Neutralization against Omicron sublineages (BA.2/BA.5/BQ.1.1/XBB/XBB.1.5) in bivalent BNT162b2-vaccinated HCWs with or without risk factors, or following BT infection with Omicron.

SARS-CoV-2-BA.4/5-adapted-bivalent-BNT162b2-vaccine (bvBNT), developed in response to the recent emergence of immune-evasive Omicron-variants, has been given to individuals who completed at least 2-doses of the monovalent-BNT162b2-vaccine (mvBNT). In the present cohort study, we evaluated neutralization-titers (NT50s) against Wuhan-strain (SCoV2Wuhan) and Omicron-sublineages including BA.2/BA.5/BQ.1.1/XBB/XBB.1.5, and vaccine-elicited S1-binding-IgG in sera from participants-vaccinated with 5th-bvBNT following 4th-mvBNT. The 5th-bvBNT-dose elicited good protective-activity against SCoV2Wuhan with geometric-mean (gMean)-NT50 of 1966-2091, higher than the peak-values post-4th-mvBNT with no statistical significance, and favorable neutralization-activity against not only BA.5 but also BA.2, with ~ 3.2-/~ 2.2-fold greater gMean-NT50 compared to the peak-values post-4th-mvBNT-dose, in participants with or without risk factors. However, neutralization-activity of sera post-5th-bvBNT-dose was low against BQ.1.1/XBB/XBB.1.5. Interestingly, participants receiving bvBNT following breakthrough (BT) infection during Omicron-wave had significantly enhanced neutralization-activity against SCoV2Wuhan/BA.2/BA.5 with ~ 4.6-/~ 6.3-/~ 8.1-fold greater gMean-NT50, respectively, compared to uninfected participants receiving bvBNT. Sera from BT-infected-participants receiving bvBNT had enhanced neutralization-activity against BQ.1.1/XBB/XBB.1.5 by ~ 3.8-fold compared to those from the same participants post-4th-mvBNT-dose, and had enhanced gMean-NT50 ~ 5.4-fold greater compared to those of uninfected-participants' sera post-bvBNT. These results suggest that repeated stimulation brought about by exposure to BA.5's-Spike elicit favorable cross-neutralization-activity against various SARS-CoV-2-variants.

Multicenter, single-arm phase II study of modified carboplatin/nab-paclitaxel in untreated performance status 2 patients with advanced non-small cell lung cancer: TORG1426.

Background: Currently, only a few treatment options exist for performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC), whereas the carboplatin/nab-paclitaxel (CBDCA/nab-PTX) regimen is attracting attention as a standard of care for PS 0-1 patients because of its wide suitability and modest risk of peripheral neuropathy. However, the treatment dose and schedule should be optimized for PS 2 patients. Therefore, we planned a single-arm phase II study to characterize the efficacy and tolerability of our modified CBDCA/nab-PTX regimen for untreated PS 2 patients with advanced NSCLC. Methods: Enrolled patients were treated with CBDCA (area under the curve 5 on day 1) plus nab-PTX (70 mg/m2 on days 1, 8, and 15) every 4 weeks for up to six cycles. The primary endpoint was the progression-free survival (PFS) rate at 6 months. As exploratory analyses, the reasons for PS 2 (disease burden versus comorbidities/indeterminant) and the Charlson Comorbidity Index (CCI) were evaluated as efficacy indicators. Results: This study was terminated early because of slow accrual. Seventeen patients [median age, 68 years (range, 50-73 years)] received a median of three cycles. The 6-month PFS rate, median PFS, and median overall survival were 20.8% [95% confidence interval (CI): 0-41.6], 3.0 months (95% CI: 1.7-4.3), and 9.5 months (95% CI: 5.0-14.0), respectively. Exploratory analyses suggested better overall survival in patients whose PS was not attributable to the disease burden (median, 9.5 vs. 7.2 months) or whose CCI was ≤3 (median, 15.5 vs. 7.2 months). Grade 3-4 adverse events occurred in 12 (71%) patients, and grade 5 pleural infection occurred in one (6%) patient. Meanwhile, only one (6%) patient each experienced grade 1 peripheral neuropathy and grade 2 interstitial pneumonitis. Conclusions: No conclusion could be drawn from this study because of its early termination. However, our modified CBDCA/nab-PTX regimen might be useful for PS 2 patients who hesitate to use regimens other than nab-PTX, and particularly patients concerned about peripheral neuropathy or interstitial pneumonitis. The potential role of PS 2 and CCI as efficacy predictors for this regimen should be further examined.

Randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous, non-small cell lung cancer: TORG (thoracic oncology research group) 1321.

INTRODUCTION: Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non-squamous, non-small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient. METHODS: Eligibility criteria included: no prior chemotherapy; advanced, non-squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation-negative. Patients (N = 108) received induction chemotherapy with cisplatin, pemetrexed, and bevacizumab every 3 weeks for four cycles, and tumor response was needed to confirm four-week response duration. Patients with at least stable disease were randomized to pemetrexed/bevacizumab or pemetrexed alone. The primary endpoint was progression-free survival (PFS) after induction chemotherapy. Myeloid-derived suppressor cell (MDSC) counts of peripheral blood samples were also analyzed. RESULTS: Thirty-five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34-0.93], log-rank p = 0.023). In patients with partial response to induction therapy, median overall survival was 23.3 months in the pemetrexed alone group and 29.6 months in the pemetrexed/bevacizumab group (log-rank p = 0.077). Pretreatment monocytic (M)-MDSC counts tended to be greater in the pemetrexed/bevacizumab group with poor PFS than in those with good PFS (p = 0.0724). CONCLUSIONS: Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non-squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M-MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.

Left Stellate Ganglion Blockade for Refractory Ventricular Arrhythmias With Aconitine Poisoning: A Case Report.

Aconitine poisoning causes refractory ventricular arrhythmias (VAs). In a 20-year-old man, VAs of unknown etiology did not respond to drugs and electrical defibrillation. However, left stellate ganglion blockade (SGB) dramatically decreased arrhythmias without complications. At a later date, we found that refractory VAs were caused by aconitine poisoning. Left SGB is effective for treating refractory VAs with aconitine poisoning and can be easily performed with few complications for VAs of unknown etiology even if patients are receiving anticoagulant therapy. Also, left SGB can be performed to diagnose refractory VAs.

Predictors of central line-associated bloodstream infections in cancer patients undergoing chemotherapy through implanted venous access ports: a retrospective, observational study.

Background: Central venous catheters (CVCs) are sometimes superior to peripheral vascular access for chemotherapy. Central line-associated bloodstream infections (CLABSIs) are an important complication of CVCs in chemotherapy. Methods: A retrospective, observational study was conducted to investigate patients with implanted venous access ports (PORTs) from July 2010 to June 2021 in a teaching hospital. General conditions of the PORTs, backgrounds, and characteristics of patients were compared between CLABSI cases and uninfected cases to identify predictors of CLABSI. Results: A total of 566 patients with PORTs who underwent chemotherapy were enrolled in this study, with CLABSI identified in 41 patients, for a total of 436,597 catheter-days. The median duration of PORT use was 26 vs. 494 days (P<0.001) in the CLABSI and uninfected groups, respectively. There were no significant differences in tumor classification, staging, white blood cell (WBC) count, neutrophil proportion, lymphocyte proportion, albumin, C-reactive protein (CRP), and performance status between the CLABSI and uninfected groups. Multivariable analysis showed that antibiotic usage within the previous week, total protein (TP), and immediate PORT use were independently associated with CLABSI, and their odds ratios (ORs) were 4.89 [95% confidence interval (CI): 1.67, 14.35], 1.95 (95% CI: 1.14, 3.53), and 3.13 (95% CI: 1.18, 8.30), respectively. The area under the curve (AUC) of the receiver-operating characteristic curve for TP was 0.63, and the cutoff value was 5.9 g/dL. Conclusions: PORT implantation should be avoided in patients who had antibiotic treatment episodes within 1 week, especially for those with low serum TP levels.

