Efficacy and safety of adapalene gel as a reactive treatment for cetuximab-induced skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck: A historical cohort comparison study.

INTRODUCTION: Despite the common occurrence of cetuximab (Cmab)-induced skin toxicity, management strategies are not well established. The traditional mainstay method consists of topical steroids, which, if used excessively, may give rise to other concerns. Alternatively, adapalene can activate epidermal growth factor receptor pathways to potentially alleviate these toxicities. METHODS: We prospectively studied 31 patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) who were eligible to use adapalene gel as a reactive treatment for topical steroid-refractory skin toxicity. For comparison, we retrospectively reviewed 99 patients with R/M SCCHN (historical control cohort) whose skin toxicity was mainly treated with topical steroids. We compared the frequency and severity of Cmab-induced skin toxicity, Cmab therapy status (e.g., dose modification), side effects caused by topical steroids and adapalene gel itself, and other medical interventions. RESULTS: Adapalene gel was used by eight patients (25.8%) in the prospective cohort. Patients in the historical control cohort more frequently required escalation of topical steroid potency (34.3% vs. 12.9%, p = 0.022). Although there was no statistically significant difference in the frequency of grade ≥3 facial skin rash and paronychia between the two cohorts, the prospective cohort showed a significantly shorter time to complete recovery from grade 2/3 paronychia (16 vs. 47 days, p = 0.017). Further, while no skin infections were observed in the prospective cohort, 13 patients in the historical control cohort developed skin infections, especially periungual infection (0% vs. 13.1%, p = 0.024). In addition, no patients in the prospective cohort received a dose reduction of Cmab due to skin toxicities, compared to 20 patients in the historical control cohort (0% vs. 20.2%, p = 0.003). No apparent adapalene gel-related side effects were observed. CONCLUSIONS: Adapalene gel may be an effective management option for topical steroid-refractory Cmab-induced skin toxicities and could improve compliance with Cmab therapy.

Clinical features of CDK4/6 inhibitor-related interstitial lung disease in patients with breast cancer: a case series study.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are the standard treatment for advanced hormone receptor-positive breast cancer. Although interstitial lung disease is a rare (1-3.3%) but serious adverse event associated with CDK4/6 inhibitors, the incidence of interstitial lung disease in Japanese patients in the real world and the risk factors of interstitial lung disease are not clear. METHODS: We retrospectively investigated the incidence of interstitial lung disease in 224 patients with advanced breast cancer who received CDK4/6 inhibitors at our hospital between 31 January 2017 and 31 January 2021. The correlation of age (>50 vs ≤50 years), presence or absence of previous history of interstitial lung disease, lung metastasis, smoking history and chest radiation with the development of interstitial lung disease was evaluated. RESULTS: In total, 177 cases received palbociclib, 39 cases received abemaciclib and 8 cases received both palbociclib and abemaciclib, constituting a palbociclib group (n = 185) and an abemaciclib group (n = 47). At a median observation period of 607 days, 8.0% (18/224) cases (13 definite and 5 probable cases) had interstitial lung disease; 6.5% (12/185) of palbociclib-treated and 13% (6/47) of abemaciclib-treated cases. The median time to interstitial lung disease onset was 178 (range, 14-750) days. There was no significant correlation between the background factors studied and the development of interstitial lung disease. CONCLUSION: The frequency of CDK4/6 inhibitor-induced interstitial lung disease was higher than that reported in clinical trials. We did not identify any risk factors for the development of interstitial lung disease in this study, and thus, larger studies that include patient predisposition are required.

[Optimal safety management procedures for medications with potent teratogenic properties: a prospective intervention cluster randomized non-inferiority comparative study].

