Gibberellin-biosynthetic ent-kaurene synthases in higher plants do not require their non-catalytic domains for the catalysis.

ent-Kaurene is a biosynthetic intermediate diterpene of phytohormone gibberellins, and is biosynthesized from geranylgeranyl diphosphate via ent-copalyl diphosphate (ent-CDP). The successive cyclization is catalyzed by two distinct diterpene synthases, ent-CDP synthase (ent-CPS) and ent-kaurene synthase (KS). Homologs of these diterpene synthase genes have been reported to be involved in the biosynthesis of specialized-metabolic diterpenoids for defense in several plant species, including rice (Oryza sativa). These diterpene synthases consist of three domains, αßγ domains. Active sites of ent-CPS exist at the interface of ß and γ domain, while those of KS are located within the α domain. We herein carried out domain-deletion experiments using several KSs and KS like enzymes (KSLs) to obtain insights into the roles of domains other than active-site domains. As previously reported in taxadiene synthase, deletion of γ or ßγ domains drastically decreased activities of specialized-metabolic OsKSL5, OsKSL8, OsKSL7 and OsKSL10 in O. sativa. However, unexpectedly, only α domains of several gibberellin-biosynthetic KSs, including OsKS1 in O. sativa, AtKS in Arabidopsis thaliana, TaKS in wheat (Triticum aestivum) and BdKS1 in Brachypodium distachyon, retained their original functions. Additionally, the specialized-metabolic OsKSL4, which is closely related to OsKS1, also functioned without its ßγ domains. Domain-swapping experiments showed that replacing ßγ domains in OsKSL7 with those from other KS/KSLs retained the OsKSL7 activity. Moreover, deletion of ßγ domains of bifunctional PpCPS/KS in moss (Physcomitrella patens) drastically impaired its KS-related activity. Thus, we demonstrate that monofunctional gibberellin-biosynthetic KSs are the unique diterpene synthases that retain their functions without ßγ domains.

Essential residues in diterpene synthases for biosynthesis of oryzalexins A-F in rice phytoalexin.

Cultivated rice (Oryza sativa) produces a variety of diterpenoid-type phytoalexins. Diterpene synthase genes that are responsible for the biosynthesis of momilactones, phytocassanes, and oryzalexins have been identified in O. sativa cv. Nipponbare. OsKSL10 (Os12t0491800 in RAP and LOC_Os12g30824 in MSU) was previously identified as an enzyme catalyzing the conversion of ent-copalyl diphosphate to ent-sandaracopimaradiene for the production of oryzalexins A to F. Our previous study on Oryza rufipogon, a wild progenitor of Asian cultivated rice, showed that both OrKSL10 and OrKSL10ind from O. rufipogon accessions W1943 and W0106, respectively, closely related to the japonica and indica subspecies, converted ent-copalyl diphosphate to ent-miltiradiene. Thus, the functional conversion of ent-miltiradiene synthase into ent-sandaracopimaradiene synthase is implied to have occurred through natural amino acid mutations, the details of which have not been elucidated. In this study, we show that introduction of A654G substitution into OrKSL10 significantly alters its function into more closely resembling that of OsKSL10. Moreover, double substitution V546I/A654G almost completely converts the function of OrKSL10 into that of OsKSL10. On the other hand, the reversed substitution I546V/G654A was insufficient to convert the function of OsKSL10 into OrKSL10, indicating the introduction of additional substitution S522I is required for the functionality of OsKSL10. Lastly, point mutations at the 654A residue in OrKSL10 suggest that hydrophobic side chains at this position have a negative influence on the production of ent-sandaracopimaradiene.

Disruption of p-coumaroyl-CoA:monolignol transferases in rice drastically alters lignin composition.

