Cystoid Macular Edema following Treatment with Nanoparticle Albumin-Bound Paclitaxel and Atezolizumab for Metastatic Breast Cancer.

Cystoid macular edema (CME) is a rare side effect associated with chemotherapy. Although the development of CME has been reported to occur following treatment with taxane drugs, such as nanoparticle albumin-bound paclitaxel (Nab-PTX), the occurrence of CME with treatment with atezolizumab has not yet been reported. Here, we report the case of a 49-year-old woman who developed CME 19 months into chemotherapy with Nab-PTX and atezolizumab. Improvement was not achieved with steroid injections into the Tenon's sac, and Nab-PTX and atezolizumab treatments were ceased. One month later, there was subjective improvement in her symptoms. Although many reports have indicated that cessation of chemotherapy has successfully improved CME, a specific treatment for CME has not yet been established. Clinicians should be aware of the ophthalmologic side effects and offer immediate treatment if symptoms develop.

Pyopneumothorax during bevacizumab-containing chemotherapy in a patient with metastatic breast cancer.

Pyopneumothorax is a rare but troubling complication of bevacizumab. We herein report a case of pyopneumothorax in a patient with metastatic breast cancer during bevacizumab treatment. A 60-year-old female who was diagnosed with metastatic breast cancer (ER+ , PgR+ , HER2-, Ki67 <14 %, metastasized to lung, pleural, brain, subcutaneous tissue, and bone) was started on bevacizumab plus paclitaxel chemotherapy. Although the disease was well-controlled, pyopneumothorax was noted after 3 months of treatment and the chemotherapy was therefore stopped immediately. The pyopneumothorax was so intractable that no conservative treatment could successfully manage it. The patient underwent a radical operation using the technique of latissimus dorsi muscle transfer. The operation improved her general condition and lead to hormonal therapy. Our case indicates the successful management of a severe side effect of bevacizumab for a breast cancer patient.

A phase I trial of CPT-11 and S-1 combination chemotherapy in patients with metastatic colorectal cancer.

BACKGROUND/AIMS: To establish a safe and practical chemotherapeutic regimen using CPT-11 in combination with an oral 5FU derivative S-1 for patients with metastatic colorectal cancer, a phase I clinical trial was conducted in an outpatient setting. METHODOLOGY: Nine patients with metastatic colorectal cancer were enrolled. S-1 was administered at approved doses of 80 mg/body/day to eligible patients with a body surface area (BSA) of less than 1.25m2, 100 mg/body/day to those with a BSA of 1.25-1.5m2, and 120 mg/body/day to those with a BSA of more than 1.5m2, for 2 weeks followed by 1 week rest, comprising one treatment cycle of 3 weeks. CPT-11 was administered on day 8 of the S-1 cycle. The dose of CPT-11 was escalated from 60-120 mg/m2 by every 20 mg/m2 for every cohort consisting of at least 3 patients in order to define dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended dose (RD) in preparation for a phase II trial. RESULTS: In regard to the hematologic toxicity, a decrease of WBC to less than grade 2 was observed in 2 patients until the dose was escalated to 100 mg/m2 of CPT-11, which delayed the treatment for 1 week in 1 patient. Regarding non-hematologic toxicity, fatigue and gastrointestinal toxicity, including anorexia and nausea/vomiting, at grades 1 and 2 were commonly observed throughout the dose levels. Diarrhea at grade 3 was observed at the 4th cycle of 100 mg/m2 CPT-11 in 2 of 3 patients, both of whom required hospitalization. All patients were able to complete more than 3 treatment cycles, and 1 patient at 80 mg/m2 of CPT-11 was able to receive 31 treatment cycles. Observed tumor responses included 1 partial response (PR), 2 moderate responses, 4 stable diseases, and 2 progressive diseases. Serum CEA level decreased in 7 of the 9 patients enrolled. CONCLUSIONS: These results suggest that this treatment regimen using CPT-11 in combination with oral S-1 therapy is a safe regimen in an outpatient setting and effective for patients with metastatic colorectal cancer. The DLT is diarrhea at a MTD of 100 mg/m2 of CPT-11, and 80 mg/m2 CPT-11 is recommended for the next phase II trial.

A phase I trial of CPT-11 in combination with 5-fluorouracil plus leucovorin chemotherapy for patients with metastatic colorectal cancer.