Using the "periodic confirmation sheet" employed in the safety management procedure of thalidomide drugs, we looked at whether patients' knowledge of compliance with the procedure varies depending on the length of the gap between confirmations. In 31 centers, 215 participants were male patients and female patients who might be pregnant participants. Subjects have treated a group of patients who used periodic confirmation slips at the standard confirmation interval and a group of patients who increase the confirmation interval to 4 or 6 months, the % of respondents that correctly answered each of all six questions in questions 1-6 on the second comprehension questionnaire, excluding question 7 to confirm behavior change, was 87.0%. Comparing the percentage of correct answers to all questions the first time and the second time, no pregnancy cases were observed and there was no decline in the percentage of accurate responses after the second attempt for either group. One cannot judge changes in behavior. The mixed-effect model also additionally demonstrated non-inferiority in the patient group with the extended confirmation interval (a difference of -6.7% in the proportion of correct answers on the comprehension test (95%CI: -20.3-7.0%)), thus it appears that going forward, both male patients and female patients of potential pregnancy should complete the periodic confirmation form once every 4 or 6 months.

Relevance of pharmacogenetic polymorphisms with response to docetaxel, cisplatin, and 5-fluorouracil chemotherapy in esophageal cancer.

PURPOSE: Docetaxel, cisplatin, and 5-fluorouracil (DCF) have high response rates, but severe neutropenia is frequently observed. The occurrence of neutropenia is associated with high histological response in solid tumors, and it might be associated with tumor shrinkage after DCF therapy. This study aimed to determine the genetic polymorphisms involved in the clinical response to preoperative DCF therapy in esophageal cancer patients. METHODS: We included 56 patients with measurable lesions who received preoperative DCF therapy for esophageal cancer. Twenty-one genetic polymorphisms were analyzed, and univariate logistic regression analysis was used to evaluate the association between genetic polymorphisms and tumor shrinkage. A multivariate logistic regression analysis adjusted for T category and tumor location and a univariate analysis for potential genetic factors with P values < 0.05 were performed to explore the predictive factors and to estimate odds ratios and their 95% confidence intervals. RESULTS: No patient achieved a complete response, whereas 20 patients achieved a partial response, 31 patients had stable disease, and 5 patients had progressive disease. Although no association was found between pharmacokinetic-related gene polymorphisms, XRCC3 rs17997944 was extracted as the only genetic factor that affected tumor shrinkage (P = 0.033) by univariate analysis. The multivariate analysis adjusted for T category and tumor site also showed that XRCC3 rs1799794: AA was a predictive factor that affected tumor shrinkage (odds ratio, 0.243; 95% confidence interval, 0.065-0.914; P = 0.036). CONLUSIONS: XRCC3 rs1799794, which is involved in homologous recombination, is a genetic factor that affects clinical responses to DCF therapy.

Retrospective cohort study of nanoparticle albumin-bound paclitaxel plus ramucirumab versus paclitaxel plus ramucirumab as second-line treatment in patients with advanced gastric cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) has shown non-inferiority to paclitaxel (PTX) as second-line therapy for advanced gastric cancer (AGC) with fewer infusion-related reactions. The efficacy and safety of nab-PTX plus ramucirumab (RAM) was reported in a phase II trial; however, there is no randomized trial comparing this regimen with PTX plus RAM in patients with AGC. This retrospective study aimed to investigate the efficacy and safety of nab-PTX plus RAM versus PTX plus RAM in patients with AGC. METHODS: This study included patients with AGC who received nab-PTX plus RAM from September 2017 to January 2019 or PTX plus RAM from June 2015 to August 2017 as second-line chemotherapy in our hospital. RESULTS: A total of 113 and 138 patients who received nab-PTX plus RAM and PTX plus RAM, respectively, were analyzed. Median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]: 3.4-4.3) in the nab-PTX plus RAM group and 3.9 months (95% CI: 3.1-4.7) in the PTX plus RAM group (hazard ratio [HR]: 1.08; 95% CI: 0.83-1.40; P = 0.573). Median overall survival (OS) was 10.9 months (95% CI: 9.3-12.7) in the nab-PTX plus RAM group and 10.3 months (95% CI: 8.5-12.0) in the PTX plus RAM group (hazard ratio: 0.82; 95% CI: 0.61-1.10; P = 0.188). In patients with moderate/massive ascites, favorable outcomes for progression-free survival were observed in the nab-PTX plus RAM group compared with the PTX plus RAM group. Although anemia and fatigue (any grade) were more frequent in the nab-PTX plus RAM group, discontinuation of study treatment was not increased in the nab-PTX plus RAM group. There was no occurrence of hypersensitivity reaction in the nab-PTX plus RAM group, while two patients (1.4%) experienced grade 3 hypersensitivity reactions in the PTX plus RAM group. CONCLUSIONS: The combination of nab-PTX plus RAM showed a similar efficacy and safety profile to PTX plus RAM as second-line treatment for patients with AGC.

