Comparison of efficacy of gefitinib and osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer in patients with poor performance status.

BACKGROUND: There is a dearth of studies on the efficacy and safety of the tyrosine kinase inhibitors osimertinib (OSI) and gefitinib (GEF) in treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), even in patients with poor performance status (PS). METHODS: We retrospectively reviewed and compared data of 113 patients with EGFR mutation-positive NSCLC with Eastern Cooperative Oncology Group PS 2-4 who were administered OSI 80 mg/day or GEF 250 mg/day from May 2016 to March 2022. RESULTS: The GEF group (39 patients; median age: 74 years) included 20 patients with a PS of 2, 17 with a PS of 3, and 2 with a PS of 4. The OSI group (74 patients; median age: 76 years) included 48 patients with a PS of 2, 24 with a PS of 3, and 2 with a PS of 4. The overall response rates were 69% and 66% in the GEF and OSI groups, respectively. The disease control and PS improvement rates were 89% and 51% in both groups, respectively. The median progression-free survival in the GEF and OSI groups was 6.9 and 9.2 months, respectively (p = 0.15). The OSI group experienced better overall survival than the GEF group (median: 20.9 vs. 13.0 months, p = 0.0031). The incidence of pneumonitis was 10% and 11% in the GEF and OSI groups, respectively. One treatment-related death owing to pneumonitis occurred in the GEF group. CONCLUSIONS: OSI may be a useful treatment for untreated EGFR mutation-positive NSCLC with poor PS.

Efficacy and safety of dexamethasone sparing for the prevention of nausea and vomiting associated with moderately emetogenic chemotherapy: a systematic review and meta-analysis of Clinical Practice Guidelines for Antiemesis 2023 from Japan Society of Clinical Oncology.

BACKGROUND: Palonosetron, a second-generation 5-HT3 receptor antagonist (5-HT3RA), is more effective than first-generation 5-HT3RA. Several studies have investigated whether dexamethasone (DEX), when combined with palonosetron as a 5-HT3RA, can be spared in the delayed phase after moderately emetogenic chemotherapy (MEC). In this systematic review, we aimed to determine which between 1- and 3-day DEX administration, when combined with palonosetron, is more useful in patients receiving MEC. METHODS: The PubMed, Cochrane Library, and Ichushi-Web databases were searched for relevant studies published between 1990 and 2020. We included studies that compared the efficacy of 1- and 3-day DEX administration in preventing nausea and vomiting associated with MEC. Outcomes were "prevention of vomiting (complete response rate and no vomiting rate)," "prevention of nausea" (complete control rate, total control rate, no nausea rate, and no clinically significant nausea rate)" in the delayed phase, "prevention of blood glucose level elevation," and "prevention of osteoporosis." RESULTS: Eight studies were included in this systematic review. The no vomiting rate was significantly higher in the 3-day DEX group than in the 1-day DEX group. However, the other efficacy items did not significantly differ between the two groups. Meanwhile, insufficient evidence was obtained for "prevention of blood glucose level elevation" and "prevention of osteoporosis." CONCLUSIONS: No significant differences in most antiemetic effects were found between 1- and 3-day DEX administration. Thus, DEX administration could be shortened from 3 days to 1 day when used in combination with palonosetron.

The histone H3K9 methyltransferase G9a regulates tendon formation during development.

G9a is a histone methyltransferase that catalyzes the methylation of histone 3 lysine 9 (H3K9), which is involved in the regulation of gene expression. We had previously reported that G9a is expressed in developing tendons in vivo and in vitro and that G9a-deficient tenocytes show impaired proliferation and differentiation in vitro. In this study, we investigated the functions of G9a in tendon development in vivo by using G9a conditional knockout (G9a cKO) mice. We crossed Sox9Cre/+ mice with G9afl/fl mice to generate G9afl/fl; Sox9Cre/+ mice. The G9a cKO mice showed hypoplastic tendon formation at 3 weeks of age. Bromodeoxyuridine labeling on embryonic day 16.5 (E16.5) revealed decreased cell proliferation in the tenocytes of G9a cKO mice. Immunohistochemical analysis revealed decreased expression levels of G9a and its substrate, H3K9me2, in the vertebral tendons of G9a cKO mice. The tendon tissue of the vertebrae and limbs of G9a cKO mice showed reduced expression of a tendon marker, tenomodulin (Tnmd), and col1a1 genes, suggesting that tenocyte differentiation was suppressed. Overexpression of G9a resulted in enhancement of Tnmd and col1a1 expression in tenocytes in vitro. These results suggest that G9a regulates the proliferation and differentiation of tendon progenitor cells during tendon development. Thus, our results suggest that G9a plays an essential role in tendon development.