Grasses are abundant feedstocks that can supply lignocellulosic biomass for production of cell-wall-derived chemicals. In grass cell walls, lignin is acylated with p-coumarate. These p-coumarate decorations arise from the incorporation of monolignol p-coumarate conjugates during lignification. A previous biochemical study identified a rice (Oryza sativa) BAHD acyltransferase (AT) with p-coumaroyl-CoA:monolignol transferase (PMT) activity in vitro. In this study, we determined that that enzyme, which we name OsPMT1 (also known as OsAT4), and the closely related OsPMT2 (OsAT3) harbor similar catalytic activity toward monolignols. We generated rice mutants deficient in either or both OsPMT1 and OsPMT2 by CRISPR/Cas9-mediated mutagenesis and subjected the mutants' cell walls to analysis using chemical and nuclear magnetic resonance methods. Our results demonstrated that OsPMT1 and OsPMT2 both function in lignin p-coumaroylation in the major vegetative tissues of rice. Notably, lignin-bound p-coumarate units were undetectable in the ospmt1 ospmt2-2 double-knockout mutant. Further, in-depth structural analysis of purified lignins from the ospmt1 ospmt2-2 mutant compared with control lignins from wild-type rice revealed stark changes in polymer structures, including alterations in syringyl/guaiacyl aromatic unit ratios and inter-monomeric linkage patterns, and increased molecular weights. Our results provide insights into lignin polymerization in grasses that will be useful for the optimization of bioengineering approaches for the effective use of biomass in biorefineries.

Coordinated regulation of the entry and exit steps of aromatic amino acid biosynthesis supports the dual lignin pathway in grasses.

Vascular plants direct large amounts of carbon to produce the aromatic amino acid phenylalanine to support the production of lignin and other phenylpropanoids. Uniquely, grasses, which include many major crops, can synthesize lignin and phenylpropanoids from both phenylalanine and tyrosine. However, how grasses regulate aromatic amino acid biosynthesis to feed this dual lignin pathway is unknown. Here we show, by stable-isotope labeling, that grasses produce tyrosine >10-times faster than Arabidopsis without compromising phenylalanine biosynthesis. Detailed in vitro enzyme characterization and combinatorial in planta expression uncovered that coordinated expression of specific enzyme isoforms at the entry and exit steps of the aromatic amino acid pathway enables grasses to maintain high production of both tyrosine and phenylalanine, the precursors of the dual lignin pathway. These findings highlight the complex regulation of plant aromatic amino acid biosynthesis and provide novel genetic tools to engineer the interface of primary and specialized metabolism in plants.

Persistent weekly paclitaxel-induced peripheral neuropathy in early breast cancer patients enrolled in a randomized trial of cryotherapy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of weekly paclitaxel-based chemotherapy for breast cancer, that can persist for years. Cryotherapy therapy is effective for preventing early CIPN, but its protective effect on persistent CIPN is uncertain. This is a cross-sectional study conducted as an ancillary analysis of a randomized trial investigating the preventive effect of cryotherapy on CIPN in breast cancer patients receiving weekly paclitaxel-based chemotherapy (UMIN000034966). Eligible patients were evaluated for CIPN at more than a year after completion of the chemotherapy (persistent CIPN). CIPN was defined as a 6 or more points reduction from baseline in the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX) score. The incidence of early and persistent CIPN was compared between cryotherapy and control groups. Thirty-eight patients were examined for both early and persistent CIPN. The median time from completion of the weekly paclitaxel-based chemotherapy to the questionnaire for persistent CIPN was 2.3 (1.3-3.1) years. In all 38 patients, persistent CIPN was demonstrated in 10 (26.3%), respectively. There was a numerical, however not significant, reduction in the incidence of persistent CIPN (15.8% vs 36.8%, P = .1) in the cryotherapy group compared with the control group, respectively. In multivariate logistic regression analysis, age ≥ 65 was a substantial risk factor for persistent CIPN (HR: 14.7, 95%CI: 1.7-130.7, P = .01). In breast cancer patients receiving adjuvant weekly paclitaxel-based chemotherapy, cryotherapy resulted in a numerical, however not significant, reduction in the incidence of persistent CIPN and age>=65 was a risk factor for persistent CIPN.

18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Predicts Tumor Immune Microenvironment Function in Early Triple-negative Breast Cancer.