Clinical impact of renal impairment on the safety and efficacy of S-1 plus oxaliplatin in patients with advanced gastric cancer: a single institutional study.

BACKGROUNDS: S-1 plus oxaliplatin appears effective in chemo-naïve patients with advanced gastric cancer. However, comprehensive safety and efficacy data for S-1 plus oxaliplatin is limited for patients with impaired renal function. METHODS: We retrospectively extracted data from advanced gastric cancer patients with normal renal function (normal group, CLcr ≥ 60 ml/min), who were treated with standard doses of S-1 (80 mg/m2) plus oxaliplatin (100 mg/m2), and patients with impaired renal function (impaired group, CLcr < 60 ml/min) who were treated with standard or reduced doses of S-1 (60 mg/m2 or 40 mg/m2) plus standard doses of oxaliplatin. Treatment efficacy and safety between the groups were compared. RESULTS: Data from 100 normal patients and 42 patients with impaired renal function were extracted. Baseline characteristics differed significantly between the two groups, including age (median, 64 vs 72 years, P < 0.0001) and body surface area (median, 1.68 vs 1.51 m2, P < 0.0001). In the impaired group, 66.6% (28/42) started with a reduced dose. Within the impaired group, more patients had a reduced initial S-1 dose when CLcr <50 ml/min (77.3%). The median progression-free and overall survival between the normal and impaired groups was 6.1 vs 5.7 months (P = 0.698) and 16.1 vs 18.5 months (P = 0.638), respectively. CONCLUSIONS: S-1 plus oxaliplatin in advanced gastric cancer patients with impaired renal function appears safe and has demonstrated efficacy given appropriate dose modification.

Risk factors for febrile neutropenia in neoadjuvant docetaxel, cisplatin, and 5-fluorouracil chemotherapy for esophageal cancer.

PURPOSE: The aim of the present study was to evaluate the incidence and explore the risk factors of febrile neutropenia (FN) in patients with esophageal cancer receiving neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy in real-world settings. METHODS: We retrospectively reviewed clinical data of 128 consecutive patients with esophageal cancer. Specifically, these patients underwent neoadjuvant DCF chemotherapy with prophylactic antibiotic administration at our institution between July 2009 and January 2015. Two FN-related endpoints were set as follows: definite FN (dFN) defined as grade 4 neutropenia at the onset of fever and clinically suspected FN (csFN), which included both patients with dFN and patients without grade 4 neutropenia but with deteriorating grade 3 neutropenia at the onset of fever who were clinically diagnosed with FN for which they underwent treatment. The risk factors for dFN and csFN were evaluated based on patients' characteristics. RESULTS: A total of 72 (56.3%) patients developed grade 3 or grade 4 neutropenia and 26 (20.3%) developed csFN including 14 (10.9%) with dFN. Multivariate analysis revealed that older age (OR 3.57, CI 1.27-10.1, P = 0.016) and living alone (OR 5.17, 95% CI 1.26-21.3, P = 0.023) were statistically significant risk factors for csFN development. As to dFN, no statistically significant risk factors were identified. CONCLUSIONS: Older age and living alone are significant risk factors for developing FN, and thus, particularly for patients with risk factors for FN, G-CSF should be considered instead of prophylactic antibiotics with careful observation.

Topical steroid versus placebo for the prevention of radiation dermatitis in head and neck cancer patients receiving chemoradiotherapy: the study protocol of J-SUPPORT 1602 (TOPICS study), a randomized double-blinded phase 3 trial.

