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.

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.

Prognostic significance of immunohistochemical classification utilizing biopsy specimens in patients with extensive-disease small-cell lung cancer treated with first-line chemotherapy and immune checkpoint inhibitors.

PURPOSE: Although immune checkpoint inhibitors (ICIs), together with cytotoxic chemotherapy (chemoimmunotherapy), have been adapted for the initial treatment of extensive-disease small-cell lung cancer (ED-SCLC), they have achieved limited success. In ED-SCLC, a subtype of SCLC, the expression of immune-related molecules and clinical data are not well understood in relation to ICI treatment efficiency. METHODS: We examined lung biopsy specimens from patients diagnosed with ED-SCLC treated with chemoimmunotherapy or chemotherapy. SCLC subtype, expression of HLA class I, and infiltration of CD8-positive cells were examined using immunohistochemistry (IHC). Subsequently, the association between clinical factors, IHC results, and progression-free survival or overall survival was assessed. RESULTS: Most of the cases showed the achaete-scute homolog 1 (ASCL1) subtype. Among the 75 SCLC cases, 29 expressed high levels of HLA class I, while 46 showed low levels or a negative result; 33 patients were characterized as CD8-high, whereas 42 were CD8-low. In the chemoimmunotherapy cohort, multivariate analysis revealed a correlation between CD8-high and improved survival. Specifically, patients in the CD8-high group of the chemoimmunotherapy cohort experienced enhanced survival compared to those in the chemotherapy cohort, which was attributed to ICI addition. IHC subtype analysis demonstrated a survival advantage in the SCLC-I and SCLC-A groups when ICI was combined with chemotherapy compared to chemotherapy alone. CONCLUSION: Our study highlights the predictive value of IHC-classified subtypes and CD8-positive cell infiltration in estimating outcomes for patients with ED-SCLC treated with chemoimmunotherapy as a first-line therapy. These findings have practical implications for daily clinical assessments and treatment decisions.

Autoimmune Pulmonary Alveolar Proteinosis during the Treatment of Idiopathic Inflammatory Myopathy.

Approximately 50% of idiopathic inflammatory myopathies (IIMs) are associated with interstitial lung disease (ILD). Typically, IIM-ILD manifests as nonspecific interstitial pneumonia. We herein report a rare case of a 78-year-old man with autoimmune pulmonary alveolar proteinosis (PAP) that developed during IIM treatment. The diagnosis of autoimmune PAP was based on detecting anti-granulocyte-macrophage colony-stimulating factor antibodies. We postulated that PAP may have been induced by IIM treatment with prednisolone. Our case suggests that the possibility of autoimmune PAP should be considered in patients with lung lesions during the clinical course of IIM.

Metastatic pulmonary pleomorphic carcinoma replaced by a granulomatous lesion after spontaneous regression and PD-1 blockade-induced regression: can epithelioid granuloma be a histological hallmark of cancer immunity?

Immune checkpoint inhibitors (ICIs) for various types of malignancy, including non-small-cell lung cancer, have improved prognosis in some cases. Granuloma formation after ICI administration suggests a tumor antigen-specific cytotoxic T cell response with abundant interferon-gamma production, which can be used to estimate the curative effect of ICIs. In this report, we present a case with a resected lung lesion, clinically suspected to be lung cancer, that consisted of a granulomatous lesion. A tumor was also found in the duodenum that was presumed to be derived from the pulmonary pleomorphic carcinoma. Duodenal tumor cells highly expressed PD-L1, suggesting PD-1/PD-L1 axis-mediated immune escape. As expected, pembrolizumab induced a complete response for the duodenal lesion. Interestingly, in histopathological analysis, the duodenal lesion was also replaced by an epithelial granuloma and multinucleated giant cells. We conclude that autoimmunity regressed the untreated primary lung lesion spontaneously, while the metastatic duodenal lesion responded to PD-1 blockade. Tumor-associated epithelioid granulomas, even before ICI administration, may be an important pathological finding indicating an immune response with interferon-gamma production by cytotoxic T cells to the tumor.

Alveolar Hemorrhage Caused by the Combination of Immune Checkpoint Inhibitors (ICIs) and Angiogenesis Inhibitors: The Underlying Long-Term Vascular Endothelial Growth Factor (VEGF) Inhibition.