BACKGROUND/AIMS: To establish a safe and practical chemotherapeutic regimen using CPT-11 in combination with 5-FU plus leucovorin (5-FU/LV) for patients with metastatic colorectal cancer in an outpatient setting, a phase I clinical trial was conducted. METHDOLOGY: Eligible patients received the RPMI regimen of I-LV (200 mg/m2, for 2 hours) plus 5-FU (333 mg/m2, bolus) weekly for 4 weeks followed by a 2-week rest. CPT-11 was administered over the 5-FU/LV therapy at the 1st and 3rd week of every treatment cycle before the bolus 5-FU. Dose escalation of CPT-11 from 25 to 100 mg/m2 was done for every cohort consisting of at least 3 patients to define a dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended dose (RD) for a phase II trial. RESULTS: Twenty-one patients with metastatic colorectal cancer were enrolled. Hematologic toxicity was very infrequently observed. One patient enrolled at level 1 (25 mg/m2 CPT-11), but not the other patients, had muscle weakness at grade 3 and needed to be hospitalized. Hair loss at grade 1 was observed in 3 of 21 patients. Gastrointestinal toxicity, including nausea, was commonly observed throughout the dose levels. Diarrhea was frequently observed at doses higher than level 4 (60 mg/m2 CPT-11), and 2 of the 3 patients at dose level 6 (100 mg/m2 CPT-11) experienced diarrhea at grade 3 and needed to be hospitalized. As for the overall tumor responses, 3 partial responses (PR), 10 stable diseases, and 6 progressive diseases were observed, with 2 of the PRs occurring at dose level 5 (80 mg/m2 CPT-11). CONCLUSIONS: These results suggest that our treatment regimen using CPT-11 in combination with 5-FU/LV is a safe regimen in an outpatient setting and effective for patients with metastatic colorectal cancer. The DLT is diarrhea at the MTD of 100 mg/m2 of CPT-11, and 80 mg/m2 CPT-11 is recommended for the next phase II trial.

Generation of antigen-presenting cells using cultured dendritic cells and amplified autologous tumor mRNA.

Novel antigen-presenting cells (APCs) were generated using cultured dendritic cells (DCs) and amplified tumor mRNA, and the potential of tumor antigen-reactive T cell induction by the tumor RNA-introduced DCs (DC/tumor RNA) was analyzed in a patient with melanoma antigen-encoding gene (MAGE3)-positive malignant melanoma of the esophagus. DCs were generated from an adherent fraction of peripheral blood mononuclear cells in the presence of granulocyte macrophage colony-stimulating factor and interleukin-4. Tumor mRNA was purified from tumor tissue, amplified in vitro using a T7 RNA polymerase system, and then introduced into DCs by electroporation (150 V/150 microF or 100 V/200 microF). The gene introduction efficiency was 44-55% as measured by enhanced green fluorescent protein reporter gene expression, and the viability of RNA-introduced DCs was approximately 80%. DC/tumor RNA could induce tumor antigen-reactive cytotoxic T lymphocytes (CTLs) in an mRNA-specific manner, but had no effect on the self-antigen-reactive T cells. DC/tumor RNA could induce the polyspecific antigen-reactive CTL responses mediated by both human leukocyte antigen class I and class II molecules, whereas MAGE3 peptide-pulsed DCs induced only the monospecific MAGE3-reactive CTL responses mediated by human leukocyte antigen class I molecules, showing the superiority of the DC/tumor RNA over the DC/peptide. It is suggested that the use of DC/tumor RNA as antigen-presenting cells may be more effective, convenient and practical for the DC-based anti-cancer immunotherapy.

Neoadjuvant therapy of rectal cancer using oral tegaful-uracil (UFT) plus concomitant radiotherapy--a case report.