BACKGROUND: To date, the clinical benefit of topical steroid use has only been demonstrated for radiation dermatitis induced by 50-60 Gy irradiation in breast cancer. However, these agents are also often used clinically for the control of radiation dermatitis induced by high-dose (>60Gy) irradiation with chemotherapy in head and neck cancer. Despite this, the prophylactic efficacy of topical steroids for radiation dermatitis induced by high-dose irradiation is still unclear. The aim of this study is to clarify the benefit of topical steroids in basic nursing care for radiation dermatitis induced by chemoradiotherapy in patients with head and neck cancer. METHODS: The study is being conducted as a multicenter 2-arm randomized double-blinded placebo-controlled Phase 3 trial in Japan. The study was started in May 2017, with participant enrollment between May 2017 and April 2019. Patients scheduled to receive definitive or postoperative chemoradiotherapy for head and neck cancer are eligible for enrollment. All patients will receive chemoradiotherapy, consisting of single agent CDDP and 70-Gy irradiation. Bilateral neck irradiation is mandatory. Supportive care for radiation dermatitis will consist of basic nursing care with topical steroid or placebo. When radiation dermatitis grade 1 is seen or total radiation dose reaches 30 Gy, minimally required intervention will be started as a first step. If radiation dermatitis worsens to grade 2, the irradiated area will be covered with a moderately absorbent surgical pad and steroid or placebo topical cream. The primary endpoint is a comparison of the proportion of patients with ≥ grade 2 radiation dermatitis by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Ethical approval has been obtained from all participating sites. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences. DISCUSSION: Evidence supporting the benefit of adding topical steroids in general nursing care for radiation dermatitis induced by high-dose irradiation with chemotherapy is insufficient. This trial aims to clarify the clinical benefit of topical steroid for radiation dermatitis induced by high-dose irradiation with chemotherapy. The trial is ongoing and is currently recruiting. TRIAL REGISTRATION NUMBER: UMIN000027161 . Protocol version 3.0, 18 April 2017.

Impact of lenvatinib-induced proteinuria and renal dysfunction in patients with thyroid cancer.

Background: Proteinuria is the most frequent adverse event of lenvatinib use. However, the association between lenvatinib-induced proteinuria and renal dysfunction remains unclear. Methods: We retrospectively reviewed medical records of patients with thyroid cancer without proteinuria treated with lenvatinib as a first-line systemic therapy at the initiation of treatment to assess the association between lenvatinib-induced proteinuria and renal function and the risk factors for the development of ≥3+ proteinuria on a dipstick test. Proteinuria was assessed by the dipstick test throughout the treatment in all cases. Results: Of the 76 patients, 39 developed ≤2+ proteinuria (low proteinuria group) and 37 developed ≥3+ proteinuria (high proteinuria group). There was no significant difference in estimated glomerular filtration rate (eGFR) between high and low proteinuria groups at each time point, but there was a trend toward a significant decrease in eGFR of -9.3 ml/min/1.73 m2 in all patients after 2 years of treatment. The percentage of change in eGFR (ΔeGFR) significantly decreased in the high proteinuria group compared to that in the low proteinuria group (ΔeGFR: -6.8% vs. -17.2%, p=0.04). However, there was no significant difference in development of severe renal dysfunction with eGFR <30 ml/min/1.73 m2 between the two groups. Moreover, no patients permanently discontinued treatment because of renal dysfunction in both groups. Furthermore, renal function after completion of lenvatinib was reversible. Conclusions: There was no association between the degree of lenvatinib-induced proteinuria and renal function. Therefore, treatment should be continued with attention to renal function, regardless of the degree of proteinuria.

A Case Series on Pain Accompanying Photoimmunotherapy for Head and Neck Cancer.

One of the most severe side effects of photoimmunotherapy (PIT) for head and neck cancer is pain. As there are presently no detailed reports on pain and pain management in PIT, we conducted a retrospective case series study. We conducted a retrospective study of five patients who had received PIT at the National Cancer Center Hospital East between January 2021 and June 2022 using medical chart data. All patients experienced pain, evidenced by an increased numerical rating scale (NRS) after PIT, regardless of the illumination method. The daily change in mean NRS rating shows that the pain was highest on the day of PIT, with ratings of 6.8 and 7.8 for the frontal and cylindrical diffuser methods, respectively; it dropped the following day quickly. Four of the five patients received fentanyl injections for postoperative pain management beginning on postoperative day (POD) 0. All patients who underwent therapy using a cylindrical diffuser required postoperative pain management with opioid drugs. Pain after PIT tended to be most intense immediately after or one hour after illumination and declined the following day, suggesting the need to have a pain relief plan in place in advance.

