Relation of overall tumor burden with severe immune-related adverse events in nivolumab plus ipilimumab treatment for lung cancer.

Compared to chemotherapy alone, monoclonal antibodies like ipilimumab and nivolumab, with or without chemotherapy, improve the prognosis of patients with non-small cell lung cancer (NSCLC), albeit with a higher incidence of immune-related adverse events (irAEs) than those with immune checkpoint inhibitor (ICI) monotherapy. Therefore, we aimed to investigate if baseline overall tumor burden was associated with the development of Grade ≥ 3 irAEs (severe irAEs) when treated with first-line ipilimumab plus nivolumab with or without chemotherapy.We retrospectively examined consecutive patients with advanced NSCLC who received nivolumab plus ipilimumab with or without chemotherapy at Hakodate Goryoukaku Hospital between December 2020 and December 2021. Baseline overall tumor burden was measured as the sum of unidimensional diameters of up to five target lesions according to the Response Evaluation Criteria in Solid Tumors, version 1.1. We defined irAEs as ICI therapy-related toxicities according to the Common Terminology Criteria for Adverse Events, version 5.0.A significant difference in tumor burden was observed between patients with and without severe irAEs (100 mm vs. 67.5 mm, p = 0.001). We evaluated various clinical parameters, including baseline overall tumor burden, before treatment initiation. Of the various parameters, only high tumor burden correlated with severe irAEs, independent of complementary chemotherapy. The multivariate odds ratio of severe irAEs and high tumor burden was 6.62.Conclusively, baseline overall tumor burden may be a risk factor for severe irAEs in patients treated with first-line combination ICI therapy. Therefore, patients with large tumor burden should be carefully monitored to prevent irAEs.

Risk factors for severe immune-related adverse events after first-line pembrolizumab monotherapy or combination chemotherapy for non-small-cell lung cancer.

Pembrolizumab treatment is associated with a favorable prognosis in patients with non-small-cell lung cancer (NSCLC). Here, we investigated the associations among pre-treatment clinical factors, baseline overall tumor burden, and development of severe immune-related adverse events (irAEs; grade ≥ 3) after pembrolizumab treatment with or without chemotherapy. We retrospectively examined consecutive patients with advanced NSCLC who received pembrolizumab with or without chemotherapy at Hakodate Goryoukaku Hospital from March 2017 to February 2021. The baseline overall tumor burden was measured as the sum of the unidimensional diameters of up to five target lesions. We defined irAEs as toxicities related to immune checkpoint inhibitors based on the Common Terminology Criteria for Adverse Events, version 5.0. Tumor burden differed significantly between patients with and without severe irAEs (85 vs. 65 mm, p = 0.0367). The cutoff value for overall tumor burden was set to 80 mm. Good performance status (PS = 0) and PD-L1 expression > 80%, but not overall tumor burden, were correlated with severe irAEs, regardless of complementary chemotherapy. The multivariate odds ratios of good PS and high PD-L1 expression for severe irAEs were 3.27 (95% confidence interval [CI]: 1.22-8.77, p = 0.019) and 4.44 (95% CI: 1.59-12.42, p = 0.0044), respectively. Baseline overall tumor burden, good PS, and high PD-L1 expression were associated with severe irAEs in patients with NSCLC treated with first-line pembrolizumab with or without chemotherapy. Patients with these factors should be carefully monitored to prevent irAEs.

Efficacy and prognosis of antiviral therapy on hepatitis C following treatment of lymphoma in HCV-positive diffuse large-cell lymphoma.

The purpose of this study is to study the usefulness of post-remission antiviral therapy in cases of HCV-RNA-positive diffuse large-cell lymphoma. Antiviral therapy against HCV was performed after remission using CHOP or CHOP-like chemotherapy in combination with rituximab in five successive cases of HCV-RNA-positive diffuse large-cell lymphoma. The control groups consisted of a group of HCV-RNA-positive diffuse large-cell lymphoma cases prior to this trial (control 1), and a group of cases that tested negative for HIV, HCV, and HBV (control 2). All the cases were in remission at the time of initial treatment. There were no significant differences between the three groups in terms of age, sex, treatment, stage, or International Prognosis Index (IPI). When HCV antiviral therapy was performed after treatment for diffuse large-cell lymphoma, we observed no recurrence or deaths, and the 2-year overall survival and progression-free survival rates were significantly greater than those in the control 1 group (P = 0.0246). It is possible that a better prognosis can be achieved by performing HCV antiviral therapy after achieving remission in cases of HCV-RNA-positive diffuse large-cell lymphoma through the use of R-CHOP or similar treatments.