A 59-year-old male patient with rectal cancer 2 cm in diameter (T2) at the peritoneal reflection with suspicious left lateral node metastasis was treated with 400 mg of preoperative oral uracil and tegaful (UFT) for 5 weeks, 5 days a week in combination with concomitant radiotherapy of 45 Gy per 25 fractions for 5 weeks. After resting for another 5 weeks, colon fiberscopy, barium enema, and computed tomography revealed a trace of the primary tumor and a 40% shrinkage of the lateral metastasis. The serum CEA level decreased to the normal range during treatment. The adverse effects were nausea, bloody stool and elevation of transaminase, all at grade 1. Low anterior resection with a left hemi-lateral lymphadenectomy was performed through a suprapubic, one hand-size incision without laparoscopy. The preoperative treatment did not affect any operative procedures, and no postoperative complications occurred. The surgical specimen showed that the rectal tumor had been remarkably shrunk by the preoperative treatment, to the level of a superficial type tumor. Histological analysis indicated moderately differentiated adenocarcinoma cells that were present at only 2 mm in diameter in the mucosal layer, 6 mm in the submucosal layer, and 1 mm or less in the muscular layer with scar formation. No metastasis was detected in the 16 lymph nodes dissected, but an organizing tumor thrombus, which had preoperatively been diagnosed as lateral node metastasis, was detected. These results suggest that preoperative oral UFT plus concomitant radiotherapy may be a feasible, tolerable and effective treatment for patients with rectal cancer.

Feasibility study of adoptive immunotherapy for metastatic lung tumors using peptide-pulsed dendritic cell-activated killer (PDAK) cells.

We have established a novel culture system to generate effector lymphocytes designated as peptide-pulsed dendritic cell-activated killer (PDAK) cells using cultured dendritic cells (DCs), synthetic peptide, peripheral blood lymphocytes, and interleukin-2 plus immobilized anti-CD3 antibody. A feasibility study of an adoptive immunotherapy trial using PDAK cells was conducted on HLA-A2 and HLA-A24 cancer patients with antigen-positive lung metastasis that was defined by serological analysis or PCR analysis. Eleven patients with lung metastasis participated in the study: 6 with colorectal cancer, 2 with pancreatic cancer, 1 each with breast and lung cancer, and 1 with melanoma. The patients received either Muc-1, CEA, gpl00, Her-2 or SART-3-PDAK cells generated in vitro, intravenously in combination with 350,000 U IL-2 weekly for 9 weeks, together with a planned dose-escalation schedule of three transfers each of 1 x 10(7), 3 x 10(7) and 1 x 10(8) PDAK cells/kg for 6 patients, and with a uniform dose of 3 x 10(7) PDAK cells/kg for the remaining 5 patients. Peptide/HLA-specific cytotoxic activity and TCRVbeta gene usage of PDAK cells were analyzed. All transfers of PDAK cells, which showed peptide/HLA-specific lysis, were well-tolerated in all patients, and adverse effects (elevation of transaminase, fever, and headache) were observed primarily at grade 1, but in no case greater than grade 2. The generation of sufficient cells to treat the patients with 3 x 10(7) PDAK cells/kg was feasible using our culture system, but we were able to generate and administer the dose of 1 x 10(8) PDAK cells/kg in only one patient. One partial response (PR) of lung metastasis occurred in a pancreatic cancer patient who received 3 x 10(7) Muc-1-PDAK cells/kg. The cytolytic units of PDAK cells in this patient appeared to be substantially higher compared to those in PD patients. TCR gene usage analysis on PDAK cells revealed preferential usage of TCRVbeta segments. These results suggest that adoptive immunotherapy using PDAK cells for cancer patients with antigen-positive lung metastasis is safe and feasible, and tumor response should be examined in a future clinical trial

Anterior resection of rectal cancer through a one hand-size incision with or without laparoscopy: proposal of one hand-size incision surgery (OHaSIS).

BACKGROUND: One hand-size incision surgery (OHaSIS) is a surgery that is carried out through one hand-size incision with or without laparoscopy. Safety, feasibility and recovery advantage of the anterior resection of rectal cancer by the OHaSIS were studied. STUDY DESIGN: Nineteen consecutive patients with rectal cancer, consisting of seven rectosigmoid, six upper rectal, and six lower rectal cancers, were treated with anterior resection, including seven high, six low, three super-low, and three partial intersphincteric resections, through a suprapubic longitudinal one hand-size incision. The initial 11 patients were treated in combination with laparoscopy and the following eight patients were treated without laparoscopy. RESULTS: All anterior resections with mesorectal excision were completed in a safe manner with acceptable operative time (average 245 min), blood loss (average 280 g), and postoperative complications without any elongation of the initial incision. When compared with 12 previous high and low anterior resections by conventional open surgery (OS), the 13 high and low anterior resections by the OHaSIS showed equivalent operative time, blood loss, anastomotic procedures of single stapling, lymph node numbers dissected, surgical margin of the anal side of the tumor, and complications. Moreover, analysis of perioperative parameters for surgical invasiveness, including a body temperature >37 degrees C, days of bed rest, and days of use of parenteral narcotics, revealed a recovery advantage in the OHaSIS group compared with that in the OS group. CONCLUSIONS: These results suggest that anterior resection for patients with rectal cancer by the OHaSIS is safe, feasible, and less invasive than conventional OS, and has sufficient operative performance. Although the survival benefit and recurrence rate by this approach must be ensured in a future trial, we would like to propose the new concept of OHaSIS for treating rectal cancer.