Efficacy and safety of dexamethasone sparing for the prevention of nausea and vomiting associated with highly emetogenic risk antineoplastic agents: a systematic review and meta-analysis of the Clinical Practice Guidelines for Antiemesis 2023 from the Japan Society of Clinical Oncology.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are common side effects, classified according to timing and severity. Conventional agents such as dexamethasone are effective but have various side effects. For moderately emetogenic chemotherapy, dexamethasone-sparing antiemetic therapies have been developed to minimize these side effects. This systematic review evaluated the efficacy and safety of dexamethasone-sparing antiemetic therapy for highly emetogenic chemotherapy (HEC). METHODS: We performed a thorough literature search for studies related to dexamethasone-sparing antiemetic therapy with neurokinin-1 antagonists (NK1RA) for HEC using the PubMed, Cochrane Library, and Ichushi-Web databases. A qualitative analysis of the combined data was performed and risk differences with confidence intervals were calculated. RESULTS: Two reviewers independently assessed the 425 records and 12 full-text articles were evaluated for eligibility. Two studies were included in the qualitative and meta-analyses. These studies included anthracycline-cyclophosphamide (AC) regimens and cisplatin-based regimens, with palonosetron as the serotonin receptor antagonist. In the two studies, no difference was found in the prevention of vomiting (delayed complete response). However, non-inferiority was not demonstrated in the subgroup that received cisplatin-containing regimens. Delayed complete control showed different results for nausea prevention; however, there was no significant difference in the meta-analysis. Only one report has shown non-inferiority for delayed total control. Although the strength of evidence for individual outcomes varied, there was no difference in the duration of dexamethasone administration. CONCLUSIONS: This systematic review and meta-analysis revealed that dexamethasone-sparing antiemetic therapy with NK1RA and palonosetron can be used to prevent CINV in HEC, limited to AC combination therapy.

The G9a histone methyltransferase represses osteoclastogenesis and bone resorption by regulating NFATc1 function.

Epigenetic modifications affect cell differentiation via transcriptional regulation. G9a/EHMT2 is an important epigenetic modifier that catalyzes the methylation of histone 3 lysine 9 (H3K9) and interacts with various nuclear proteins. In this study, we investigated the role of G9a in osteoclast differentiation. When we deleted G9a by infection of Cre-expressing adenovirus into bone marrow macrophages (BMMs) from G9afl/fl (Ehmt2fl/fl) and induced osteoclastic differentiation by the addition of macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), the number of TRAP-positive multinucleated osteoclasts significantly increased compared with control. Furthermore, the mRNA expression of osteoclast markers, TRAP, and cathepsin K, and to a lesser extent, NFATc1, a critical transcription factor, increased in G9a KO cells. Infection of wild-type (WT) G9a-expressing adenovirus in G9a KO cells restored the number of TRAP-positive multinucleated cells. In G9a KO cells, increased nuclear accumulation of NFATc1 protein and decreased H3K9me2 accumulation were observed. Furthermore, ChIP experiments revealed that NFATc1 binding to its target, Ctsk promoter, was enhanced by G9a deletion. For in vivo experiments, we created G9a conditional knock-out (cKO) mice by crossing G9afl/fl mice with Rank Cre/+ (Tnfrsf11aCre/+) mice, in which G9a is deleted in osteoclast lineage cells. The trabecular bone volume was significantly reduced in female G9a cKO mice. The serum concentration of the C-terminal telopeptide of type I collagen (CTX), a bone-resorbing indicator, was higher in G9a cKO mice. In addition, osteoclasts differentiated from G9a cKO BMMs exhibited greater bone-resorbing activity. Our findings suggest that G9a plays a repressive role in osteoclastogenesis by modulating NFATc1 function.

Lung squamous cell carcinoma responding to nivolumab retreatment six years after initial treatment: A case report.