Effect of Adjuvant and Palliative Chemotherapy in Large Cell Neuroendocrine Carcinoma of the Lung: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare subset of lung carcinoma with poor overall survival. METHODS: A systematic review following a meta-analysis of studies was performed to identify the effect of different selections of chemotherapy in LCNEC. Articles providing overall survival data for adjuvant chemotherapy or palliative chemotherapy for LCNEC were eligible. The odds ratio (OR) of mortality at one or two years after chemotherapy was evaluated. RESULTS: A total of 16 reports were finally included in the quantitative synthesis, involving a total of 5916 LCNEC patients. Adjuvant chemotherapy was administered to 1303 patients, and palliative chemotherapy was administered to 313 patients using either a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC) regimen. The OR for adjuvant chemotherapy was 0.73 (95% confidence interval (CI): 0.59 to 0.89, p = 0.002). The SCLC regimen showed an OR of 0.52 (95% CI: 0.11 to 2.38, p = 0.40) after one year, and 0.32 (95% CI: 0.11 to 0.89, p = 0.03) after two years, compared with the NSCLC regimen. CONCLUSIONS: Adjuvant chemotherapy for pulmonary large cell neuroendocrine carcinoma improved the outcome after surgery. The SCLC regimen showed better survival than the NSCLC regimen as palliative chemotherapy.

Correlates of neutralizing/SARS-CoV-2-S1-binding antibody response with adverse effects and immune kinetics in BNT162b2-vaccinated individuals.

While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 healthy individuals in Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions) with various determinants were examined and the potency of sera against variants of concerns was determined. Significant rise in NT50s was seen in sera on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation seen between NT50s and adverse effects. NT50s and SARS-CoV-2-S1-binding-IgG levels on day 28 post-1st dose and pain scores following the 2nd dose were greater in women than in men. The average half-life of NT50s was ~ 68 days, and 23.6% (49 out of 208 individuals) failed to show detectable neutralizing activity on day 150. While sera from elite-responders (NT50s > 1,500: the top 4% among the participants) potently to moderately blocked all variants of concerns examined, some sera with low NT50s failed to block the B.1.351-beta strain. Since BNT162b2-elicited immunity against SARS-CoV-2 is short, an additional vaccine or other protective measures are needed.

Effectiveness of Cell-Free and Concentrated Ascites Reinfusion Therapy in the Treatment of Malignancy-Related Ascites: A Systematic Review and Meta-Analysis.

BACKGROUND: Malignancy-related ascites (MRA) is one of the symptoms causing discomfort in advanced cancer patients. Cell-free and concentrated ascites reinfusion therapy (CART) is one of the palliative treatments widely conducted in Japan only. METHODS: A systematic review following a meta-analysis of CART was performed. The efficiency and adverse events were evaluated. RESULTS: A total of 2567 patients and 6013 procedures of CART were identified in this study. The mean volume of MRA collected was 4.29 (95% confidence interval (CI) 3.47-5.11) L, and the volume reinfused after concentrating was 0.49 (95% CI 0.39-0.60) L. A total of 86.1 (95% CI 77.1-95.2) g protein and 42.9 (95% CI 36.0-50.0) g albumin was reinfused. The mean time to the next paracentesis was 20.7 (95% CI 15.6-25.8) days. The body weight was reduced by 3.38 (95% CI 1.90-4.86; p < 0.01) kg, and abdominal circumference was reduced by 7.86 (95% CI 6.58-9.14; p < 0.001) cm. Serum albumin increased an average of 0.14 (95% CI -0.01-0.28; p = 0.07) mg/dL the day after CART. Abdominal distension, dyspnea, and fatigue were alleviated by 6.0 (95% CI 5.59-6.51), 2.66 (95% CI 2.05-3.28), and 2.64 (95% CI 1.86-3.42) points using a numerical rating scale system ranging from 0 to 10. Overall, 17% (95% CI 0.03-0.31%) of patients had improved performance status after CART. Significant body temperature elevation was observed, at an average of 0.4 °C (95% CI 0.18-0.62 °C). CONCLUSIONS: CART might be a safe and effective palliative therapy in MRA and further clinical trials are necessary.

