Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel.

INTRODUCTION: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients. METHODS: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients. RESULTS: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0-70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3-9.4) and 16.5 (95% CI: 13.9-22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI <45 (OS: 23.4 and 13.9 months, respectively, p = 0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS. CONCLUSION: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC.

Acute respiratory failure developing in a patient with lymphomatoid granulomatosis.

Lymphomatoid granulomatosis (LYG) is a rare B cell lymphoproliferative disorder associated with Epstein-Barr virus infection. LYG diagnosis is often difficult because of non-specific and varied radiological and pathological findings. The lung is the most common organ of LYG occurrence, but extrapulmonary lesions involving the central nervous system, skin, kidneys and liver are observed. A surgical biopsy is often inevitable for LYG diagnosis.We encountered a man in his 50s who presented with progressive dyspnoea. Extrapulmonary lesions were not observed. Although he developed respiratory failure within a short period, a low dose of corticosteroid relieved his symptoms. Video-assisted thoracoscopic lung biopsy revealed grade 1 LYG. The patient was successfully treated with chemotherapy, including rituximab. Only a few cases of LYG with progressive respiratory failure are reported, and most have been diagnosed via autopsy. Our case highlights the importance of performing a surgical lung biopsy at the appropriate time to diagnose LYG.

Hyperprogressive disease in lung metastases without target lesion progression after durvalumab consolidation therapy: A case report.

Hyperprogressive disease (HPD) is a novel progressive pattern that occurs after immune checkpoint inhibitor (ICI) administration. Here, a 74-year-old woman who had undergone right lower lobectomy for lung cancer received curative chemoradiotherapy followed by consolidation therapy with durvalumab for metastatic recurrence confined to the mediastinal lymph nodes. Three weeks later, multiple randomly distributed nodular shadows appeared on chest CT, and thoracoscopic lung biopsy led to the diagnosis of multiple pulmonary metastases. HPD may be suspected when multiple metastases appear in new organs early after the administration of ICIs. This phenomenon may occur not only with ICI monotherapy but also with the administration of ICIs after chemoradiotherapy. Therefore, patients who have received radiation therapy should also be given similar attention early after the administration of ICIs.

Using the neutrophil-to-lymphocyte ratio to predict the outcome of individuals with nonsquamous non-small cell lung cancer receiving pembrolizumab plus platinum and pemetrexed.

BACKGROUND: Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb-Plt-PEM) in nonsquamous non-small cell lung cancer (non-sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non-sq NSCLC. METHODS: We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non-sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan-Meier method were used to compare progression-free survival (PFS) and overall survival (OS). RESULTS: The response rate was 51.2% (95% CI: 44.9-57.5%). The median PFS and OS after beginning Pemb-Plt-PEM were 8.8 (95% CI: 7.0-11.9) months and 23.6 (95% CI: 18.7-28.6) months, respectively. The NLR independently predicted the efficacy of Pemb-Plt-PEM-the PFS and OS were more prolonged in individuals with NLR <5 than in those with NLR ≥5 (PFS: 12.8 vs. 5.3 months, p = 0.0002; OS: 29.4 vs. 12.0 months, p < 0.0001). BMI predicted the treatment response-individuals with BMI ≥22.0 kg/m2 had longer OS than did those with BMI < 22.0 kg/m2 (OS: 28.4 vs. 18.4 months, p = 0.0086). CONCLUSIONS: The NLR significantly predicted PFS and OS, whereas BMI predicted OS, in individuals who initially received Pemb-Plt-PEM for non-sq NSCLC. These factors might be prognosis predictors in non-sq NSCLC.

Herpes zoster in patients with lung cancer treated with PD-1/PD-L1 antibodies.

Background: There are no available clinical data on immunotherapy and the risk of herpes zoster. Materials & methods: This retrospective study included patients with recurrent or advanced lung cancer who were inoperable and ineligible for radiotherapy and were treated with either a PD-1/PD-L1 antibody (136 patients) or an EGFR tyrosine kinase inhibitor (149 patients) at Jichi Medical University Hospital between January 2016 and December 2018. Results: Herpes zoster-free survival was significantly shorter in the PD-1/PD-L1 antibody-treated group compared with the EGFR tyrosine kinase inhibitor-treated group (hazard ratio: 0.20; 95% CI: 0.048-0.84; p = 0.016). PD-1/PD-L1 antibody administration was independently and significantly associated with herpes zoster occurrence. Conclusion: Clinicians should anticipate herpes zoster in patients with lung cancer during treatment with PD-1/PD-L1 antibodies.