A 61-year-old man presented to our hospital with a chief complaint of chronic cough. He was diagnosed with lung squamous cell carcinoma at clinical stage cT2aN3M1a. He received chemotherapy up to the fourth line, but both the primary tumor and lymph node metastases increased in size. Nivolumab, administered as the fifth line, resulted in a complete response (CR) that continued for 2 years and 8 months. Treatment was stopped due to the appearance of common terminology criteria for adverse events grade 1 pneumonitis. He was followed up without treatment for 3 years and 8 months, but a left supraclavicular fossa lymph node metastasis appeared. Retreatment with nivolumab was initiated, and the patient achieved CR again. One year and 6 months after retreatment, CR was maintained with nivolumab. This case represents a rare instance in which nivolumab yielded a significant response after a prolonged immune checkpoint inhibitor (ICI)-free interval. Our experience has shown that the long-term response to ICIs may deteriorate in the future. Therefore, retreatment with ICIs may be effective when the initial therapy is successful.

Multicenter Pharmacokinetic and Pharmacodynamic Study of Pembrolizumab for Non-small-Cell Lung Cancer in Patients Aged 75 Years and Older.

Pembrolizumab is a major treatment for recurrent or advanced non-small-cell lung cancer (NSCLC). However, data on its use and pharmacokinetics (PK) in older patients are limited. This open-label, multicenter, observational study evaluated real-world data on the safety, efficacy, and PK of pembrolizumab in older patients with NSCLC. In 99 patients aged ≥75 years, PK was determined by liquid chromatography-mass spectrometry on pretreatment samples. Performance status (PS), geriatric assessment (GA), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The median age was 78 (75-87) years. PS was 2-3 in 14 patients. The median ORR, PFS, and OS were 47.5%, 8.0, and 20.5 months, respectively. Although PK and ORR were not significantly associated, patients with the lowest Cycle 1-trough quartile (Q1) experienced poorer PFS (Q1 vs. Q2-4; 3.4 vs. 11.8 months, P = 0.006) and OS (Q1 vs. Q2-4; 9.9 vs. 21.7 months, P = 0.005) than in other quartiles overall, and even in the PD-L1 ≥50% subset (PFS, Q1 vs. Q2-4; 4.1 vs. 14.7 months, P = 0.005; OS, Q1 vs. Q2-4; 9.4 vs. 22.1 months, P = 0.010). The Q1 subgroup was characterized by poor PS and lower albumin, and more frequent "weight loss ≥ 10%" on the GA. Pembrolizumab therapy had similar PK and efficaciousness in older as well as younger patients. In patients with PS ≥2, low albumin, and vulnerable GA, early increases in PK levels are less likely, potentially diminishing efficacy even when PD-L1 ≥50%.

Real-World Data on Subsequent Therapy for First-Line Osimertinib-Induced Pneumonitis: Safety of EGFR-TKI Rechallenge (Osi-risk Study TORG-TG2101).

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis. PATIENTS AND METHODS: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020. RESULTS: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03). CONCLUSIONS: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge.

Primary lung cancer with pulmonary alveolar proteinosis treated with immune checkpoint inhibitor: A case report.

Primary lung cancer with pulmonary alveolar proteinosis (PAP) is a rare condition. We present a case of a patient with primary lung cancer with PAP treated with an immune checkpoint inhibitor (ICI). A 62-year-old man was diagnosed with autoimmune PAP 8 years prior to current admission. Lung adenocarcinoma was found in his right lung, and platinum-based chemotherapy was administered, followed by atezolizumab. He experienced disease progression after atezolizumab treatment, whereas ICI-induced pneumonia or exacerbation of PAP did not occur. This indicates that ICI may be safely used in patients with primary lung cancer with PAP.

Cytokine Release Syndrome More than Two Years after Pembrolizumab Introduction.

A 71-year-old man with advanced lung adenocarcinoma was treated with carboplatin, pemetrexed, and pembrolizumab in June 2020. Pemetrexed and pembrolizumab maintenance therapy were continued until November 2022. A fever and severe fatigue occurred in December 2022; however, the cause of the infection was inconclusive based on the patient's symptoms, imaging findings, and culture tests. Although the patient was administered antibiotics, his general condition worsened. Considering the possible diagnosis of immune-related cytokine release syndrome (CRS), the patient was administered prednisolone (1 mg/kg/day) and showed improvement. In conclusion, CRS can occur even long after the initial administration of immune checkpoint inhibitor therapy.

Epigenetic modifier G9a is involved in regulation of mouse tongue development.