Correlates of Neutralizing/SARS-CoV-2-S1-binding Antibody Response with Adverse Effects and Immune Kinetics in BNT162b2-Vaccinated Individuals.

BACKGROUND: While mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the features of immune response remain to be clarified. METHODS: In the present prospective observational study, 225 healthy individuals in Kumamoto General Hospital, Japan, who received two BNT162b2 doses in February 2021, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT 50 ; assessed using infectious virions and live target cells) with SARS-CoV-2-S1-binding-IgG and -IgM levels, adverse effects (AEs), ages, and genders were examined. The average half-life of neutralizing activity and the average time length for the loss of detectable neutralizing activity were determined and the potency of serums against variants of concerns was also determined. FINDINGS: Significant rise in NT 50 s was seen in serums on day 28 post-1st dose. A moderate inverse correlation was seen between NT 50 s and ages, but no correlation was seen between NT 50 s and AEs. NT 50 s and IgG levels on day 28 post-1st dose and pain scores following the 2nd shot were greater in women than in men. The average half-life of neutralizing activity in the vaccinees was approximately 67.8 days and the average time length for their serums to lose the detectable neutralizing activity was 198.3 days. While serums from elite-responders (NT 50 s>1,500-fold: the top 4% among all participants' NT 50 s) potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT 50 s failed to block the infectivity of a beta strain. INTERPRETATION: BNT162b2-elicited immune response has no significant association with AEs. BNT162b2-efficacy is likely diminished to under detection limit by 6-7 months post-1st shot. High-level neutralizing antibody-containing serums potently to moderately block the infection of SARS-CoV-2 variants; however, a few moderate-level neutralizing antibody-containing serums failed to do so. If BNT162b2-elicited immunity memory is short, an additional vaccine or other protective measures would be needed. RESEARCH IN CONTEXT: Evidence before this study: While mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the salient features of immune response including the persistence of protection remain to be clarified. There is a report that anti-SARS-CoV-2 antibodies persist through 6 months after the second dose of mRNA-1273 vaccine (Doria-Rose et al. N Engl J Med . 2021;384:2259-2261); however, more definite immune kinetics following mRNA-vaccine-elicited protection have to be clarified. The mRNA-vaccine-elicited protection against SARS-CoV-2 variants are also to be determined. Added value of this study: In the present prospective study, 225 twice-BNT162b2-dose-receiving individuals in Japan were enrolled. No significant correlation was seen between 50% neutralizing titers (NT 50 s), determined by using infectious SARS-CoV-2 virions and live target cells, and adverse effects. Largely, NT 50 s and IgG levels were greater in women than in men. Following 28 days post-2 nd shot, significant reduction was seen in NT 50 s, IgG, and IgM levels. The average half-life of NT 50 s was ∼68 days and the average time-length for participants' serums to lose the detectable activity was ∼198 days. Although serums from elite-responders potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT 50 s failed to block the infectivity of a beta strain. Implications of all the available evidence: BNT162b2 efficacy is likely to be diminished to under detection limit by 6-7 months post-1 st shot on average. Individuals with moderate NT 50 s may fail to block beta variants. If BNT162b2-elicited immune memory is lost soon, additional vaccine(s) or other protective means would be needed.