There are no available clinical data on immunotherapy and the risk of herpes zoster. This retrospective study included patients with recurrent or advanced lung cancer who were inoperable and ineligible for radiotherapy and were treated with either an immune checkpoint inhibitor (136 patients) or an EGFR tyrosine kinase inhibitor (149 patients) through the authors' university between January 2016 and December 2018. The herpes zoster-free period was significantly shorter in the immune checkpoint inhibitor-treated group compared with the EGFR tyrosine kinase inhibitor-treated group (hazard ratio: 0.20; 95% CI: 0.048­0.84; p = 0.016). Immune checkpoint inhibitor antibody administration was independently and significantly associated with herpes zoster occurrence. Clinicians should be cautious of herpes zoster in patients with lung cancer during treatment with immune checkpoint inhibitors.

Opioid Prescription Method for Breathlessness Due to Non-Cancer Chronic Respiratory Diseases: A Systematic Review.

A previous pooled analysis demonstrated significant relief of breathlessness following opioid administration in patients with chronic obstructive pulmonary disease. However, in clinical practice, it is important to know the characteristics of patients responding to opioids, the best prescription methods, and the evaluation measures that can sufficiently reflect these effects. Thus, we performed a systematic review of systemic opioids for non-cancer chronic respiratory diseases. Fifteen randomized controlled studies (RCTs), four non-randomized studies, two observational studies, and five retrospective studies were included. Recent RCTs suggested that regular oral opioid use would decrease the worst breathlessness in patients with a modified Medical Research Council score ≥ 3 by a degree of 1.0 or less on a scale of 1-10. Ergometer or treadmill tests indicated mostly consistent significant acute effects of morphine or codeine. In two non-randomized studies, about 60% of patients responded to opioids and showed definite improvement in symptoms and quality of life. Furthermore, titration of opioids in these studies suggested that a major proportion of these responders had benefits after administration of approximately 10 mg/day of morphine. However, more studies are needed to clarify the prescription method to reduce withdrawal due to adverse effects, which would lead to significant improvements in overall well-being.

Immunoglobulin G4-related Pleuritis Complicated with Minimal Change Disease.

A 70-year-old woman with bilateral pleural effusion and respiratory failure was admitted to our hospital. Nephrotic syndrome due to minimal change disease had been diagnosed four months before admission. Because blood tests and a pleural fluid analysis did not reveal the etiology of her condition, we performed a video-assisted thoracoscopic pleural biopsy. No specific thoracoscopic findings were noted. The pathological findings revealed an increase in immunoglobulin G4 (IgG4)-positive cells; IgG4-related pleuritis was diagnosed. Her pleuritis improved with oral corticosteroid therapy. A further investigation was performed on previous kidney samples; however, the etiology of the nephrotic syndrome was not IgG4-related disease but minimal change disease.

A case of prominent immunoglobulin G4-positive lymphadenopathy in response to microscopic lung cancer.

Immunoglobulin G4 (IgG4)-related disease is established as a new clinical entity, characterized by high levels of plasma IgG4 and IgG4-positive plasma cell infiltration. However, the elevation of plasma IgG4 and infiltration of IgG4-positive cells have been observed in other diseases, including malignancy. We experienced a case of prominent IgG4-positive lymphadenopathy, which was diagnosed as a reactive lesion in response to lung cancer. The cancerous lesion was so small in size that it was difficult to reveal the coexisting lung cancer. Surgical lymph node biopsy and endobronchial ultrasound-guided transbronchial needle aspiration did not reveal lymph node metastasis of cancer. Mediastinal lymph node dissection finally revealed it. After the right upper lobectomy, the patient underwent postoperative chemotherapy and remains cancer-free after 1 year. Our case suggests that close examination and careful follow-up are necessary when IgG4-positive lymphadenopathy is observed.

Clinical case of lung spindle cell carcinoma markedly responsive to pembrolizumab.