OBJECTIVES: The tongue comprises multiple tissues of different embryonic origins, including pharyngeal arch, somite, and cranial neural crest (CNC). However, its developmental regulatory mechanisms, especially those involving epigenetic modifiers, remain poorly understood. This study examined the roles of the epigenetic modifier G9a in murine tongue development. METHODS: We deleted G9a using Sox 9 (SRY-related HMG-box gene 9)-Cre recombinase, which acts in tongue progenitor cells, including CNC-derived cells, to generate G9a conditional knockout (cKO) mice. Histochemical and immunohistochemical analyses were conducted on sections prepared from tongue tissues of control and cKO mice. RESULTS: Cre-dependent LacZ reporter mice, generated by crossing Rosa-LacZ mice with sox9-Cre mice, revealed Cre recombinase activity in the mucosal epithelium and tongue connective tissue of the embryonic tongue. Tongue volume was significantly reduced on embryonic day 17.5 (E17.5) and postnatal day 0 (P0) in cKO mice. Histological sections showed that the lingual mucosal epithelium was thinner in cKO mice. Reduced G9a levels were accompanied by decreased levels of a G9a substrate, dimethylated lysine 9 in histone H3, in the embryonic tongue. BrdU injection at E16.5 revealed reduced numbers of BrdU-positive cells in the mucosal epithelium and underlying connective tissue at E17.5 in cKO mice, indicating suppression of cell proliferation in both tissues. Investigation of keratin 5 and 8 protein localization showed significantly suppressed expression in the lingual mucosal epithelium in cKO mice. CONCLUSIONS: G9a is required for proper proliferation and differentiation of sox9-expressing tongue progenitor cells and is thereby involved in tongue development.

Prognosis of frail older patients treated with intubation and artificial ventilation for respiratory failure.

BACKGROUND: Older patients with severe respiratory failure have higher mortality rates and are more likely to experience impairments in activities of daily living (ADL). METHODS: We retrospectively reviewed patients (??75 years) who received intubation and artificial ventilation for respiratory failure at Shimane University Hospital between November 2014 and December 2020. We compared the outcomes of frail patients with those of self-sufficient patients. RESULTS: Thirty-two patients were included. ADL ability before respiratory failure was rated self-sufficient in 18 patients (self-sufficient group) and not self-sufficient in 14 patients (frail group). None of the patients in either group underwent advanced care planning prior to the onset of respiratory failure. In the self-sufficient and frail groups, the in-hospital mortality rates were 33% and 50%, and the incidence of bedridden patients at discharge was 6% and 43%, respectively. Most patients in the frail group (93%) died or were bedridden. The median hospitalization cost was JPY 2,984,000 for the self-sufficient group and JPY 3,008,000 for the frail group. CONCLUSION: The overall prognosis of frail older patients who underwent intubation and artificial ventilation was poor. When providing intensive care to such patients, it is important to carefully consider their suitability for the treatment. J. Med. Invest. 70 : 494-498, August, 2023.

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration-induced nephropathy.

AIMS: Long-term administration of pemetrexed (PEM) in patients with lung cancer can cause renal damage, leading to treatment discontinuation. Previous reports have suggested that specific single nucleotide polymorphisms (SNPs) in the folylpolyglutamate synthase (FPGS) gene affect therapeutic efficacy; however, whether the FPGS SNPs affect renal function is unclear. Identifying SNPs related to renal damage during PEM administration may help predict the decrease in renal function caused by PEM. METHODS: We retrospectively examined age, sex, body weight, total administered PEM, combined platinum, estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) levels before and after PEM administration in patients with non-small cell lung cancer and searched for the alleles of FPGS SNPs (rs1544105 and rs10106) using DNA extracted from whole blood samples of patients. RESULTS: Renal function decreased after PEM administration in 26 cases overall. The SCr and eGFR indices showed decreased renal function irrespective of concomitant cisplatin use. Based on promoter activity and miRNA binding predictions, rs1544105-C and rs10106-T were hypothesized to increase FPGS expression. Single SNP analyses showed no significant differences in renal function between groups with and without each SNP. Multiple regression analysis revealed that the most significant factors for decreased renal function were sex on SCr and the number of SNPs on eGFR. In subgroup analyses, the patients with rs10106-T showed a decline in renal function in the older group. CONCLUSIONS: The number of FPGS SNPs may contribute to PEM-induced renal impairment. Detecting FPGS SNPs may help predict PEM-induced renal damage.

A Retrospective Study of Pneumococcal Pneumonia in Hospitalized Patients Aged ≥65 Years in Izumo, Japan: 2010 to 2014.