The combination of immune checkpoint inhibitors (ICIs) and other anticancer agents is the standard of care for various cancers. Bevacizumab, an anti-angiogenesis inhibitor, causes serious adverse events such as pulmonary hemorrhage (PH). Here, we present a case of drug-induced diffuse alveolar hemorrhage (DAH), an adverse event, in a patient with hepatocellular carcinoma who was treated with a combination of ICIs and anti-angiogenesis inhibitors after long-term use of lenvatinib, which inhibits vascular endothelial growth factor (VEGF). An 85-year-old man with hepatocellular carcinoma initially received lenvatinib, a multi-kinase inhibitor, but the drug was later switched to bevacizumab-atezolizumab combination therapy owing to disease progression. After five cycles, he developed dyspnea and diffuse ground-glass opacities, which improved with discontinuation of the combination therapy and initiation of steroid pulse therapy. Our case findings indicate that both ICIs and anti-angiogenesis inhibitors cause drug-induced DAH, and their combination may increase the severity of DAH. Moreover, long-term VEGF inhibition may induce the development of DAH. Clinicians need to be aware that long-term VEGF inhibition may be associated with DAH and should consider the risk management of such adverse events while using this combination therapy.

Immunological and nutritional predictive factors in patients receiving pembrolizumab for the first-line treatment of non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) have prolonged the survival of patients with various carcinomas, including non-small cell lung cancer (NSCLC), and have caused a paradigm shift in cancer treatment. Although programmed death-ligand 1 (PD-L1) expression in tumor cells is a predictive marker of therapeutic efficacy, additional predictive markers are required. This study aimed to explore the role of immunological and nutritional parameters in the prediction of treatment response. METHODS: Patients diagnosed with NSCLC and treated with pembrolizumab were examined retrospectively. Body weight was measured 4-6 weeks before the start of the first treatment, immediately before treatment, and 4-6 weeks after the start of the first treatment. Progression-free survival (PFS) was defined as the time from the start of pembrolizumab treatment to the last follow-up date or until disease progression. Statistical analyses were performed to confirm the association between various factors and association between these factors and PFS. RESULTS: Thirty-eight patients with advanced NSCLC were included. We observed a significant association of weight loss and PD-L1 expression with PFS in the multivariate analysis. A significant correlation was found between the advanced lung cancer inflammation index and neutrophil-to-lymphocyte ratio. A weight loss of > 5% after the start of treatment was significantly associated with worse PFS. CONCLUSIONS: Weight loss is an important negative prognostic factor in patients with NSCLC receiving immunotherapy. Weight maintenance may be important for good ICI treatment efficacy, and future interventions in cancer cachexia are expected to further enhance the treatment efficacy of ICIs.

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 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.

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.

Pseudocirrhosis due to liver metastasis from lung adenocarcinoma.

Pseudocirrhosis is a radiological diagnosis of cirrhosis without histological evidence and occurs as a complication of liver metastases from solid tumors. A 50-year-old man without any previous history of liver disease was diagnosed with adenocarcinoma of the left upper lung lobe and liver metastasis. After chemotherapy, the liver metastases shrank; however, over time, the liver shrank and showed cirrhosis-like morphological changes. His performance status deteriorated due to ascites and leg edema, and chemotherapy was terminated. Physicians treating lung adenocarcinoma with liver metastases should be aware that pseudocirrhosis is a rare but important complication that can worsen performance status (PS) and hinder treatment continuation.

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.

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.

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.

Comparison of ultrathin bronchoscopy with conventional bronchoscopy for the diagnosis of peripheral lung lesions without virtual bronchial navigation.

BACKGROUND: For the precise management of advanced lung cancers, bronchoscopy with a high diagnostic yield and abundant tumor specimens are required. In recent years, new devices and techniques have been rapidly developed, including the endobronchial ultrasound (EBUS) using a guide sheath, virtual bronchoscopic navigation (VBN), and ultra-thin bronchoscope (UTB), for the diagnosis of peripheral pulmonary lesions (PPLs). These techniques increase the diagnostic yield for PPL, thus requiring fewer biopsy specimens. VBN is generally not available at the city hospitals in Japan. In this study, using fluoroscopy without VBN, we studied whether the histologic diagnostic yield of radial EBUS for PPLs would be higher using a UTB (without guide sheath) or conventional bronchoscope (CB) (with guide sheath). METHODS: We retrospectively reviewed consecutive patients with suspected lung cancer who underwent bronchoscopy at the Hakodate Goryoukaku Hospital from April 2017 to March 2019. We analyzed 168 patients-102 using UTB and 66 using CB. RESULTS: The diagnostic yields for PPL were significantly higher in the UTB group than in the CB group (74.5% vs. 59.1%; P = 0.04). The median examination time was significantly longer in the UTB group than in the CB group (24 vs. 20 min; P = 0.01). There were no statistically significant differences in the complication rate between the UTB and CB groups (3.9% vs. 3.0%; P = 0.69). CONCLUSIONS: UTB had a significantly higher tissue diagnostic yield than CB, without the use of VBN.

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.