BACKGROUND/AIM: The maximum standardized uptake value (SUVmax) obtained using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is presumed to indicate tumor and active immune cells in the tumor immune microenvironment (TIME) based on their glycolysis activity. Therefore, this study investigated whether the metabolic parameter SUVmax could provide information regarding TIME in triple-negative breast cancer (TNBC) patients. PATIENTS AND METHODS: Fifty-four patients with TNBC underwent FDG PET/CT before neoadjuvant chemotherapy. Pretreatment biopsy specimens were pathologically evaluated. Expression statuses of CD8, forkhead box P3 (FOXP3), programmed cell death-1 (PD-1), and programmed cell death-ligand 1 (PD-L1) were assessed by immunohistochemistry. The relationships between immunological factors, including the tumor-infiltrating lymphocyte (TIL) grade and SUVmax or pathological complete response (pCR), were investigated. RESULTS: CD8, FOXP3, PD-1, and PD-L1 were high in 15 (27.8%), 39 (72.2%), 18 (33.3%), and 26 (48.2%) patients, respectively. SUVmax was significantly correlated with tumor size, Ki-67 labeling index, and CD8/FOXP3 ratio. Multiple linear regression analysis indicated that tumor size and the CD8/FOXP3 ratio predicted SUVmax. Seventeen patients (31.5%) achieved a pCR; TILs, the CD8/FOXP3 ratio, PD-1, and PD-L1 were significantly correlated with pCR rate. Multivariate analysis indicated that the CD8/FOXP3 ratio was the only independent predictive factor for pCR. CONCLUSION: SUVmax could provide metabolic information regarding TIME for TNBC patients and might be beneficial for formulating a treatment strategy and predicting pCR after neoadjuvant chemotherapy.

Impact of oral hygiene on febrile neutropenia during breast cancer chemotherapy.

PURPOSE: Oral hygiene is crucial in the management of oral and febrile complications during chemotherapy for cancer. This study aimed to investigate the impact of oral hygiene on the incidence of febrile neutropenia (FN) throughout the course of chemotherapy for breast cancer. METHODS: A total of 137 patients with breast cancer who underwent four cycles of adjuvant chemotherapy with docetaxel and cyclophosphamide (TC) combination therapy or docetaxel alone were assessed for oral hygiene by quantifying the number of oral bacteria they harbored. These patients received professional oral health care (POHC). Eighteen patients underwent primary prophylaxis with granulocyte colony-stimulating factors. The relationship between oral bacteria count and FN incidence was retrospectively assessed. RESULTS: The FN incidence rate was 47.4% throughout all treatment cycles (32.8%, 13.5%, 14.3%, and 14.4% in cycles 1, 2, 3, and 4, respectively). The oral bacteria count decreased with each treatment cycle (cycle 1: 9.10 × 106 colony-forming units (CFU)/mL, cycle 2: 5.89 × 106 CFU/mL, cycle 3: 4.61 × 106 CFU/mL, cycle 4: 5.85 × 106 CFU/mL, P = 0.004). Among 281 treatment cycles, FN occurred in 63 (22.4%). In the treatment cycle-based analysis, high oral bacteria count was an independent risk factor for FN. CONCLUSION: FN incidence decreased with each treatment cycle and was associated with changes in oral bacteria counts. The oral bacterial count was one of risk factors for FN development in breast cancer.

Lignocellulose molecular assembly and deconstruction properties of lignin-altered rice mutants.

Bioengineering approaches to modify lignin content and structure in plant cell walls have shown promise for facilitating biochemical conversions of lignocellulosic biomass into valuable chemicals. Despite numerous research efforts, however, the effect of altered lignin chemistry on the supramolecular assembly of lignocellulose and consequently its deconstruction in lignin-modified transgenic and mutant plants is not fully understood. In this study, we aimed to close this gap by analyzing lignin-modified rice (Oryza sativa L.) mutants deficient in 5-HYDROXYCONIFERALDEHYDE O-METHYLTRANSFERASE (CAldOMT) and CINNAMYL ALCOHOL DEHYDROGENASE (CAD). A set of rice mutants harboring knockout mutations in either or both OsCAldOMT1 and OsCAD2 was generated in part by genome editing and subjected to comparative cell wall chemical and supramolecular structure analyses. In line with the proposed functions of CAldOMT and CAD in grass lignin biosynthesis, OsCAldOMT1-deficient mutant lines produced altered lignins depleted of syringyl and tricin units and incorporating noncanonical 5-hydroxyguaiacyl units, whereas OsCAD2-deficient mutant lines produced lignins incorporating noncanonical hydroxycinnamaldehyde-derived units. All tested OsCAldOMT1- and OsCAD2-deficient mutants, especially OsCAldOMT1-deficient lines, displayed enhanced cell wall saccharification efficiency. Solid-state nuclear magnetic resonance (NMR) and X-ray diffraction analyses of rice cell walls revealed that both OsCAldOMT1- and OsCAD2 deficiencies contributed to the disruptions of the cellulose crystalline network. Further, OsCAldOMT1 deficiency contributed to the increase of the cellulose molecular mobility more prominently than OsCAD2 deficiency, resulting in apparently more loosened lignocellulose molecular assembly. Such alterations in cell wall chemical and supramolecular structures may in part account for the variations of saccharification performance of the OsCAldOMT1- and OsCAD2-deficient rice mutants.

