Impact of salvage chemotherapy after immune checkpoint inhibitor for recurrent or metastatic head and neck cancer.

BACKGROUND: It is unclear witch regimen is optimal as salvage chemotherapy (SCT) after immune checkpoint inhibitor (ICI) monotherapy for recurrent or metastatic head and neck cancer (RM-HNC). METHODS: This study enrolled 109 patients. Overall survival (OS) and progression-free survival 2 (PFS2) were compared between patients stratified by SCT regimen. RESULTS: Of the 109 patients, 55 underwent SCT after the failure of ICI monotherapy. The OS of these 55 patients was longer than that of patients who did not undergo SCT. The OS and PFS2 were similar between patients treated with paclitaxel (PTX) and cetuximab (Cmab) combination and those treated with PTX monotherapy. The occurrence of irAEs did not impact PFS2 nor OS. CONCLUSIONS: SCT can improve the survival outcomes of patients with RM-HNC. In addition to PTX and Cmab, PTX monotherapy is also considered an effective SCT regimen. SCT is effective regardless of the presence or absence of irAEs.

Suitability of Polymyxin B as a Mucosal Adjuvant for Intranasal Influenza and COVID-19 Vaccines.

Polymyxin B (PMB) is an antibiotic that exhibits mucosal adjuvanticity for ovalbumin (OVA), which enhances the immune response in the mucosal compartments of mice. Frequent breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants indicate that the IgA antibody levels elicited by the mRNA vaccines in the mucosal tissues were insufficient for the prophylaxis of this infection. It remains unknown whether PMB exhibits mucosal adjuvanticity for antigens other than OVA. This study investigated the adjuvanticity of PMB for the virus proteins, hemagglutinin (HA) of influenza A virus, and the S1 subunit and S protein of SARS-CoV-2. BALB/c mice immunized either intranasally or subcutaneously with these antigens alone or in combination with PMB were examined, and the antigen-specific antibodies were quantified. PMB substantially increased the production of antigen-specific IgA antibodies in mucosal secretions and IgG antibodies in plasma, indicating its adjuvanticity for both HA and S proteins. This study also revealed that the PMB-virus antigen complex diameter is crucial for the induction of mucosal immunity. No detrimental effects were observed on the nasal mucosa or olfactory bulb. These findings highlight the potential of PMB as a safe candidate for intranasal vaccination to induce mucosal IgA antibodies for prophylaxis against mucosally transmitted infections.

Response to mRNA SARS-CoV-2 vaccination evaluated by B-cell receptor repertoire after tixagevimab/cilgavimab administration.

The use of anti-SARS-CoV-2 antibody products like tixagevimab/cilgavimab represents an important strategy to protect immunocompromised patients with haematological malignancies from COVID-19. Although patients who receive these agents should still be vaccinated, the use of tixagevimab/cilgavimab can mask the production of anti-spike antibody after vaccination, making it hard to assess vaccine response. We have newly established a quantification method to assess the response to SARS-CoV-2 vaccination at the mRNA level using B-cell receptor (BCR) repertoire assay and the Coronavirus Antibody Database (CoV-AbDab). Repeated blood samples before and after vaccination were analysed for the BCR repertoire, and BCR sequences were searched in the database. We analysed the number and percentage frequency of matched sequences. We found that the number of matched sequences increased 2 weeks after the first vaccination and quickly decreased. Meanwhile, the number of matched sequences more rapidly increased after the second vaccination. These results show that the postvaccine immune response can be assessed at the mRNA level by analysing the fluctuation in matching sequences. Finally, BCR repertoire analysis with CoV-AbDab clearly demonstrated the response to mRNA SARS-CoV-2 vaccination even after tixagevimab/cilgavimab administration in haematological malignancy patients who underwent allogeneic haematopoietic stem cell transplantation.

Comparable efficacy and safety of COVID-19 vaccines for patients receiving tegafur-uracil as postoperative adjuvant chemotherapy.