Purpose: In Japan, both a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and a 13-valent pneumococcal conjugate vaccine (PCV13) are available. Although randomized controlled trials have examined the effects of pneumococcal vaccines, few epidemiological studies have investigated the onset of pneumococcal pneumonia in general practice. In Izumo, Shimane Prefecture, Japan, a public subsidy for PPSV23 inoculation began in November 2012. Patients and Methods: The subjects were pneumonia patients aged 65 and over who were admitted to a hospital in Izumo. This retrospective study analyzed the following data extracted from medical records: pneumococcal pneumonia prevalence, pneumonia severity, mortality rate, PPSV23 vaccination rate, and length of hospital stay. The 2 years before the start of the public subsidy were defined as the early phase, and the 2 years after the subsidy initiation were defined as the late phase. We compared the two phases in terms of PPSV23 vaccination rate, prevalence and severity of pneumococcal pneumonia, and mortality rate. Results: We investigated data from a total of 1188 and 1086 patients in the early and late phases, respectively. The prevalence of pneumococcal pneumonia was 21.0% and 21.3% in the early and late phases, respectively. The mortality rate from pneumococcal pneumonia was 10.4% and 5.4% in the early and late phases, respectively (p = 0.080), indicating a 50% reduction. The PPSV23 vaccination rate (p < 0.001) and the comorbidity rates of chronic respiratory disease (p = 0.022) and chronic renal disease (p < 0.001) were significantly different between the early and late phases. Conclusion: This study showed that the rate of in-hospital deaths due to pneumococcal pneumonia was halved after the PPSV23 vaccine was subsidized. The causal relationship between the pneumococcal vaccination rate and the mortality rate of pneumococcal disease was unclear. Further investigation is deemed necessary.

Immunohistochemical analysis of B7-H3 expression in patients with lung cancer following various anti-cancer treatments.

B7 homolog 3 protein (B7-H3), an immune checkpoint molecule belonging to the B7 family, has been studied as a target for the development of anti-cancer treatment; however, changes in B7-H3 expression during the clinical course remain unknown. This retrospective study aimed to investigate changes in B7-H3 expression of lung cancer specimens in patients with advanced lung cancer following various anti-cancer treatments. The immunohistochemistry (IHC) score was evaluated on a 0-3 scale, and B7-H3 expression was considered positive for grade ≥ 2. The difference in IHC scores before and after anti-cancer treatment was defined as the change in B7-H3 expression. Among 160 patients with lung cancer who received anti-cancer treatment, 88 (55%) and 101 (63%) had B7-H3 expression before and after anti-cancer treatment, respectively. Before treatment, B7-H3 expression was significantly more common in squamous cell carcinoma specimens than in adenocarcinoma specimens (95% vs. 49%, P < 0.001). Of the 19 patients with squamous cell carcinoma, 18 (95%) continued to have high (IHC score: 3) B7-H3 expression following treatment. In contrast, of the 130 patients with adenocarcinoma, 46 (35%) and 17 (13%) showed an increased and a decreased expression, respectively. Patients who received targeted therapy had a significant increase in B7-H3 expression compared with those who received chemotherapy alone (P = 0.015). Overall, squamous cell carcinoma specimens maintained high B7-H3 expression during the clinical course, whereas adenocarcinoma specimens showed changes in expression following anti-cancer treatments. Our results provide the basis for further studies on the development of anti-cancer treatments targeting B7-H3.

An 83-year-old patient with RET fusion-positive non-small cell lung cancer experiencing severe hepatic disorder due to selpercatinib administration.

An 83-year-old woman with RET fusion-positive advanced lung adenocarcinoma was administered selpercatinib 320 mg/day. Despite the shrinking of the tumour, fever, fatigue, and anorexia developed on day 17. Selpercatinib administration was interrupted. On day 21, elevated blood aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. On day 28, AST and ALT levels increased to demonstrate Grade 4 in CTCAE Ver.5. The patient received a glycyrrhizin-compounding agent and steroid treatment, and AST and ALT levels gradually decreased. On day 63, selpercatinib 160 mg/day was restarted after improvement of the hepatic disorder. Since then, selpercatinib was continued without any severe adverse events. Selpercatinib is a reasonable treatment option for RET fusion-positive advanced non-small cell lung cancer even in older patients. However, old age may be a risk factor for adverse events including hepatic disorders. For safe treatment in such patients, careful follow-up is required.

Immune-related adverse events in hepatitis treated with thiopurine-based immunosuppressants: A case report.

An 82-year-old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune-related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine-based immunosuppressant was effective against irAE hepatitis, therefore thiopurine-based immunosuppressants may be effective against steroid-refractory hepatitis.