Enhancing effect of PS-K on IL-2-induced lymphocyte activation: possible involvement of antagonistic action against TGF-beta.

Effects of protein-bound polysaccharide (PS)-K on interleukin (IL)-2-induced responses of peripheral blood mononuclear cells (PBMCs) were studied. PS-K (50 mcg/ml) was observed to enhance proliferative responses, cytotoxic activities against K562 and Daudi target cells, CD25+ cell population and telomerase activity of PBMCs stimulated with IL-2. The cytotoxic effector cells could be generated in the presence of PS-K even with a minimum amount of IL-2. The enhancing effect of PS-K on the IL-2-induced lymphocyte activation was more evident in PBMCs from cancer patients than in those from healthy volunteers, suggesting that PS-K may be beneficial if combined in the IL-2-based immunotherapy of cancer. TGF-beta inhibited the IL-2-induced lymphocyte activation of proliferative responses, cytotoxic activities and CD25+ cell population, the inhibitions of which were abrogated with PS-K. PS-K also abrogated the TGF-beta-induced anchorage-independent growth of normal rat kidney cells. Flow cytometric analysis using a labeled TGF-beta revealed that PS-K blocked the binding of TGF-beta at its receptor level on the surface of PBMCs. It is suggested that PS-K enhances IL-2-induced lymphocyte activation through, in part, an antagonistic action against TGF-beta.

Host-oriented peptide evaluation using whole blood assay for generating antigen-specific cytotoxic T lymphocytes.

A whole blood assay using antigenic peptide was established to predict host cytotoxic T lymphocyte (CTL) precursor status. Blood samples from HLA-A24 donors and colorectal cancer patients were directly diluted with RPMI-1640 medium to a 20% blood concentration, then distributed to tubes and a peptide of an HLA-A24-restricted CEA peptide panel (20 microM) was added to the tubes. Incubation was performed for 4-5 days and supernatants were subjected to ELISA specific for IFN-gamma protein. It was observed that certain CEA peptides could stimulate the diluted blood samples to produce IFN-gamma. Only the peripheral blood mononuclear cells (PBMCs) that were purified from the IFN-gamma-positive samples of the whole blood assay showed positive spots, detected with IFN-gamma ELISPOT assay, and could proliferate with the stimulation of immobilized anti-CD3 antibody plus interleukin-2 (CD3/IL-2 system). The proliferating PBMCs expressed cytotoxic activity against HLA-A24+ CEA-expressing tumor cells and the TISI target cells pulsed with the CEA peptide that had been used to stimulate the PBMCs to produce IFN-gamma, but they did not kill the target cells pulsed with peptides that had failed to stimulate IFN-gamma production, nor did they kill the target cells alone. Theses findings suggest that the IFN-gamma production of the blood samples detected by the whole blood assay identifies the peptide that can induce the CEA antigen-specific CTL response. Detection of IFN-gamma gene expression using real-time-PCR analysis could identify the peptide within 6 hours, which is earlier than the protein analysis by ELISA. The whole blood assay using the CEA peptide panel for healthy donors and colorectal cancer patients revealed that IFN-gamma-inducible peptides were different among the individual samples tested, indicating that the CEA peptides that should be used for generating CTLs are different in individual patients. The whole blood assay using a CEA antigen peptide panel is simple and beneficial for identifying candidate peptides. The host-oriented peptide evaluation (HOPE) approach may provide hope for the augmentation of clinical efficacies for peptide-based cancer immunotherapy.