PURPOSE: Many effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed, but a weaker response in individuals undergoing anticancer treatment has been reported. This study evaluates the immunogenic status and safety of SARS-CoV-2 vaccines for patients with non-small-cell lung cancer (NSCLC), receiving tegafur-uracil (UFT) as postoperative adjuvant chemotherapy. METHODS: The subjects of this prospective study were 40 patients who underwent surgery for NSCLC and received SARS-CoV-2 vaccines postoperatively. We compared the antibody titers of SARS-CoV-2 vaccines and the adverse events between patients who received adjuvant UFT and patients who did not. RESULTS: The mean anti-S1 IgG titers were not significantly different between the UFT and without-UFT groups (mean optimal density, 0.194 vs. 0.205; P = 0.76). Multivariate analysis identified the period after the second vaccination as an independent predictor of anti-S1 IgG titer (P = 0.049), but not the UFT status (with or without-UFT treatment; P = 0.47). The prevalence of adverse events did not differ significantly between the groups, and no severe adverse events occurred. CONCLUSIONS: The efficacy and safety of the SARS-CoV-2 vaccines for NSCLC patients who received postoperative adjuvant UFT chemotherapy were comparable to those for NSCLC patients who did not receive postoperative adjuvant UFT chemotherapy. CLINICAL TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (UMIN) in Japan (UMIN000047380).

Urinary Biopyrrin Levels and Their Relationship with the Menstrual Cycle and Concomitant Symptoms Among Healthy Nonpregnant Women of Reproductive Age: A Cohort Study.

Background: Urinary biopyrrin (UBP) is an oxidative metabolite formed from the reaction of bilirubin with reactive oxygen species. Previous studies have explored the relationship between UBP levels and certain diseases or pregnancy. However, UBP levels in healthy nonpregnant women have not been well examined. We aimed to clarify the representative value of UBP in healthy nonpregnant women and explore its relationship with menstrual cycles and concomitant symptoms. Methods: We included healthy, nonpregnant Japanese women aged 20-39 years with normal body mass index and menstrual cycle. In total, 1260 urine samples collected during 43 menstrual cycles of 36 women were analyzed to determine the representative values and reference intervals of UBP levels. The correlation between daily UBP levels and the order of the day was explored, and median UBP levels of 5-day clusters were compared using Friedman and Mann-Whitney U tests. These analyses were also conducted in women with concomitant symptoms during the menstrual cycle. Results: The median UBP level in all samples was 0.2291 (reference: 0.0102-2.9335) µmol/gCr. There was no significant relationship between the median UBP level and menstrual cycle, regardless of the presence of self-manageable symptoms during or before menstruation. Conclusions: The representative UBP value and its reference interval can serve as standards for comparison with other populations. Our findings suggest that the UBP level may be an objective oxidative stress indicator that is less sensitive to menstrual cycle and concomitant symptoms. UBP levels in healthy nonpregnant women could be assessed regardless of the menstrual cycle and concomitant symptoms.

A Third Dose COVID-19 Vaccination in Allogeneic Hematopoietic Stem Cell Transplantation Patients.

We previously reported that a second dose of BNT162b2 was safe and effective for allogeneic hematopoietic stem cell transplantation (HSCT) patients. Here, we investigated the safety and efficacy of a third dose of COVID-19 mRNA vaccine in allogeneic HSCT patients. Antibody titers against the S1 spike protein were measured using the QuaResearch COVID-19 Human IgM IgG ELISA kit. The previous study included 25 allogeneic HSCT patients who received two doses of BNT162b2. Following the exclusion of three patients because of the development of COVID-19 (n = 2) and loss to follow-up (n = 1), the study evaluated 22 allogeneic HSCT patients who received a third dose of COVID-19 mRNA vaccine (BNT162b2 [n = 15] and mRNA-1273 [n = 7]). Median age at the time of the first vaccination was 56 (range, 23-71) years. Five patients were receiving immunosuppressants at the third vaccination, namely calcineurin inhibitors (CI) alone (n = 1), steroids alone (n = 2), or CI combined with steroids (n = 2). Twenty-one patients (95%) seroconverted after the third dose. None of our patients had serious adverse events, new-onset graft-versus-host disease (GVHD), or GVHD exacerbation after vaccination. A third dose of the BNT162b2 and mRNA-1273 COVID-19 vaccines was safe and effective for allogeneic HSCT patients.

