Plasma level of prostate related-antigen peptide-reactive IgG is a prognostic factor of patients with breast cancer treated with personalized peptide vaccines.

The present study assessed plasma IgG in patients with metastatic recurrent breast cancer (mrBC) that is reactive to various T-cell epitope peptides of prostate-related antigens (PRAs), such as prostate-specific antigen, prostate-specific membrane antigen and prostate acid phosphatase. Patients were treated with personalized peptide vaccines (PPVs) which were selected and administered from a panel of candidate peptides based on human leukocyte antigen-types and prevaccination IgG levels to each peptide. The peptide panel consisted of 27 cytotoxic T-lymphocyte-epitope peptides derived from tumor-associated antigens, not including PRA. PRA peptides and peptide panels were retrospectively analyzed in 77 PPV-treated patients. The results revealed that PRA reactive IgG levels were increased after vaccination in 31 of the 97 patients included in the present study. Although there was no significant association between anti-PRA peptide levels and progression-free survival (PFS) or overall survival, anti-PRA peptide levels were significantly associated with PFS (P=0.009) in estrogen-receptor positive (ER+) patients with cancer. The results suggested that plasma anti-PRA IgG levels may be a useful prognostic marker for monitoring PPVs, particularly for ER+ patients with mrBC (trial registration no. from the UMIN Clinical Trials Registry, UMIN000001844).

[Triple-Tracer Technique of Sentinel Lymph Node Biopsy Using Blue Dye plus Radioisotope Combined with Real-Time Indocyanine Green(ICG)Fluorescence Imaging Procedures for Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy].

Clinical evidence has indicated that, after neo-adjuvant chemotherapy(NAC), sentinel node(SN)identification rates(IR) were lower and false-negative rates(FNR)were higher for patients(pts)with local advanced breast cancer(BC)than for pts with early stage BC who did not receive NAC. Our previous clinical trial indicated that the real-time indocyanin green (RT-ICG)fluorescence imaging technique could improve the diagnostic sensitivity and detection accuracy of sentinel node biopsy(SNB). Nine pts with histologically confirmed Stage ⅡA to ⅢB, T1-T3, N0-2, M0 BC were selected to receive NAC, and the standard surgeries were performed after NAC completion. The SNs were detected by using conventional procedures with the blue dye(indigo carmine)plus 99mTc radioisotope techniques combined with concurrent RT-ICG. Clinically positive nodes were diagnosed by the radiologists using axillary ultrasound, MRI, and/or CT scans. All pts provided written informed consent before surgery. The surgical SNB was guided via RT-ICG fluorescence under standard light conditions by using the HEMS imaging system as previously published. All pts underwent SNB followed by completion node dissection(CND). The IR and FNR were calculated by comparing the results of the SNB and the histopathology of the resection specimens obtained via CND. The IR and FNR for each procedure of SNB were, respectively, 35.3% and 41.7% when indigo carmine blue was used, 82.4% and 0 when ICG fluorescence was used, and 58.8% and 5% when RI was used. In contrast, the total calculation of the triple tracer showed that IR reached 100% and FNR was 0. These data suggest that IR and FNR of SNB might be improved in pts with BC treated with NAC by using the novel triple tracer technique.

Early phase II study of mixed 19-peptide vaccine monotherapy for refractory triple-negative breast cancer.

We undertook an early phase II study of mixed 19-peptide cancer vaccine monotherapy for 14 advanced metastatic triple-negative breast cancer (mTNBC) patients refractory to systemic chemotherapy to develop a new type of cancer vaccine. The treatment protocol consisted of a weekly vaccination for 6 weeks, and there were no severe adverse events related to the vaccination throughout the trial. Increase of peptide-specific IgG against the vaccinated human leukocyte antigen-matched peptides, but not against the nonmatched peptides, was positively correlated with overall survival (OS) (P < .01). The median OS was 11.5 or 24.4 months in all 14 patients or the 10 patients who completed the vaccination. The patients with lower C-reactive protein levels or 3 or fewer systemic chemotherapies were favorable candidates for this treatment. Advancement of this therapy to the next stage of study could be warranted based on the safety and immune boosting determined herein (clinical trial registration number: UMIN000014616).

Predictive factors of the tumor immunological microenvironment for long-term follow-up in early stage breast cancer.