Effect of Secondary Prophylactic G-CSF on the Occurrence of Febrile Neutropenia in Breast Cancer.

BACKGROUND/AIM: Docetaxel and cyclophosphamide (TC) combination therapy is widely used as adjuvant chemotherapy for early-stage breast cancer and is associated with a high incidence of febrile neutropenia (FN). Granulocyte colony-stimulating factor (G-CSF) is recommended in the primary prevention of febrile neutropenia (FN). This study aimed to evaluate the FN-suppressing effect of G-CSF in patients with breast cancer receiving TC. PATIENTS AND METHODS: We performed 272 treatment cycles after FN onset in 106 patients with breast cancer receiving TC. We retrospectively evaluated the effect of G-CSF as secondary prophylaxis. The frequency of FN was calculated based on the treatment cycles to adjust for differences in the number of cycles per case and FN occurrence. RESULTS: FN occurred in 58 cycles (21.3%). The incidence of FN with and without secondary prophylactic G-CSF was 10.1% and 25.9%, respectively (p=0.003). Multivariate analysis showed secondary prophylactic G-CSF administration to be an independent predictor of FN incidence [odds ratio (OR)=0.33, 95% confidence interval (CI)=0.14-0.74, p=0.007]. CONCLUSION: Secondary prophylaxis with G-CSF is recommended for patients with breast cancer undergoing TC chemotherapy to reduce the incidence of FN.

[Two Cases of Therapy-Related Myeloid Neoplasms after Docetaxel with Cyclophosphamide Therapy for Breast Cancer].

Docetaxel with cyclophosphamide(TC)is used as a perioperative chemotherapy. Therapy-related myeloid neoplasms(t- MN)are a rare adverse event of TC therapy. We report 2 cases of t-MN after TC therapy for breast cancer. Case 1 involved a 72-year-old woman who received 4 courses of TC therapy and radiation therapy after surgery. Two years and eight months after surgery, she presented with night sweats, coughing, headaches, and a low-grade fever. Laboratory examination revealed leukocytosis, and a bone marrow aspiration biopsy confirmed acute myelogenous leukemia with myeloid morphology- related changes and secondary acute myelogenous leukemia. Case 2 involved a 71-year-old woman who received 4 courses of TC therapy and radiation therapy after surgery. Three years and six months after surgery, ultrasonography detected right cervical lymphadenopathy. Resection of the right cervical lymph nodes and bone marrow aspiration biopsy confirmed mixed-phenotype acute leukemia(MPAL). Both patients are currently being treated.

Point mutations that boost aromatic amino acid production and CO2 assimilation in plants.

Aromatic compounds having unusual stability provide high-value chemicals and considerable promise for carbon storage. Terrestrial plants can convert atmospheric CO2 into diverse and abundant aromatic compounds. However, it is unclear how plants control the shikimate pathway that connects the photosynthetic carbon fixation with the biosynthesis of aromatic amino acids, the major precursors of plant aromatic natural products. This study identified suppressor of tyra2 (sota) mutations that deregulate the first step in the plant shikimate pathway by alleviating multiple effector-mediated feedback regulation in Arabidopsis thaliana. The sota mutant plants showed hyperaccumulation of aromatic amino acids accompanied by up to a 30% increase in net CO2 assimilation. The identified mutations can be used to enhance plant-based, sustainable conversion of atmospheric CO2 to high-energy and high-value aromatic compounds.

A "Mammalian-like" Pycnodont Fish: Independent Acquisition of Thecodont Implantation, True Vertical Replacement, and Carnassial Dentitions in Carnivorous Mammals and a Peculiar Group of Pycnodont Fish.

Vertebrates developed tooth replacement over 400 million years ago. Then, 200 million years later, the combination of vertical tooth replacement with the thecodont implantation (teeth in bone sockets) appeared a key morphological innovation in mammalian evolution. However, we discovered that an extinct fish taxon, Serrasalmimus secans, showed the same innovation in the lineage Serrasalmimidae, which survived the end Cretaceous mass extinction event. The carnassial teeth are known in both mammals and pycnodont fish, but these teeth do not share the same tissues or developmental processes. Therefore, this serrasalmimid pycnodont fish might have independently acquired mammal-like tooth replacement and implantation, indicating that the fish and mammals convergently evolved the carnassial dental morphologies at about the same time, approximately 60 My ago, in separate ecosystems.