Impact of tumor burden on survival in patients with recurrent or metastatic head and neck cancer treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have become the standard treatment for recurrent or metastatic head and neck cancer (RM-HNC). However, many patients fail to benefit from the treatment. Previous studies have revealed that tumor burden predicts the efficacy of ICIs, but this association remains unclear for RM-HNC. We retrospectively analyzed 94 patients with RM-HNC treated with ICI monotherapy. We estimated the tumor burden using the baseline number of metastatic lesions (BNML) and the baseline sum of the longest diameters of the target lesions (BSLD), and evaluated the association between BNML, BSLD, and standardized uptake value (SUV) and clinical outcomes. The median progression-free survival (PFS) was 7.1 and 3.1 months in the low-BNML and high-BNML groups, respectively (p = 0.010). The median PFS was 9.1 and 3.5 months in the low-BSLD and high-BSLD groups, respectively (p = 0.004). Moreover, patients with high SUVmax levels had worse overall survival (OS) and PFS. BNML, BSLD, and SUVmax are useful prognostic factors in patients with RM-HNC treated with ICIs. Imaging examinations before ICI treatment are recommended to predict the efficacy of ICIs. If the tumor burden is high, cytotoxic anticancer agents may be administered concomitantly with or prior to ICI monotherapy.

Promising Efficacy of a Third Dose of mRNA SARS-CoV-2 Vaccination in Patients Treated with Anti-CD20 Antibody Who Failed 2-Dose Vaccination.

Anti-CD20 antibodies react with CD20 expressed not only on malignant B cells, but also on normal B cells. It has been reported that patients treated with anti-CD20 antibodies had an insufficient response to two-dose mRNA SARS-CoV-2 vaccination. To investigate the efficacy of a third dose in these patients, we investigated serum IgG antibody titers for the S1 protein after a third vaccination in 22 patients treated with the anti-CD20 antibody who failed two-dose vaccination. Results showed that overall, 50% of patients seroconverted. Although no patient who received the third dose within 1 year of the last anti-CD20 antibody administration showed an increase in S1 antibody titer, 69% of patients who received the third dose more than 1 year after the last anti-CD20 antibody administration seroconverted. Our data show that a third dose of vaccination is effective in improving the seroconversion rate in patients treated with the anti-CD20 antibody who failed standard two-dose vaccination.

The Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Japanese Patients after Allogeneic Stem Cell Transplantation.

Patients who have undergone hematopoietic stem cell transplantation (HSCT) for hematological disease experience high mortality when infected by coronavirus disease 2019 (COVID-19). However, the safety and efficacy of the COVID-19 vaccine in HSCT patients remain to be investigated. We prospectively evaluated the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine (Pfizer BioNTech) in 25 Japanese allogeneic HSCT patients in comparison with 19 healthy volunteers. While anti-S1 antibody titers in almost all healthy volunteers after the second dose were higher than the cut-off value reported previously, levels in HSCT patients after the second dose were diverse. Nineteen patients (76%) had seroconversion of anti-S1 IgG. The median optical density of antibody levels in HSCT patients with low IgG levels (<600 mg/dL), steroid treatment, or low lymphocytes (<1000/µL) was significantly lower than that in the other HSCT patients. There were no serious adverse events (>Grade 3) and no new development or exacerbation of graft-versus-host disease after vaccination. We concluded that the BNT162b2 mRNA vaccine is safe and effective in Japanese allogeneic HSCT patients.

Safety and immunogenicity of the COVID-19 vaccine BNT162b2 in patients undergoing chemotherapy for solid cancer.