Pretreatment neutrophil-to-lymphocyte ratio predicts treatment efficacy and prognosis of cytotoxic anticancer drugs, molecular targeted drugs, and immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has recently attracted attention as a prognostic predictor in patients with non-small cell lung cancer (NSCLC) who receive immune checkpoint inhibitors (ICIs). However, the utility of NLR in relation to cytotoxic anticancer drugs or molecular targeted drugs remains unclear. We determined if NLR could predict the treatment efficacy and prognosis in NSCLC patients who receive cytotoxic anticancer drugs or molecular targeted drugs, as well as ICIs, in a cross-sectional manner. METHODS: Of 658 patients with advanced NSCLC who received first-line systemic treatment in our hospital between 2008 and 2019, 312 who met the analytical criteria were included in the study. We retrospectively analyzed the ability of NLR with a cut-off value of 5 to predict time to treatment failure (TTF) and overall survival (OS) in patients who received the following treatments: first-line treatment with molecular targeted drugs (mt group, n=100); first-line treatment with cytotoxic anticancer drugs (wt group, n=212); and first-line treatment with cytotoxic anticancer drugs followed by ICIs (ICI group, n=58). RESULTS: In the high- and low-NLR mt subgroups, median TTFs were 6.7 and 14.9 months (P<0.01), respectively, and median survival times (MSTs) were 17.8 and 39.1 months (P<0.01), respectively. In the high- and low-NLR wt subgroups, median TTFs were 1.5 and 5.8 months (P<0.01), and MSTs were 6.3 and 20.7 months (P<0.01), respectively. In the high- and low-NLR ICI subgroups, median TTFs were 1.3 and 6.8 months (P<0.01), and MSTs were 9.2 and 25.8 months (P<0.01), respectively. Multivariate analysis identified NLR as a significant independent predictor of TTF [hazard ratio (HR) 1.89, P=0.01; HR 2.51, P<0.01; and HR 5.06, P<0.01 in the mt, wt, and ICI groups, respectively) and OS (HR 3.81, P<0.01; HR 2.59, P<0.01; and HR 2.48, P<0.01, respectively). CONCLUSIONS: This study showed that NLR might be a predictor of treatment efficacy and prognosis in advanced NSCLC patients who receive various systemic treatments. This finding of consistent applicability of NLR to a wide variety of systemic treatments is of great significance.

Importance and Difficulty of Differentiating BMA-induced AFF Prodromal Symptoms from Hormonal Therapy-related Femoral Pain.

We herein report a case of breast cancer in a 74-year-old woman treated with exemestane as fourth-line hormonal therapy and bone-modifying agents for long time. She suddenly developed a right femoral shaft fracture during treatment. Her femoral fracture had a beaking sign on radiogram. Given this finding, her fracture was ultimately diagnosed as atypical femoral fracture (AFF). In this case, it was difficult to recognize the difference between groin pain as a prodromal symptom of AFF and that due to an adverse reaction to hormonal therapy. Therefore, clinicians should recognize the difficulty of this differentiation and consider the situation with caution.

Successful Treatment with Taxane-Based Chemotherapy in Advanced Sebaceous Carcinoma: A Case Report and Literature Review.

For sebaceous carcinoma (SC), a rare malignant tumor, no standard chemotherapy regimen for patients with distant metastasis has been studied. We experienced a case of eyelid SC with multiple lung metastases that responded to combination chemotherapy with carboplatin and paclitaxel with 11-month progression-free survival (PFS). This patient also responded to second-line treatment with docetaxel, another taxane, with 7-month PFS, resulting in at least 18 months of survival at the time of reporting. This report shows that taxane-based chemotherapy may be effective for advanced SC, for which no standard therapy has been established.

Significance of Earlier Initiation of Chemotherapy for Lung Cancer Complicated with Primary or Secondary Nephrotic Syndrome following Its Appropriate Differential Diagnosis.