Risk factors for severe immune-related pneumonitis after nivolumab plus ipilimumab therapy for non-small cell lung cancer.

BACKGROUND: The efficacy of anti-CTLA-4 antibody (ipilimumab) plus anti-programmed cell death 1 antibody (nivolumab) in treating advanced non-small cell lung cancer (NSCLC) is impeded by an elevated risk of severe immune-related adverse events. However, our understanding of associations among pre-existing fibrosis, emphysematous changes, and objective indicators as predictive factors is limited for severe pneumonitis in NSCLC patients receiving this combination therapy. Thus, we retrospectively investigated these associations, including overall tumor burden, before treatment initiation in the Japanese population. METHODS: We focused on patients (n = 76) with pre-existing interstitial lung disease (ILD) to identify predictors of severe pneumonitis. Variables included age, sex, smoking status, programmed cell death ligand 1 expression, overall tumor burden, chest computed tomography-confirmed fibrosis, serum markers, and respiratory function test results. RESULTS: Severe pneumonitis was more frequent in patients with squamous cell carcinoma, fibrosis, low diffusing capacity for carbon monoxide (%DLCO), and high surfactant protein D (SP-D) level. Notably, squamous cell carcinoma, baseline %DLCO, and SP-D level were significant risk factors. Our findings revealed the nonsignificance of tumor burden (≥85 mm) in predicting severe pneumonitis, emphasizing the importance of pre-existing ILD. Conversely, in cases without pre-existing fibrosis, severe pneumonitis was not associated with %DLCO or SP-D level (93.2% vs. 91.9%, and 63.3 vs. 40.9 ng/mL, respectively) and was more common in patients with a large overall tumor burden (97.5 vs. 70.0 mm). CONCLUSION: Vigilant monitoring and early intervention are crucial for patients with squamous cell carcinoma, high SP-D level, or low %DLCO undergoing ipilimumab plus nivolumab therapy.

Long-term response to osimertinib in elderly patients with lung adenocarcinoma harbouring de novo EGFR T790M: a case report and literature review.

Osimertinib is a potent and irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that selectively acts on both EGFR-sensitive and EGFR T790M-resistant mutations. Patients with pre-treatment EGFR T790M mutations (de novo EGFR T790M) respond poorly to existing EGFR-TKIs, whereas osimertinib has positive effects. However, the safety data for first-line osimertinib treatment in patients aged >75 years are insufficient. We treated two elderly patients with de novo EGFR T790M mutations with osimertinib as the first-line therapy. We found that the first-line treatment with osimertinib was safe and resulted in a long-term response in elderly patients with de novo EGFR T790M-mutated lung adenocarcinoma.

Diffuse alveolar haemorrhage due to pheochromocytoma crisis.

Clinicians should be aware that interstitial shadows with extreme hypertension should be considered as indicators for diffuse alveolar haemorrhage due to pheochromocytoma crisis.

Long-term response to afatinib in an elderly patient with uncommon epidermal growth factor receptor mutation-positive lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. Uncommon mutations, excluding exon 19 deletions and exon 21 L858R, comprise 7%-23% of EGFR mutation-positive NSCLC. The treatment of uncommon EGFR mutation-positive NSCLCs is controversial. Here, we present the case of an 81-year-old man who was diagnosed with lung adenocarcinoma cStage IVA harboring the uncommon EGFR L861Q mutation. The patient received oral afatinib treatment (40 mg/day). One month after the initiation of afatinib treatment, Common Terminology Criteria for Adverse Events version 4.0 grade 2 stomatitis was observed. It improved upon afatinib withdrawal. After 10 days of withdrawal, afatinib treatment was resumed at a reduced dose of 20 mg/day. Subsequently, the patient continued treatment with afatinib. A partial response to afatinib treatment was maintained for 49 months until primary tumor regrowth. Afatinib treatment was continued after disease progression, but the patient died of bacterial pneumonia 59 months after initiation of afatinib treatment. Several studies have previously reported a large number of compound mutations with uncommon mutations, and that compound mutation-induced cells are most susceptible to afatinib. This suggests the efficacy of afatinib in clinical practice and that afatinib may be safely administered to elderly patients with appropriate dose reductions.