BACKGROUND: Although COVID-19 severity in cancer patients is high, the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing chemotherapy for solid cancers in Japan have not been reported. METHODS: We investigated the safety and immunogenicity of BNT162b2 in 41 patients undergoing chemotherapy for solid cancers and in healthy volunteers who received 2 doses of BNT162b2. We evaluated serum IgG antibody titers for S1 protein by ELISA at pre-vaccination, prior to the second dose and 14 days after the second vaccination in 24 cancer patients undergoing cytotoxic chemotherapy (CC group), 17 cancer patients undergoing immune checkpoint inhibitor therapy (ICI group) and 12 age-matched healthy volunteers (HV group). Additionally, inflammatory cytokine levels were compared between the HV and ICI groups at pre and the next day of each vaccination. RESULTS: Anti-S1 antibody levels were significantly lower in the ICI and CC groups than in the HV group after the second dose (median optimal density: 0.241 [0.063-1.205] and 0.161 [0.07-0.857] vs 0.644 [0.259-1.498], p = 0.0024 and p < 0.0001, respectively). Adverse effect profile did not differ among the three groups, and no serious adverse event occurred. There were no differences in vaccine-induced inflammatory cytokines between the HV and ICI groups. CONCLUSION: Although there were no significant differences in adverse events in three groups, antibody titers were significantly lower in the ICI and CC groups than in the HV group. Further protection strategies should be considered in cancer patients undergoing CC or ICI.

Limited increase in antibody titers following mRNA SARS-CoV-2 vaccination for more than 3 years after final dose of anti-CD20 antibody.

We investigated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody. Although T-cell-mediated immune responses were detected even in patients receiving R-CHOP treatment, the S1 antibody titer following BNT162b2 vaccination remained only marginally increased for more than 3 years after the final dose of anti-CD20 antibody. We found no relationship between the percent of B-cells and S1 antibody titer. The duration of this suppression was much longer than we anticipated. Further protection and treatment strategies against COVID-19 for these patients are warranted.

Novel Prognostic Score for recurrent or metastatic head and neck cancer patients treated with Nivolumab.

Although several prognostic factors in nivolumab therapy have been reported in recurrent or metastatic head and neck cancer (RM-HNC) patients, these factors remain controversial. Here, we conducted a multicenter retrospective cohort study to investigate the impact of clinico-hematological factors on survival in RM-HNC patients treated with nivolumab. We reviewed 126 RM-HNC patients from seven institutes. We evaluated the prognostic effects of clinico-hematological factors on survival. The median overall survival (OS) was 12.3 months, and the 1 year-OS rate was 51.2%. Patients without immune-related adverse events, lower relative eosinophil count, worse best overall response, higher performance status, and higher modified Glasgow Prognostic Score had worse survival. The score, generated by combining these factors, was associated with survival. Patients with score of 4-5 had worse survival than those with score of 2-3 and 0-1 [adjusted HR for PFS: score of 4-5, 7.77 (3.98-15.15); score of 2-3, 3.44 (1.95-6.06), compared to score of 0-1], [adjusted HR for OS: score of 4-5, 14.66 (4.28-50.22); score of 2-3, 7.63 (2.29-25.37), compared to score of 0-1]. Our novel prognostic score utilizing clinico-hematological factors might be useful to establish an individual treatment strategy in RM-HNC patients treated with nivolumab therapy.

The Chemical Basis of Species, Sex, and Individual Recognition Using Feces in the Domestic Cat.

Scents emitted from excretions provide important information about the owner. Volatile compounds with higher levels in a species and/or sex, or that vary among individuals could be odor cues for species and/or sex, or individual recognition. However, such compounds have been identified in only a few vertebrate species. In domestic cats (Felis silvestris catus), it is known that unburied cat feces are territorial markers asserting the border of their home range, but little was known which fecal compounds are scent cues for species, sex, and individual recognition in cats. In the present study, we demonstrated the chemical basis for species, sex, and individual recognition using feces of cats. For males, major contents were fatty acids and 3-mercapto-3-methyl-1-butanol (MMB), a derivative of the unusual amino acid, felinine. MMB emission levels from feces had sex-based differences (male > female) and dynamic temporal changes during aging. Cats distinguished fecal odors with and without MMB, and different fatty acid compositions among individuals. No cat-specific compound, such as MMB, was detectable from their anal odor emitting fatty acids. We concluded that fecal MMB is a male sex recognition pheromone in cats and also provides a temporal trace of the owner. After sensing MMB, they may distinguish individual differences of conspecific feces with variable subsets of fatty acids. In contrast to scent marks, since cats can obtain species information from visual cues before sniffing conspecific anal odors, they may use their efforts to distinguish individual differences of anal odors during sniffing.