Conservation paleobiology on Minami-Daito Island, Okinawa, Japan: anthropogenic extinction of cave-dwelling bats on a tropical oceanic island.

BACKGROUND: With strong environmental and geographic filtration, vertebrates incapable of flying and swimming are often extirpated from island ecosystems. Minami-Daito Island is an oceanic island in Okinawa, Japan that harbors the Daito flying fox (Pteropus dasymallus daitoensis), a subspecies of the fruit bat and the only extant mammal endemic to the island. However, the skeleton of a cave-dwelling bat Rhinolophus sp. and fossil guano were briefly reported in a previous study. METHODS: Here, we present evidence for the anthropogenic extirpation of two species of cave-dwelling bats (Miniopterus sp. & Rhinolophus sp.) from Minami-Daito Island. Our goal is to reliably constrain the ages of the extirpated bat species by a multiproxy approach. Because skeletal materials did not preserve sufficient bone collagen for direct radiocarbon dating, we alternatively examined guano-like deposits based on SEM observation and Fourier-transform infrared spectroscopy (FTIR) along with stable carbon and nitrogen isotope analyses for possible indirect dating. We also examined stable carbon isotopes in bone apatite, assuming that an isotopic signal of C4 plants on the bat bones links to sugarcane plantation on the island based on the historical knowledge that early human settlers quickly replaced the island's native C3 forests with sugarcane (C4 perennial grass) plantation from 1900 onward. RESULTS: Our cave survey documents the remains of Miniopterus sp. from the island for the first time. Based on the unique taphonomic conditions (unpermineralized bones, disarticulated skeletons closely scattered without sediment cover, various degrees of calcite crystal growth around bones) and a radiocarbon age of a humic sample, we suggest that the maximum age constraint of Miniopterus sp. and Rhinolophus sp. is 4,640 calBP. Based on a series of analyses, we conclude that the guano-like deposits are composed not of bat guano but mainly of humic substances; however, a hydroxyapatite crust associated with bat-lying stalagmites may be derived from bat feces. Stable carbon isotope analysis of bone apatite revealed C4 signals in various degrees, confirming that small populations of cave-dwelling bats persisted on Minami-Daito Island after 1900. CONCLUSIONS: The results of this study indicate that these populations remained rather small and did not leave many generations and that the estimated ages can be bracketed from 4,640 calBP to the post-1900 (perhaps, until the 1950s). They likely faced a continuously high mortality risk due to severe anthropogenic stresses on the island, where most of the forests were turned into sugarcane plantations within a few decades in the early 20th century. A result of hearing surveys to local residents suggests the latest remnants most likely disappeared on the island concurrently with the introduction of chemical pesticides after World War II.

The TILs-US score on ultrasonography can predict the pathological response to neoadjuvant chemotherapy for human epidermal growth factor receptor 2-positive and triple-negative breast cancer.

BACKGROUND: The tumor-infiltrating lymphocyte (TIL)-ultrasonography (US) score determined through characteristic US findings has predictive performance of lymphocyte-predominant breast cancer (LPBC). This study aimed to investigate whether the TIL-US score before neoadjuvant chemotherapy (NAC) can predict the pathological complete response (pCR). METHODS: We evaluated patients with human epidermal growth factor receptor type 2 (HER2)-positive breast cancer (n = 55) and triple-negative breast cancer (TNBC) (n = 24) who underwent surgery after NAC from November 2012 to April 2019. Pre-NAC biopsy examination was performed to examine stromal TILs; the cutoff value for predicting pCR was defined as ≥50% stromal TILs. The TILs-US score was calculated from the pre-NAC US findings. Based on previous data, the cutoff value for predicting pCR was set at ≥4 points. RESULTS: Forty-six patients achieved pCR. The TIL-US score was significantly associated with the pCR rate (p = 0.003) but not the pre-NAC biopsy findings (p = 0.055). Multivariate logistic regression analysis revealed that a TILs-US score ≥4 and HER2 positivity were significant pCR predictors (odds ratio [OR] 3.69; p = 0.031; OR 8.74; p = 0.025). CONCLUSIONS: TILs-US scores can be used to evaluate the therapeutic effect of NAC, and may be used as a non-invasive, convenient, and an alternative method to assess stromal TILs in pre-treatment biopsies.