Fulminant amebic colitis in a patient with concomitant cytomegalovirus infection after systemic steroid therapy: A case report.

BACKGROUND: Amebic colitis is an infection caused by Entamoeba histolytica and most commonly observed in regions with poor sanitation. It is also seen as a sexually transmitted disease in developed countries. While amebic colitis usually has a chronic course with repeated exacerbations and remissions, it may also manifest as a fulminant form that rapidly progresses and leads to severe, life-threatening complications, such as intestinal perforation, peritonitis, and sepsis, that have a high mortality rate. CASE SUMMARY: A 68-year-old man was admitted to our hospital with chest pain and acute dyspnea. He was diagnosed with acute coronary syndrome, acute heart failure, and bacterial pneumonia. His respiratory condition worsened despite receiving intensive care and intravenous antibiotics. On the fifth day of hospitalization, he was diagnosed with acute respiratory distress syndrome and was started on steroid therapy. He subsequently developed bloody stools and was diagnosed with cytomegalovirus (CMV) enterocolitis based on biopsy results and a peripheral blood CMV pp65 antigenemia test result. Although we started antiviral therapy with ganciclovir, which was successful in reducing his antigen titers, he continued to have bloody diarrhea. Three weeks after initiation of ganciclovir therapy and six weeks after his admission, the patient died from intestinal perforation. We only posthumously diagnosed him with amebic colitis and CMV enterocolitis based on autopsy findings of transmural necrosis of the entire colon with massive ameba infiltration. CONCLUSION: We urge clinicians to consider Entamoeba histolytica infection if severe colitis progresses after steroid therapy. Preemptive treatment is recommended then.

Transbronchial needle aspiration with endobronchial ultrasonography and ultrathin bronchoscopy for peripheral pulmonary lesions.

BACKGROUND: Although the efficacy of lung cancer treatment has improved, it is dependent on a reliable diagnosis via bronchoscopy. Transbronchial biopsy using ultrathin bronchoscopy can help detect small peripheral pulmonary lesions (PPLs), with a high diagnostic yield. However, the diagnosis rate using forceps biopsy when the radial endobronchial ultrasonography (rEBUS) probe is adjacent to a lesion tends to be low. Transbronchial needle aspiration (TBNA) may improve the diagnostic yield from adjacent lesions. Recently, PeriView FLEX, a new TBNA needle that can be inserted into ultrathin bronchoscopes, has become available. We examined whether TBNA with PeriView FLEX and forceps biopsy improved adjacent lesion diagnosis when using ultrathin bronchoscopes. METHODS: We retrospectively examined 51 consecutive patients who underwent TBNA and forceps biopsy using ultrathin bronchoscopes under rEBUS for small PPLs at the Hakodate Goryoukaku Hospital between November 2019 and August 2020. The histological diagnosis rate using TBNA and forceps biopsy, TBNA alone, or forceps biopsy alone was compared between cases where the rEBUS probe was "Within" and "Adjacent To" the lesions. RESULTS: The diagnosis rate using TBNA and forceps biopsy was 86.3% (95.7% vs. 78.6%; p = 0.08) for all lesions (Within cases vs. Adjacent To cases). The corresponding rate using TBNA alone was 68.6% (69.6% vs. 67.9%; p = 0.57), and that using forceps biopsy alone was 72.5% (91.3% vs. 57.1%; p = 0.0067). CONCLUSIONS: Forceps biopsy with TBNA during ultrathin bronchoscopy for small PPLs improved the diagnostic yield when lesions were adjacent to the rEBUS probe.

Spontaneous pneumothorax during nintedanib therapy in patients with systemic sclerosis-associated interstitial lung disease.

Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc). Nintedanib, an antifibrotic drug, has recently been approved for treating SSc-ILD. Although there have been no reports suggesting the development of pneumothorax with nintedanib use, its safety in patients with impaired lung function is unclear. We observed the development of refractory spontaneous pneumothorax during nintedanib therapy in two patients with SSc-ILD and impaired lung function. Nintedanib use for SSc-ILD, an extensive disease, may therefore increase the risk of pneumothorax. In addition, pneumothorax is more likely to be refractory in these cases; initiation of nintedanib treatment and follow-up should be considered carefully.

Sedation with fentanyl and midazolam without oropharyngeal anesthesia compared with sedation with pethidine and midazolam with oropharyngeal anesthesia in ultrathin bronchoscopy for peripheral lung lesions.

BACKGROUND: In advanced lung cancer, precision medicine requires repeated biopsies via bronchoscopy at therapy change. Since bronchoscopies are often stressful for patients, sedation using both fentanyl and midazolam is recommended in Europe and America. In Japan, bronchoscopies are generally orally performed under midazolam and oropharyngeal anesthesia. Nasal intubation creates a physiological route to the trachea, causing less irritation to the pharynx than intubation via the oral cavity; however, the necessity of oropharyngeal anesthesia remains unclear. We aimed to compare the safety, patient discomfort, and diagnostic rates for oropharyngeal anesthesia and sedation with pethidine and midazolam (Group A) and sedation with midazolam and fentanyl without oropharyngeal anesthesia (Group B) for ultrathin bronchoscopy of peripheral pulmonary lesions (PPLs) via nasal intubation. METHODS: We retrospectively reviewed 74 consecutive potential lung cancer patients who underwent ultrathin bronchoscopies at the Hakodate Goryoukaku Hospital between July 2019 and June 2020. We reviewed the following: diagnostic rates; cumulative doses of lidocaine, midazolam, and fentanyl; hemodynamic changes; procedural complications in both groups. Pharyngeal anesthesia in group A was administered by spraying 2% (w/v) lidocaine into the pharynx. The chi-squared test was used for statistical analyses. RESULTS: There were no significant changes in hemodynamic parameters and complications. The mean level of discomfort for bronchoscopic examinations was significantly lower in Group B (2.39 vs. 1.64; P = 0.014), with no significant inter-group difference in the diagnostic yields for PPLs (63.0% vs. 71.4%; P = 0.46). CONCLUSIONS: Our findings indicate the advantages of sedation with fentanyl and midazolam without oropharyngeal anesthesia for ultrathin bronchoscopy through nasal intubation.

Lung adenocarcinoma with tumor resolution and dystrophic calcification after salvage surgery following immune checkpoint inhibitor therapy: A case report.

A clinical trial of immune checkpoint inhibitors for advanced non-small cell lung cancer reported an overall survival plateau with a long tail to the survival curve, suggesting that immune checkpoint inhibitors prolong survival. However, little evidence supports the efficacy of immune checkpoint inhibitors as neoadjuvant chemotherapy. We performed salvage surgery on a patient who was treated with an anti-programmed cell death protein-1 (PD-1) antibody and whose tumor size had not changed over time. A 69-year-old Japanese female with advanced lung adenocarcinoma was initially administered pembrolizumab therapy; however, owing to the development of various immune-related adverse events (irAEs), the patient was switched to chemotherapy following steroid therapy. The tumor continued to shrink and calcification within the tumor increased. We performed salvage surgery following which the tumor cells disappeared and necrosis and calcification were detected in the tumor. We concluded that if calcification develops within the tumor and tumor shrinkage is maintained after treatment with anti-PD-1 drugs, the calcification may be dystrophic owing to drug-induced tumor necrosis, and salvage surgery might be beneficial in removing the tumor. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: If calcification develops within the tumor and tumor shrinkage is maintained after treatment with anti-PD-1 drugs, the calcification may be dystrophic owing to tumor necrosis caused by drug effects, and salvage surgery might be beneficial in removing the tumor. WHAT THIS STUDY ADDS: This study showed the efficacy of immune checkpoint inhibitors as neoadjuvant chemotherapy to be followed by salvage surgery for unresectable advanced lung adenocarcinoma.