Discrimination of malignant transformation from benign endometriosis using a near-infrared approach.

The aim of the present single-center retrospective study was to investigate the discrimination of malignant transformation from ovarian endometrioma (OE) using a near-infrared approach ex vivo. Cystic fluid samples were collected from patients with OE (n=34) and endometriosis-associated ovarian cancer (EAOC) (n=12). The light reflected from each sample of cystic fluid [change in luminance, Δl (cd/m2) = background luminance-cystic fluid luminance at 800 nm] was spectrally measured by a near-infrared CCD camera with band-path filter (800 nm). The Δl in EAOC was significantly lower compared with that in OE. On regression analysis, a positive correlation was observed between the Δl and Hb level in the cystic fluid, and this association was exponential. The diagnostic sensitivity and specificity of Δl was 83.3 and 94.1% at the cutoff value of 21.5 cd/m2, with an area under the ROC curve of 0.897. The present ex vivo study potentially provides a powerful near-infrared approach for quantitative discrimination between EAOC and benign OE, with high sensitivity and specificity, which may have clinical applications.

LC-MS/MS quantification of felinine metabolites in tissues, fluids, and excretions from the domestic cat (Felis catus).

Domestic cat urine contains large concentrations of the unusual amino acid, felinine (2-amino-7-hydroxy-5,5-dimethyl-4-thiaheptanoic acid). A felinine derivative, 3-mercapt-3-methylbutanol is a potential scent signal for letting other animals know that the scent owners are cats. 3-Methylbutanol-glutathione (MBG) is an upstream precursor of the biosynthetic pathway of felinine that may be produced in hepatocytes by conjugation of glutathione with isopentenyl pyrophosphate, an intermediate for cholesterol biosynthesis. However, little evidence exists to support the biosynthesis of MBG in the liver. This study examined the distribution of metabolites of the felinine biosynthetic pathway in multiple tissues, body fluids, and excretions of cats. MBG, the felinine precursor, 3-methylbutanol-cysteinylglycine (MBCG), felinine, and felinine N-acetyl derivative were quantified by liquid chromatography-electron spray ionization-tandem mass spectrometry. All compounds were detected in cat serum. In males, MBG and MBCG contents were significantly higher than felinine and N-acetylfelinine contents. MBG was detected in multiple tissues, including the salivary gland, heart, liver, spleen, gut, kidney, bladder, adipose tissue, and muscle. Sex differences in MBG levels were observed in the liver and other tissues. Felinine and N-acetylfelinine were also detected in those tissues. Furthermore, we detected all compounds in cat bile and fecal samples, indicating that felinine is excreted into the feces via bile from the liver. We conclude that MBG is synthesized in several tissues in a sex-dependent manner. These findings improve our understanding of felinine metabolism and function in cats.

Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency.

Iron plays the central role in oxygen transport by erythrocytes as a constituent of heme and hemoglobin. The importance of iron and heme is also to be found in their regulatory roles during erythroblast maturation. The transcription factor Bach1 may be involved in their regulatory roles since it is deactivated by direct binding of heme. To address whether Bach1 is involved in the responses of erythroblasts to iron status, low iron conditions that induced severe iron deficiency in mice were established. Under iron deficiency, extensive gene expression changes and mitophagy disorder were induced during maturation of erythroblasts. Bach1-/- mice showed more severe iron deficiency anemia in the developmental phase of mice and a retarded recovery once iron was replenished when compared with wild-type mice. In the absence of Bach1, the expression of globin genes and Hmox1 (encoding heme oxygenase-1) was de-repressed in erythroblasts under iron deficiency, suggesting that Bach1 represses these genes in erythroblasts under iron deficiency to balance the levels of heme and globin. Moreover, an increase in genome-wide DNA methylation was observed in erythroblasts of Bach1-/- mice under iron deficiency. These findings reveal the principle role of iron as a regulator of gene expression in erythroblast maturation and suggest that the iron-heme-Bach1 axis is important for a proper adaptation of erythroblast to iron deficiency to avoid toxic aggregates of non-heme globin.