Association between baseline blood pressure and the incidence of lenvatinib-induced hypertension in patients with thyroid cancer.

BACKGROUND: Hypertension is the most frequently occurring adverse event of lenvatinib, recognized relatively early in its course. However, the trend in blood pressure after the initiation of lenvatinib and the outcomes with antihypertensive treatment are unclear. This study aimed to clarify the association between baseline blood pressure and the incidence of lenvatinib-induced hypertension in patients with thyroid cancer. METHODS: This retrospective study included 65 patients without hypertension at the time of lenvatinib initiation. Patients were divided into two groups: those who developed hypertension grade ≥3 (HTN group) and those who did not develop hypertension grade ≥3 (non-HTN group). RESULTS: Of the 65 patients, 46 (71%) developed hypertension grade ≥3. In both HTN and non-HTN groups, blood pressure significantly increased the day after lenvatinib initiation. There was no significant difference in the elevated values of both the changes in systolic blood pressure (ΔSBP) and diastolic blood pressure (ΔDBP) between the two groups, with an average increase of 20 mmHg in SBP and 13 mmHg in DBP from baseline. The median (range) time to the onset of hypertension grade ≥3 was 2 days (1-12 days). In the multivariable analysis, patients with normal (SBP 120-129 mmHg and/or DBP 80-84 mmHg) or high-normal baseline blood pressure (SBP 130-139 mmHg and/or DBP 85-89 mmHg) were at higher risk of developing hypertension grade ≥3 than those with optimal baseline blood pressure (SBP <120 mmHg and DBP <80 mmHg) (odds ratio [OR], 5.07; 95% confidential interval [CI] 1.09-23.54 and OR, 7.48; 95% CI, 1.67-33.51, respectively). CONCLUSIONS: Lenvatinib-induced hypertension appears the day after administration, and higher baseline blood pressure is a significant risk factor for developing hypertension grade ≥3. In cases of increased blood pressure with lenvatinib, early initiation of antihypertensives may prevent treatment interruption due to hypertension and maintain the therapeutic intensity of lenvatinib.

A pharmacist-led opioid de-escalation program after completion of chemoradiotherapy in locally advanced head and neck cancer.

Background: Persistent opioid use frequently leads to substantial negative impacts on quality of life, and as the outlook for numerous cancer types continues to improve, these complications become increasingly crucial. It is essential to acknowledge that extended or excessive opioid use may result in adverse effects in patients who completed radiation therapy (RT). Methods: In this time-series analysis, we compared the outcomes of patients who participated in the pharmacist-led opioid de-escalation (PLODE) program after completing concurrent radiotherapy (CRT) between June 2018 and February 2019 against patients who completed CRT between June 2017 and March 2018 and did not participate in the program. Results: Among 61 patients, 16 (26%) used opioids after completing CRT and participated in the PLODE program. Before starting the program, 93 patients completed CRT between June 2017 and March 2018 and 32 (34%) used opioids at CRT completion. These patients were deemed the control group. In the PLODE group, outpatient pharmacist intervention was performed, with 29 total interventions related to opioid use, of which 16 (55%) recommended tapering or discontinuing opioids according to the definition of this program. Patients who participated in the PLODE program discontinued opioids significantly earlier than those in the control group (median time to opioid discontinuation 11 days vs. 24.5 days, p < 0.001). None of the patients in the PLODE group resumed opioid use following discontinuation or escalated opioid dosing due to worsening pain. Conclusion: This study showed the utility of pharmacist-initiated interventions for opioid use in patients with head and neck cancer who had completed CRT.

Clinical and biomarker factors affecting survival in patients with platinum-sensitive relapsed ovarian cancer receiving olaparib monotherapy: a multicenter retrospective study.

