEA value. These findings indicated the presence of IgG type human anti-mouse antibodies (HAMA), which interfered the measurement by AIA. Although we could not identify the reason why HAMA was produced in this patient, the facts that the false positive phenomenon was observed after the initiation of DCT and ALT, and that CEA value decreased after theses therapies were discontinued, indicated that immuno-modulaton by DCT and ALT may have a close relationship to HAMA production. It was probable that DCT and ALT activated preexisting heterophile-antibody-producing cells, which stimulated HAMA production. The incidence of such false positive reaction of CEA by HAMA in patients with DCT and ALT was low, but as the number of the patient with immuno-cell therapy increases, the incidence of such phenomenon surely increases. Because HAMA reacts to all types of immunoassay, careful attention should be paid to the evaluation of laboratory findings in patients undergoing with such immuno-cell therapies.

[Hyperthermic immuno-cellular therapy-basic and clinical study].

BASIC: We treated mice inoculated LLC tumors with hyperthermia or activated lymphocytes. Both of hyperthermia and activated lymphocytes therapy reduced not only a tumor growth but also lung metastasis. And a combination therapy of hyperthermia and activated lymphocytes therapy reduced more of the tumor growth and lung metastasis synergistically. CLINICAL: We proceeded with hyperthermia (HT) for 472 cancer patients and activated lymphocytes (CAT) therapy for 384 patients and dendritic cell (DC) therapy for 94 patients. Two-hundred-thirty-eight patients of them underwent a combination therapy with hyperthermia and CAT therapy. And 92 patients received a combination therapy with hyperthermia and DC therapy. We proceeded with hyperthermia or immunotherapy for 526 cancer patients. And we have 67 clinical benefit cases including 8 complete response (CR) cases. These basic and clinical results indicate an effectiveness of a combination therapy with hyperthermia and cellular-immunotherapy for cancer patients.

Separation methods of T cells, natural killer, and dendritic cells from peripheral blood of cancer patients using interleukin-2 and functional analysis of natural killer cells after separation.

We aimed to induce three different immune cell subsets from a single blood sample from cancer patients to target different biological characters of cancer cells. In the presence of 6000 IU/ml IL-2, natural killer (NK) cells adhere to plastic. By using this ability, we could separate dendritic cells, T cells, and NK cells from peripheral blood mononuclear cells. The cultured NK cells demonstrated higher nonspecific cytotoxicity against tumor cell lines than did the T cells. Furthermore, adherent NK cells demonstrated higher cytotoxicity than nonadherent NK cells, although there was no difference between adherent and nonadherent NK cells in natural cytotoxicity receptors (NKp30, NKp44, NKp46) and NKG2D expression. With these results, we confirmed that we could induce dendritic cell, T cell, and higher cytotoxic NK cells from a single blood draw, and this methodology facilitates to the use of these cells for clinical grade conditions.

[Combined cell therapy by using dendritic cells, T-cells and NK cells to human polymorphic cancer].

Although an expression of MHC molecules and tumor associated antigens of the cancer are not uniform, we consider that the cancer immunotherapy for some specific tumor antigens cannot correspond to molecular biological varieties of the cancer. Consequently, we tried to develop a method to separate dendritic cells (DC), T-cells and natural killer (NK) cells from peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers. PBMC were separated by centrifugation on Ficoll-Hypaque gradients from peripheral blood obtained from healthy volunteers. After separating these cells, the cells were put into a plastic flask, and we isolated monocyte fraction (dendritic cells), NK cell fraction and T-cell fraction one after another by the difference in its ability to adhere to a plastic flask. We analyzed surface markers and activation states of these groups. We could induce dendritic cells from the monocyte fraction, CD3-activated T-cells (CAT) from the T-cell fraction, and adherent lymphokine activated-killer cells (A-LAK) from the NK cell fraction. Therefore, we indicate the possibility of the combined cell therapy with three immune cell fractions in which we can induce from the same blood at once.

[Preparation of NK-enriched LAK cells--their potential cytotoxic and ADCC activities].

We examined several culture methods to induce proliferation of natural killer (NK) cells from peripheral blood mononuclear cells (PBMC). In the presence of IL-2, a remarkable proliferation of NK cells was observed when PBMC were co-cultured with MMC-treated K562, which is known as a highly sensitive in vitro target cell for the NK assay. Addition of OK-432 or TNF-alpha and IL-1 beta also induced marked NK proliferation in a dose dependent manner. These NK-enriched lymphokine activated killer (LAK) cells showed highly cytotoxic activities against various MHC class I positive or negative tumor cells. They also showed potent ADCC activities against Herceptin-coated SK-BR-3, a HER2/neu positive breast cancer cell line. These results indicated that NK-enriched LAK cells are potent effector cells, and suggested novel therapeutic strategies for nonspecific immunotherapy as well as target immunotherapy in combination with anticancer antibodies, such as Herceptin.

[Phenotypical analysis of effector cells on nonspecific cancer cell therapy].

In the present study, we examined the contributions of lymphocyte subpopulations in lymphokine activated killer (LAK) activity. LAK cells prepared from peripheral blood mononuclear cells (PBMC) of healthy donors showed highly cytotoxic activities against target tumor cells. When CD16 and CD56 positive cells in LAK cells were depleted by magnetic cell sorting, their cytotoxic activities were dramatically decreased. In contrast, little change was observed by the depletion of CD3 positive cells, suggesting that CD16 and/or CD56 positive populations, but not CD3 positive populations, including natural killer (NK) cells are the major cell types involved in LAK activity. Indeed, NK-enriched LAK cells prepared by culturing PBMC with IL-2 and OK-432 showed a more potent LAK activity than conventional LAK cells and CD3-activated T cells. These results suggest that selective expansion and activation of CD16 and CD56 positive cells in LAK cells is a useful strategies to improve their anti-tumor potential in nonspecific immunotherapy, and possibly in combination therapy with other target immunotherapies as well.