Four Patterns of Abnormal Ring-Like Uptakes on Dedicated Breast PET.

ABSTRACT: The high resolution of dedicated breast PET (dbPET) enables the visualization of small breast cancers and a heterogeneity of breast tumors. Some tumors present with a ring-like appearance, the central uptake defect possibly reflecting intratumoral fibrosis and necrosis, associated with high-grade malignancy, and a triple-negative subtype. However, a ring-like finding is not only found in high-grade breast cancers. We describe 4 representative patterns of ring-like uptakes on dbPET: high-grade invasive cancer, intracystic tumor, extended noninvasive carcinoma, and change after vacuum-assisted breast biopsy. Ring-like uptakes on dbPET should be evaluated in association with clinical information.

Deficiency in flavonoid biosynthesis genes CHS, CHI, and CHIL alters rice flavonoid and lignin profiles.

Lignin is a complex phenylpropanoid polymer deposited in the secondary cell walls of vascular plants. Unlike most gymnosperm and eudicot lignins that are generated via the polymerization of monolignols, grass lignins additionally incorporate the flavonoid tricin as a natural lignin monomer. The biosynthesis and functions of tricin-integrated lignin (tricin-lignin) in grass cell walls and its effects on the utility of grass biomass remain largely unknown. We herein report a comparative analysis of rice (Oryza sativa) mutants deficient in the early flavonoid biosynthetic genes encoding CHALCONE SYNTHASE (CHS), CHALCONE ISOMERASE (CHI), and CHI-LIKE (CHIL), with an emphasis on the analyses of disrupted tricin-lignin formation and the concurrent changes in lignin profiles and cell wall digestibility. All examined CHS-, CHI-, and CHIL-deficient rice mutants were largely depleted of extractable flavones, including tricin, and nearly devoid of tricin-lignin in the cell walls, supporting the crucial roles of CHS and CHI as committed enzymes and CHIL as a noncatalytic enhancer in the conserved biosynthetic pathway leading to flavone and tricin-lignin formation. In-depth cell wall structural analyses further indicated that lignin content and composition, including the monolignol-derived units, were differentially altered in the mutants. However, regardless of the extent of the lignin alterations, cell wall saccharification efficiencies of all tested rice mutants were similar to that of the wild-type controls. Together with earlier studies on other tricin-depleted grass mutant and transgenic plants, our results reflect the complexity in the metabolic consequences of tricin pathway perturbations and the relationships between lignin profiles and cell wall properties.

Factors Associated with Cancer-Related Pain Requiring High-Dose Opioid Use in Palliative Cancer Patients.

Background: There are no universal tools to predict the necessity of high-dose opioid use for cancer-related pain. Early recognition and interventions for intractable cancer pain could minimize the distress of palliative patients. Objective: We sought to identify the clinical factors associated with high-dose opioid use in advanced cancer patients to recognize palliative patients who would develop intractable cancer pain, as early as possible. Setting/Subjects: Among 385 in-hospital cancer patients from April 1, 2014 to July 31, 2019, who were referred to the palliative care team for cancer-related pain, clinical factors significantly correlated to high-dose opioid use were retrospectively analyzed. Measurements: We conducted a multiple logistic regression analysis to identify variables significantly related to high-dose opioid use (>120 mg/day oral morphine equivalent dose). Results: Independent factors of high-dose opioid use included younger age (odds ratio [OR] 0.965, 95% confidence interval [CI] 0.944-0.986, p = 0.001), respiratory cancers (OR 1.882, 95% CI 1.069-3.312, p < 0.001), and opioid switch (OR 2.869, 95% CI 1.497-5.497, p = 0.001). The percentage of correct classifications of the regression equation was 86.9%. Conclusions: Younger age, respiratory cancers, and opioid switch were related to high-dose opioid use. Our findings may help palliative caregivers to deal with intractable cancer pain in palliative patients, and thus relieve their distress.

Breast cancer detection by dedicated breast positron emission tomography according to the World Health Organization classification of breast tumors.