The standard treatment for platinum-sensitive relapsed ovarian cancer (PSROC) is platinum-based chemotherapy followed by olaparib monotherapy. A retrospective study was conducted to identify factors affecting the survival of patients with PSROC undergoing olaparib monotherapy in real-world clinical settings. The study enrolled 122 patients who received olaparib monotherapy between April 2018 and December 2020 at three national centers in Japan. The study used the Kaplan-Meier method and univariable and multivariable Cox proportional hazards models to evaluate the associations between factors and progression-free survival (PFS). Patients with BRCA1/2 mutations had a significantly longer median PFS than those without these mutations. Both the BRCA1/2 mutation-positive and mutation-negative groups exhibited a prolonged PFS when the platinum-free interval (PFI) was ≥ 12 months. Cancer antigen 125 (CA-125) level within reference values was significantly linked to prolonged PFS, while a high platelet-to-lymphocyte ratio (≥ 210) was significantly associated with poor PFS in the BRCA1/2 mutation-negative group. The study suggests that a PFI of ≥ 12 months may predict survival after olaparib monotherapy in patients with PSROC, regardless of their BRCA1/2 mutation status. Additionally, a CA-125 level within reference values may be associated with extended survival in patients without BRCA1/2 mutations. A larger prospective study should confirm these findings.

Cancer-Chemotherapy-Related Regimen Checks Performed by Pharmacists of General Hospitals Other than Cancer Treatment Collaborative Base Hospitals: A Multicenter, Prospective Survey.

Although prescription review is an important role for pharmacists in anticancer drug therapy, there are no guidelines in Japan that specify what pharmacists should check for in chemotherapy regimens. This prospective multicenter survey aimed to investigate the implementation of chemotherapy regimen checks by pharmacists in general hospitals by focusing on 19 recommended confirmation items designed to enhance chemotherapy safety. This study involved 14 hospitals within the National Hospital Organization in different regions of Japan. The top five cancers in Japan (gastric, colorectal, lung, breast, and gynecological) were targeted and specific chemotherapy regimens were analyzed. This study assessed the amount of time required for regimen checks, the number of confirmation items completed, the number and the content of inquiries raised regarding prescriptions, and the pharmacists' opinions using a questionnaire that had a maximum score of 10 points. Pharmacists checked 345 and 375 chemotherapies of patients in the control group (CG) and recommended items group (RIG), respectively. The mean time periods required for completing a chemotherapy regimen check were 4 min and 14 s (SD ±1 min and 50 s) and 6 min and 18 s (SD, ±1 min and 7 s) in the CG and RIG, respectively. The mean of the recommended items for the CG = 12.4 and for the RIG = 18.6. The items that the pharmacists did not confirm included urine protein (sixty-nine cases, 18.4%), allergy history (four cases, 1%), previous history (two cases, 0.5%), and a previous history of hepatitis B virus (sixty-nine cases, 18.4%). The number of inquiries for a doctor's prescription order was higher in the RIG than in the CG (41 vs. 27 cases). This multicenter survey demonstrated the potential effectiveness of implementing 19 recommended confirmation items in the regimen checks by pharmacists in general hospitals other than cancer treatment collaborative base hospitals.

The impact of the COVID-19 pandemic on perioperative chemotherapy for breast cancer.

BACKGROUND: Since it was first reported in December 2019, coronavirus disease 2019 (COVID-19) spread rapidly across the globe resulting in a pandemic. As of August 2022, seven outbreak peaks have been confirmed in Tokyo, and the numbers of new cases in the fifth and later outbreak periods have been far greater than in the preceding periods. This retrospective study examined the impact of the COVID-19 pandemic on perioperative chemotherapy for breast cancer. METHODS: Patients with breast cancer who received perioperative chemotherapy at the National Cancer Center Hospital East were divided into 2 groups: 120 and 384 patients who started chemotherapy before and during the pandemic, respectively. The incidence of critical events that had potential detrimental effects on the prognosis, such as start of adjuvant chemotherapy ≥91 days after surgery and relative dose intensity of chemotherapy <85% were compared between groups. RESULTS: No significant difference in the incidence of critical events was found. When stratified by outbreak period, the incidence of critical events was positively correlated with the increasing number of new cases of COVID-19 (r = 0.83, p = 0.04). Moreover, 25/173 patients (14%) who started perioperative chemotherapy during the fifth and sixth outbreak periods developed COVID-19 infection, 80% of whom (20/25) had a delay or interruption to their surgery or other perioperative treatments. CONCLUSIONS: Although the impact of the COVID-19 pandemic on perioperative chemotherapy on whole groups of patients was not evident when comparing periods before and after the pandemic, the impact is becoming prominent in parallel with increasing numbers of new COVID-19 cases.