A 52-year-old man underwent pneumonectomy of the left lung for previously diagnosed primary spindle cell carcinoma (pT4aN1M0, stage III B) with programmed death-ligand 1 expression (tumor proportion score ≥95%) and without epidermal growth factor receptor gene mutation and anaplastic lymphoma kinase fusion gene. However, brain metastasis and chest wall tumor relapse occurred. Considering insufficient improvement with gamma knife treatment for brain metastasis and combination chemotherapy (paclitaxel, carboplatin, and bevacizumab), pembrolizumab monotherapy and palliative irradiation therapy for chest metastases were started after brain tumor volume reduction using craniotomy. Brain edema and chest wall metastases markedly improved following a pseudoprogression of the brain edema accompanied by a performance status decline; this effect continued until 11 cycles of pembrolizumab administration.

Dramatic response to alectinib in a patient with ALK-rearranged squamous cell lung cancer.

Lung cancers with anaplastic lymphoma kinase (ALK) rearrangements are highly sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Due to the very low rate of patients with squamous cell carcinoma enrolled in clinical trials, the efficacy of ALK inhibitors in patients with ALK-rearranged squamous cell carcinoma in the lung remains unclear. Herein, we present the case of a 70-year-old female patient with squamous cell lung cancer harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene. The patient was treated with the ALK-TKI alectinib as first-line regimen and achieved a dramatic response without severe adverse events, demonstrating alectinib as a therapeutic option for patients with ALK-positive squamous cell carcinoma.

Secondary pulmonary hypertension due to pulmonary Langerhans cell histiocytosis accompanied with panhypopituitarism.

A 65-year-old man presented to our hospital with complaint of acute dyspnoea. He smoked 30 cigarettes per day from age 20 to 52 years. Immunocytochemical findings revealed 6.3% of positive CD1a cells in the cell fraction of bronchoalveolar lavage, thus suggesting a diagnosis of pulmonary Langerhans cell histiocytosis (PLCH), after nine years since the first suspicion of PLCH. Furthermore, he was diagnosed with secondary pulmonary hypertension (PH) caused by progressed PLCH by right heart catheterization. At 59 years of age, he was diagnosed with panhypopituitarism, and persistent hormone replacement therapy was subsequently started by an endocrinologist. After the initiation of oxygen therapy and treatment with a combination of sildenafil and warfarin, an estimated pulmonary artery systolic pressure reduced 97.9 to 64.0 mmHg. We believed this is a rare case of PLCH with irreversible central nervous system (CNS) disorder in whom severe PH developed due to a long-term burden of PLCH in a middle-aged male.

Steroid resistance in organizing pneumonia caused by pulmonary cryptococcosis.

Cryptogenic organizing pneumonia (COP) usually responds well to steroid therapy; however, recurrence is commonly observed when the steroid dose is tapered. A 74-year-old man suspected of having steroid-resistant COP presented to our hospital. Chest computed tomography (CT) revealed new consolidations of the left inferior lobe despite administration of a moderate dose of oral steroids. Repeated transbronchial lung biopsy showed pulmonary cryptococcosis. The left interior consolidations shrank gradually after antifungal therapy was initiated. Immunocompromised patients with pulmonary cryptococcosis show various CT findings, and consolidation is frequently observed. Superimposed pulmonary cryptococcosis infection should be considered in cases of steroid-refractory COP.

Erdheim-Chester disease progression from miliary pulmonary nodules to large tumours.

Erdheim-Chester disease (ECD), a rare form of non-Langerhans cell histiocytosis, affects long bones, the retroperitoneal region, and the central nervous, cardiovascular, and pulmonary systems. Most patients with ECD show interlobular septal thickening, centrilobular micronodules, and ground glass opacities on chest computed tomography (CT). We encountered a 66-year-old man with ECD who presented at first visit with randomly distributed multiple pulmonary nodules and who then developed large tumour shadows, observed on chest CT. To our knowledge, this random distribution pattern of multiple pulmonary nodules has not previously been reported.

Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia.

Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically.

A young immunocompetent patient with spontaneous Aspergillus empyema who developed severe eosinophilia.