OBJECTIVE: Considering the difficulty in detecting primary breast cancers using whole-body positron emission tomography (WBPET) owing to its limited spatial resolution, we aimed to evaluate the detectability of breast cancer by ring-type dedicated breast PET (DbPET) on the World Health Organization (WHO) histological classification in comparison with WBPET. METHODS: A total of 938 patients with breast cancer underwent WBPET and ring-type DbPET, and 1021 lesions were histologically assessed based on the WHO classification of tumors of the breast. The findings of WBPET and DbPET were retrospectively evaluated and compared. RESULTS: The size-related sensitivity of DbPET was superior to that of WBPET for subcentimetric tumors (81.9% vs. 52.4%, P < 0.001). The histological distribution was as follows: 11 lobular carcinoma in situ, 158 ductal carcinoma in situ, 738 infiltrating duct carcinoma not otherwise specified (NOS), 12 lobular carcinoma NOS, 40 mucinous adenocarcinoma, 13 tubular carcinoma, 36 invasive breast carcinoma others, and 13 papillary neoplasms. WBPET had low sensitivity for lobular carcinoma in situ, ductal carcinoma in situ, lobular carcinoma NOS, mucinous adenocarcinoma, and tubular carcinoma. DbPET showed improved sensitivity for all the above except lobular and tubular carcinoma. The maximum standardized uptake values (SUVmax) of DbPET were significantly higher than those of WBPET for histological types, excluding lobular carcinoma in situ. The SUVmax of papillary neoplasms was high regardless of low-grade histology and Ki-67 labeling index. CONCLUSIONS: DBPET was found to have high sensitivity and SUVmax values for all histologic types that showed low sensitivity of detection on WBPET, except lobular carcinoma in situ.

Febrile neutropenia and role of prophylactic granulocyte colony-stimulating factor in docetaxel and cyclophosphamide chemotherapy for breast cancer.

PURPOSE: Febrile neutropenia (FN) incidence during docetaxel and cyclophosphamide (TC) chemotherapy, known as a high-risk regimen, differs among countries. The role of prophylactic granulocyte colony-stimulating factor (G-CSF) in FN is unclear. This study aimed to investigate FN frequency and relative dose intensity (RDI) of TC chemotherapy in patients with breast cancer and identify the correct population requiring prophylactic G-CSF. METHODS: In total, 205 patients with breast cancer were scheduled for TC chemotherapy (docetaxel/cyclophosphamide 75/600 mg/m2, every 3 weeks, 4 cycles) as adjuvant chemotherapy. Trastuzumab (8 mg/kg; continued with 6 mg/kg) was administrated intravenously for human epidermal growth factor receptor 2 (HER2)-positive cancer. Fifty-five patients received primary prophylactic measures (G-CSF: 20 and antibiotics: 35). We investigated the frequency of FN and hospitalization, RDI, and the factors related to FN, adverse events, hospitalization, and RDI. RESULTS: FN occurred in 70 patients (35.7%). FN incidence was noted in 41.1% without any prophylactic measures and in 5.0% with prophylactic G-CSF. In multivariate analysis, the independent risk factors of FN were older age (≥ 60 years, P = 0.017) and without primary prophylactic G-CSF (P = 0.011). Eleven patients (5.6%) were hospitalized of which 8 (72.7%) were elderly. The median RDIs of docetaxel and cyclophosphamide were 96.7% and 99.7%, respectively. CONCLUSION: FN frequency during TC chemotherapy was high, and primary prophylactic G-CSF reduced FN incidence. Primary prophylactic G-CSF is an effective therapy for preventing FN during TC chemotherapy. However, prophylactic G-CSF should be considered for elderly patients based on the low hospitalization rate and the high RDI.

Tumor-infiltrating Lymphocyte Score Based on FDG PET/CT for Predicting the Effect of Neoadjuvant Chemotherapy in Breast Cancer.

AIM: To investigate whether tumor-infiltrating lymphocyte (TIL) scoring based on 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) can predict the pathological response to neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 261 patients with breast cancer underwent complete resection after neoadjuvant chemotherapy. PET-TIL score was calculated using tumor size, Ki-67 labeling index, and maximum standardized uptake value (SUVmax) on FDG PET/CT. The efficacy of the PET-TIL score in predicting the pathological complete response (pCR) was retrospectively evaluated. RESULTS: pCR rates were 11.4%, 58.6%, and 38.8% in luminal, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative breast cancer, respectively. The corresponding median PET-TIL scores were 28, 37, and 45. pCR rates were 20.0% and 44.2% in the low and high PET-TIL score groups, respectively (p<0.001). HER2-positive and triple-negative subtypes and high PET-TIL score were independent predictors for pCR. CONCLUSION: PET-TIL score can predict pCR after neoadjuvant chemotherapy in breast cancer.