Interleukin 6/gp130 axis promotes neural invasion in pancreatic cancer.

BACKGROUND: Nerve invasion (N-inv) is an important prognostic factor in pancreatic ductal adenocarcinoma (PDAC). Elucidation of circulating N-inv stimulators could provide deeper insights and novel perspectives for PDAC therapy. The interleukin (IL)-6/gp130 axis was evaluated in this study as a candidate N-inv stimulator. METHODS: A human pancreatic cancer (PC) cell, Capan-1, was confirmed to have the stimulant activity of IL-6/gp130 axis through the evaluation of mRNA, cell surface protein and intracellular protein levels and chemotaxis and wound healing assay. The upregulation of IL-6/gp130 axis was evaluated using tumor-derived IL-6 level and intratumoral pSTAT3 expression in N-inv of murine sciatic nerves by intraneural injection of Capan-1 cell (N-inv model) and using resected pancreatic cancer tissue and clinical data from 46 PDAC patients. RESULTS: mRNA and protein expressions of IL-6 and IL-6 receptor were found in whole cell lysate and condition medium from PC cell. Cell surface protein expression of gp130 were clearly detected on PC cell. IL-6 promoted migration and chemotaxis of PC cell. Serum IL-6 and tumoral IL-6 mRNA levels in N-inv model mice were significantly higher than those in subcutaneous tumor mice (p = 0.004 and p = 0.002, respectively). Silencing of IL-6 and gp130 on PC cell and administration of an anti-IL-6 receptor antibody, tocilizumab, suppressed N-inv, compared to each control (p = 0.070, p = 0.118 and p = 0.122, respectively). In PDAC patients, the high-N-inv group showed poor prognosis (p =0.059) and elevated serum levels of IL-6 and C-reactive protein, synthesis of which is promoted by IL-6, compared to those in the low-N-inv group (p = 0.006 and p = 0.075, respectively). Tumoral gp130 expression at N-inv was higher than that in the primary pancreatic tumor (p = 0.026). CONCLUSION: Biological activity of IL-6/gp130 axis promoted N-inv in murine model and was upregulated in PDAC patients with severe N-inv. This study is the first evidence that the IL-6/gp130 axis offers a potential therapeutic target in PDAC with N-inv.

Impact of Older Age and Medico-social Factors on the Decision to Offer Adjuvant Chemotherapy to Patients With Breast Cancer.

BACKGROUND/AIM: Although clinicians are expected to set a higher threshold for administering adjuvant chemotherapy to older than younger patients with breast cancer, the extent to which older patients are less likely to be offered adjuvant chemotherapy and the medico-social factors that influence decision-making are unclear. PATIENTS AND METHODS: We retrospectively evaluated the correlations of clinicopathological factors, including age (≥75 years vs. <75 years), for all candidates for adjuvant chemotherapy, and of additional medico-social factors, including the number of family members living together, for older patients, with the rate of referral from breast surgeons to medical oncologists. RESULTS: Among 872 candidates for adjuvant chemotherapy, age ≥75 years was significantly correlated with a lower referral rate (24 % vs. 44%, p<0.001). In the analysis by age group, we did not identify specific medicosocial factors that were differentially emphasized, but older patients who lived with ≥2 other family members tended not to be referred to a medical oncologist compared to those who lived alone or with one family member (1/23 vs. 15/47). Although 5 of 22 older patients (23%) who were referred to a medical oncologist actually received adjuvant chemotherapy (vs. 60% of younger patients), all needed treatment modifications. CONCLUSION: Breast surgeons regard age ≥75 years as a key factor for avoiding adjuvant chemotherapy but they also consider similar medico-social factors irrespective of the patient's age regarding the decision to refer patients to medical oncologists.

Patient-associated risk factors for severe anemia in patients with advanced ovarian or breast cancer receiving olaparib monotherapy: A multicenter retrospective study.