Aspergillus empyema is usually reported as a complication of surgical procedures, and spontaneous cases are quite rare. Here, we describe the case of a 16-year-old man who suddenly developed dyspnea despite previously being healthy. Chest computed tomography showed multiple mass-containing cavity lesions, pneumothorax, and pleural effusion in the left thorax. Within 2 weeks, Aspergillus fumigatus grew from his pleural effusion, thus he was diagnosed with Aspergillus empyema. He also developed severe eosinophilia after admission, and was treated with anti-fungal drugs. Although there are many factors that can cause eosinophilia, we suspect that infection with Aspergillus fumigatus was the major cause of the eosinophilia in this patient. The lack of bronchial symptoms and lesions were not consistent with a diagnosis of allergic bronchopulmonary aspergillosis. As far as we know, this is the first case of spontaneous Aspergillus empyema resulting in severe eosinophilia.

A highly specific and sensitive massive parallel sequencer-based test for somatic mutations in non-small cell lung cancer.

Molecular targeting therapy for non-small cell lung cancer (NSCLC) has clarified the importance of mutation testing when selecting treatment regimens. As a result, multiple-gene mutation tests are urgently needed. We developed a next-generation sequencer (NGS)-based, multi-gene test named the MINtS for investigating driver mutations in both cytological specimens and snap-frozen tissue samples. The MINtS was used to investigate the EGFR, KRAS, BRAF genes from DNA, and the ERBB2, and the ALK, ROS1, and RET fusion genes from RNA. We focused on high specificity and sensitivity (≥0.99) and even included samples with a cancer cell content of 1%. The MINtS enables testing of more than 100 samples in a single run, making it possible to process a large number of samples submitted to a central laboratory, and reducing the cost for a single sample. We investigated 96 cytological samples and 190 surgically resected tissues, both of which are isolated in daily clinical practice. With the cytological samples, we compared the results for the EGFR mutation between the MINtS and the PNA-LNA PCR clamp test, and their results were 99% consistent. In the snap-frozen tissue samples, 188/190 (99%) samples were successfully analyzed for all genes investigated using both DNA and RNA. Then, we used 200 cytological samples that were serially isolated in clinical practice to assess RNA quality. Using our procedure, 196 samples (98%) provided high-quality RNA suitable for analysis with the MINtS. We concluded that the MINtS test system is feasible for analyzing "druggable" genes using cytological samples and snap-frozen tissue samples. The MINtS will fill a needs for patients for whom only cytological specimens are available for genetic testing.

Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP. CASE PRESENTATION: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high. CONCLUSIONS: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.

Two Cases of Legionella pneumophila Pneumonia with Prolonged Neurologic Symptoms and Brain Hypoperfusion on Single-Photon Emission Computed Tomography.

Cerebral and cerebellar symptoms are frequently associated with Legionnaires' disease. However, corresponding brain lesions are difficult to demonstrate using either computed tomography (CT) or magnetic resonance imaging (MRI). We report here two patients with Legionella pneumophila pneumonia accompanied by prolonged neurologic symptoms. In contrast to brain CT and MRI, which failed to detect any abnormalities, single-photon emission computed tomography (SPECT) showed multiple sites of hypoperfusion within the brains of both patients. These cases suggest that vasculopathy, which is detectable by SPECT, might be one of the causes of neurologic symptoms in patients with Legionnaires' disease.

Invasive tracheobronchial aspergillosis progressing from bronchial to diffuse lung parenchymal lesions.

Invasive tracheobronchial aspergillosis that is entirely limited or predominantly confined to tracheobronchial lesions is a relatively rare form of invasive pulmonary aspergillosis. Extended parenchymal opacities that are radiological manifestations of invasive aspergillosis sometimes occur following invasive tracheobronchial aspergillosis. However, it remains unclear whether or not invasive tracheobronchial aspergillosis is the initial stage of invasive pulmonary aspergillosis. A 61-year-old woman was admitted because of severe diarrhea and dehydration. Three days after admission, she complained of dyspnea. A computed tomography (CT) scan of the chest showed bronchial wall thickening. She developed respiratory failure despite antibiotic therapy. A CT scan showed obstructions of bronchial lumens and bronchiectasis in the right upper lobe. A spergillus fumigatus was identified from samples obtained in bronchoscopic examination. Bronchial lesions rapidly progressed to be extended. A spergillus infection with multiple parenchymal opacities was observed on CT scan. She responded to treatment with antifungal drugs.