The aim of this research was to investigate the correlation of immunologic factors in the tumor environment of breast cancer, using immunohistological staining to evaluate the expression of programmed death 1/programmed death ligand 1 (PD-1/PD-L1), phosphatase and tensin homolog (PTEN), tumor infiltrating lymphocytes (TILs), and macrophages, and to analyze the association between the immunologic factors and clinical outcome for patients with early stage breast cancer (EBC). A total of 97 EBC patients who underwent standard surgery were investigated. Expression of PD-1/PD-L1 and PTEN and the density of CD3+ TILs, CD8+ TILs, and CD163+ macrophages were evaluated by immunohistochemical analysis. The association between the immunologic factors and clinical outcome was statistically analyzed. The density of CD3+ TILs, CD8+ TILs, and CD163+ macrophages and non-expression of PTEN was significantly higher in cases of triple negative breast cancer. CD8+ TIL density and CD8+ /PD-L1+ expression were predictive factors for disease-free survival and overall survival (OS). Human epidermal growth factor 2 (HER2)-positive patients with PTEN expression and luminal/HER2-negative patients without PD-L1 expression had significantly longer OS compared to patients without PTEN expression (P = 0.049) and with PD-L1 expression (P = 0.036), respectively. Furthermore, patients with PD-L1+ /CD8+ expression had worse median progression-free survival (P = 0.022) and median OS (P = 0.037) compared with patients without PD-L1+ /CD8+ expression. The CD3+ TILs, CD8+ TILs, and CD163+ macrophages were shown to infiltrate the tumor area of EBC. In particular, triple negative breast cancer had a higher rate of TIL infiltration within the tumor environment. Expression of PTEN and lack of PD-L1 expression were associated with favorable survival in HER2-positive and luminal/HER2-negative EBC patients, respectively. The PD-L1 expression combined with CD8+ density was significantly associated with an aggressive clinical outcome.

A case of retrograde intussusception at Roux-en-Y anastomosis 10 years after total gastrectomy: review of the literature.

A 63-year-old man, who had undergone total gastrectomy and Roux-en-Y reconstruction for gastric cancer 10 years previously, was admitted to our hospital with complaints of abdominal pain, palpable abdominal tumor, and hematemesis. On admission, the abdominal tenderness was improving and no abdominal tumor was palpable. Mild inflammatory changes and anemia were noted on blood examination. Abdominal computed tomography revealed a tumor with a layered structure in the left abdomen. The patient was diagnosed with intestinal obstruction secondary to intussusception, and surgery was performed. Retrograde intussusception was found at the site of the Y anastomosis. We conducted manual reduction using the Hutchinson procedure. The intestinal color after the reduction was good, and no intestinal resection was required. Postoperative recovery was uneventful, and the patient was discharged 12 days after surgery. Reports of jejunal intussusception after total gastrectomy with Roux-en-Y reconstruction are relatively rare. Here, we report a case of jejunal intussusception after total gastrectomy with Roux-en-Y reconstruction.

[Development of Peptide Vaccines for Triple-Negative Breast Cancer Treatment].

Our previous phase II clinical trial showed that therapeutically selected personalized peptide vaccines(PPVs)were effective at boosting anticancer immunity; the immune response after PPV was associated with a clinical outcome as a prognostic factor for metastatic breast cancer(mBC). We conducted an early phase II study to evaluate the safety and efficacy of a new regimen using multiple peptide vaccines(KRM-19)for patients with metastatictriple -negative breast cancer. KRM-19 consisted of 19 mixed peptides chosen from the previously reported 31 PPVs according to their anti-tumor immunologiceffec ts and safety profiles for patients with mBC. All patients had histologically confirmed measurable ER-PgR-HER2- mBC and their human leukocyte antigen(HLA) / -A molecules were A2, A3, A11, A24, A26, A31, or A33. KRM-19(19mg/mL)was administrated subcutaneously every week for a total of 6 doses. Concurrent conventional chemo- and/or endocrine therapy were not permitted during treatment. This was an open-label, early phase II study. The primary endpoint was safety and anti-tumor immunologic effect, while the secondary endpoints were clinical responses and progression-free survival(PFS). The estimated enrollment was 10-15 and 8 patients were enrolled(Clinical trial registry number: UMIN000014616). Measurement of peptide-specific cytotoxic T lymphocyte and IgG responses were conducted before and after vaccination. The correlation between PFS and the increased IgG response and/or CTL levels were investigated.