Locoregional immunotherapy of malignant ascites from gastric cancer using DTH-oriented doses of the streptococcal preparation OK-432: Treatment of Th1 dysfunction in the ascites microenvironment.

Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists in the microenvironment of malignant ascites from gastric cancer, in which IL-10 may, in part, play a role. The up-regulation of Th1 responses by OK-432 may result in positive clinical responses. The DTH reaction to OK-432 may be a useful tool not only for predicting clinical response but also for selecting the optimal dose of OK-432.

[Generation of TRiDAK (tumor RNA-introduced dendritic cell-activated killer) cells].

Tumor-reactive effector lymphocytes were generated using tumor-derived amplified RNA and cultured dendritic cells (DC). Tumor RNAs were extracted from gastric cancer cell line MKN45 or cancer cells of malignant effusions, and were processed with T7 amplification. DCs were induced from an adherent cell population of peripheral blood mononuclear cells (PBMCs) with GM-CSF and IL-4. Tumor-RNA was introduced into DCs using electroporation. Effector cells were generated by stimulating a non-adherent fraction of PBMCs with tumor RNA-introduced DCs. It was observed that milligram RNA could efficiently be amplified from microgram RNA. The effector cells, designated as tumor-RNA-introduced DC-activated killer (TRiDAK) cells, showed IFN-gamma spots in a tumor-specific manner when examined using ELISPOT analysis, and demonstrated cytotoxic activities against tumor cells from which RNA was extracted. TRiDAK cells produced more tumor-specific IFN-gamma spots when stimulated repeatedly. These results suggest that TRiDAK cells are practical and may be effective lymphocytes for adoptive cancer immunotherapy.

[Tumor RNA introduction into dendritic cells and Epstein-Barr virus transformed B cells].

In induction of autologous tumor-reactive antigen (TRA) specific cytotoxic T lymphocytes (CTLs) using antigenic peptides and cultured dendritic cells (DCs), identification of the adequate tumor antigens and HLA typing of individuals are required. These restrictions have promoted the use of tumor cells themselves, including tumor cell lysates and tumor cell-DC fusion cells. However, it is very difficult to obtain enough tumor cells for treatment in the clinical setting. We have studied the use of RNA derived from tiny tumor cells. RNA was reverse-transcribed into cDNA, after which T7-amplification and in vitro transcription were carried out. The amplified RNA was successfully electroporated into DCs, and polyclonal polyspecific CTLs could be generated. EBV transformed B cells were also good candidates to be electroporated with the RNA. This suggests that tumor RNA amplification followed by introduction into DCs or EBV transformed B cells is a feasible and practical method to prepare potent APCs.

Adoptive immunotherapy of cancer using activated autologous lymphocytes--current status and new strategies.

After the discovery of interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), and cytotoxic T lymphocytes (CTLs) sensitized with the mixed lymphocyte-tumor culture (MLTC) system have been conducted in adoptive immunotherapy (AIT) trials during past 15 years. Although the overall response rate of tumor shrinkage was marginal (9%), locoregional administration of TILs for malignant effusions was effective (77%) for a decrease or disappearance of the effusions even in terminally-ill patients, resulting in an improvement of QOL. Recent advances for molecular understanding of antigen presentation and recognition have promoted us to enhance the efficacy of AIT by using cultured dendritic cells (DCs) for generating antigen-specific CTLs in vitro. The peptide-pulsed DC-activated killer (PDAK) cells showed tumor recognition against antigen-expressing cells, and were efficiently propagated with the IL2 plus immobilized anti-CD3 antibody (IL-2/CD3) culture system. Clinical trials using PDAK cells against patients with lung metastases are now progressed, in which peptides suitable for generating CTLs were chosen in individual patients using the method designated as host-oriented peptide evaluation (HPOE) approach. Moreover, DCs were introduced with tumor-derived RNA, which was amplified with the T7 promoter system, and then were used for stimulating lymphocytes. The tumor RNA-introduced DC-activated killer (TRiDAK) cells showed tumor-specific interferon-gamma spots even in a patient in whom we failed to generate PDAK cells using DCs and peptides, suggesting that the clinical trial of AIT using TRiDAK cells is warranted for the treatment of patients with metastatic cancer. Thus, more understanding of antigen-presentation and -recognition mechanisms and immune regulation systems may promote clinical applications of AIT to establish a novel modality of cancer treatment.