We encountered a case of primary lung cancer complicated with membranous nephropathy as primary nephrotic syndrome. Because treatment approaches vary greatly for primary and secondary nephrotic syndrome, a renal biopsy was performed for diagnosis. Much time was required to make a definitive diagnosis of primary nephrotic syndrome, as opposed to paraneoplastic nephrotic syndrome. Consequently, the subsequent chemotherapy was ineffective and caused significant toxicity due to reduced performance status (PS) and progression of hypoalbuminemia. Therefore, it is imperative that a diagnosis be made and treatment be initiated without delay before PS declines and hypoalbuminemia progresses.

Need for Flexible Adjustment of the Treatment Schedule for Aprepitant Administration against Erlotinib-Induced Refractory Pruritus and Skin Rush.

Common dermatological side-effects associated with erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), include pruritus and skin rash, which are mediated by substance P, leading to the occasional discontinuation of cancer treatment. Aprepitant is an antagonist of neurokinin-1 receptor, through which substance P activates the pruritogens. Thus, aprepitant is expected to offer a promising option for the treatment of erlotinib-induced pruritus. However, the appropriate treatment schedule for aprepitant administration is under consideration. Here, we discuss the need for flexible adjustment of the treatment schedule for aprepitant administration against erlotinib-induced refractory pruritus and skin rush. A 71-year-old female smoker presented with stage IV EGFR-mutated lung adenocarcinoma. She was started on erlotinib at 150 mg/day. However, by 28 days, severe pruritus and acneiform skin rush resistant to standard therapies occurred, resulting in the interruption of erlotinib therapy. After recovery, she was restarted on erlotinib at 100 mg/day. However, severe pruritus and skin rush developed again within 2 weeks. Then, we started the first 3-day dose of aprepitant (125 mg on day 1, 80 mg on day 3, and 80 mg on day 5) based on the results of the previous prospective study, which showed the success rate of 100% with at least the second dose of aprepitant. However, the pruritus and skin rush exacerbated again within 4 weeks. Therefore, we started the second 3-day dose of aprepitant, but in vain. At this point, as the patient-centered medicine, bi-weekly schedule of the 3-day dose of aprepitant was considered and, then, adopted. As the results, the pruritus and skin rush remained well-controlled throughout the subsequent treatment with erlotinib.

Promising Combination Therapy with Bevacizumab and Erlotinib in an EGFR-Mutated NSCLC Patient with MET Amplification Who Showed Intrinsic Resistance to Initial EGFR-TKI Therapy.

In lung cancer, several potential mechanisms of intrinsic and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been explored, including mesenchymal-epithelial transition factor (MET) signaling pathway activation. On the other hand, vascular endothelial growth factor (VEGF) production of EGFR-mutated lung cancer cells is stimulated by predominantly activated MET signaling pathway. Therefore, the inhibition of VEGF axis as the downstream target of MET signaling pathway seems promising. Here, for the first time, we report the potential efficacy of combination therapy with bevacizumab and erlotinib in an EGFR-mutated NSCLC patient with MET amplification who showed intrinsic resistance to initial EGFR-TKI therapy. The patient was a 60-year-old male smoker, showing performance status (PS) 2, who presented with stage IV lung adenocarcinoma (cT4N2M1a) harboring the EGFR exon 19 deletion mutation. He was started on gefitinib at 250 mg/day. However, by 28 days, his symptoms further deteriorated along with the increased tumor size, resulting in PS 3. Then, repeat biopsy was performed, showing the positive MET amplification and the preserved EGFR exon 19 deletion mutation. Therefore, on the basis of the potential efficacy for activated MET signaling pathway as well as the confirmed safety by the known phase II trial for EGFR-mutated patients, the patient was started on combination therapy with bevacizumab at 15 mg/kg every 3 weeks plus erlotinib at 150 mg/day. By 21 days, his symptoms gradually improved along with the decreased tumor size, resulting in better PS with no severe toxicities.