Background: Olaparib-induced anemia is a frequently occurring complication in patients with advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and is associated with a marked deterioration in patients' health-related quality of life. This study aimed to clarify patient-specific risk factors for severe anemia in patients with advanced ovarian or breast cancer receiving olaparib monotherapy in a real-world setting. Methods: This multicenter, retrospective, observational study enrolled consecutively presenting patients with advanced ovarian or breast cancer who received olaparib monotherapy as maintenance or palliative treatment between April 2018 and December 2020 at three participating medical institutions in Japan. The primary endpoint was patient-associated risk factors underlying the onset of grade ≥3 anemia from olaparib treatment initiation to 90 days after treatment. Receiver operating characteristic curves were constructed and univariable and multivariable logistic regression analyses were performed to evaluate the association between patient-associated risk factors and grade ≥3 anemia. Results: Of 113 patients evaluated in this study, 32.7% (n = 37) had grade ≥3 anemia. Multivariable logistic regression analysis revealed that low baseline red blood cell (RBC) count (<3.3 × 106 cells/µL), low baseline hematocrit level (<35%), low baseline hemoglobin level (<11.6 g/dL), and breast cancer susceptibility (BRCA1/2) mutation were significantly associated with the onset of grade ≥3 anemia (adjusted odds ratio [OR], 3.39; 95% confidence interval [CI], 1.28-9.62; P = 0.017, adjusted OR, 3.63; 95% CI, 1.28-11.64; P = 0.021, adjusted OR, 3.89; 95% CI, 1.39-12.21; P = 0.014, and adjusted OR, 4.09; 95% CI, 1.55-11.67; P = 0.006, respectively). Conclusions: Our findings suggest that low baseline RBC count, low baseline hematocrit level, and low baseline hemoglobin level might be the patient-associated risk factors for severe anemia induced by olaparib monotherapy. Additionally, BRCA1/2 mutation was suggested to be a patient-related risk factor for anemia regardless of severity. Therefore, applying these patient-associated risk factors would help classify and screen patients at risk of severe anemia.

Comprehensive Analysis of Chemotherapeutic Agents That Induce Infectious Neutropenia.

Chemotherapy-induced neutropenia (CIN) has been associated with a risk of infections and chemotherapy dose reductions and delays. The chemotherapy regimen remains one of the primary determinants of the risk of neutropenia, with some regimens being more myelotoxic than others. Although a number of clinical trials have currently highlighted the risk of CIN with each chemotherapy regimen, only a few ones have comprehensively examined the risk associated with all chemotherapeutic agents. Therefore, this study aimed to investigate the risk factors and characteristics of CIN caused by each neoplastic agent using data from the large voluntary reporting Food and Drug Administration Adverse Event Reporting System database. Initially, univariate analysis showed that an age ≥ 65 years, the female sex, and treatment with chemotherapeutic agents were factors that caused CIN. Then, cluster and component analyses showed that cytotoxic agents (i.e., alkylating agents, antimetabolic agents, antineoplastic antibiotics, platinating agents, and plant-derived alkaloids) were associated with infection following neutropenia. This comprehensive analysis comparing CIN risk suggests that elderly or underweight patients treated with cytotoxic drugs require particularly careful monitoring.

Evaluation of the Expression Profile of Irinotecan-Induced Diarrhea in Patients with Colorectal Cancer.

Irinotecan (CPT-11) is widely used for the treatment of unresectable colorectal cancer in combination with fluoropyrimidines, such as 5-fluorouracil and S-1. Diarrhea is one of the adverse effects associated with CPT-11 and frequently reported by patients treated with CPT-11-containing regimens combined with oral fluoropyrimidines. However, the mechanisms involved in this process, as well as whether fluctuations in the frequency and differences in the onset time of diarrhea with each CPT-11-containing regimen are caused by drug interactions remain unclear. Therefore, we examined the incidence of diarrhea caused by each CPT-11-containing regimen in patients with colorectal cancer using data from the large voluntary reporting Japanese Adverse Drug Event Report (JADER) database. Firstly, we searched for suspected drugs related to the occurrence of diarrhea using reported odds ratio and calculated the signal score to assess drug-drug interactions. Subsequently, we conducted a time-to-onset analysis using Weibull distribution. The results showed that the combination of CPT-11 with S-1 increased the frequency of diarrhea due to a pharmacological interaction but delayed its onset. The present results may contribute to the appropriate management of drug-induced adverse effects by healthcare professionals.