KRASG12C Inhibitor as a Treatment Option for Non-Small-Cell Lung Cancer with Comorbid Interstitial Pneumonia.

Non-small-cell lung cancer (NSCLC) with comorbid interstitial pneumonia (IP) is a population with limited treatment options and a poor prognosis. Patients with comorbid IP are at high risk of developing fatal drug-induced pneumonitis, and data on the safety and efficacy of molecularly targeted therapies are lacking. KRAS mutations have been frequently detected in patients with NSCLC with comorbid IP. However, the low detection rate of common driver gene mutations, such as epidermal growth factor receptor and anaplastic lymphoma kinase, in patients with comorbid IP frequently results in inadequate screening for driver mutations, and KRAS mutations may be overlooked. Recently, sotorasib and adagrasib were approved as treatment options for advanced NSCLC with KRASG12C mutations. Although patients with comorbid IP were not excluded from clinical trials of these KRASG12C inhibitors, the incidence of drug-induced pneumonitis was low. Therefore, KRASG12C inhibitors may be a safe and effective treatment option for NSCLC with comorbid IP. This review article discusses the promise and prospects of molecular-targeted therapies, especially KRASG12C inhibitors, for NSCLC with comorbid IP, along with our own clinical experience.

Hypersensitivity pneumonitis with Paecilomyces as suspected inciting antigen.

A 73-year-old man visited our hospital for persistent cough. Chest high-resolution CT (HRCT) showed infiltration shadows in lower lobes and diffuse ground glass opacities in the upper lobes. Blood tests showed elevated white blood cell, C-reactive protein, surfactant protein D, and Krebs von den Lungen-6 levels. After an antigen avoidance test, his HRCT and blood test findings improved; we diagnosed him with hypersensitivity pneumonitis (HP). A culture of the rotting interior walls within his home revealed Paecilomyces, which we believe caused his HP. Given the few patients with Paecilomyces-induced HP, systematic approach was important to identify the inciting antigen.

Concordance between transbronchial lung cryobiopsy and surgical lung biopsy in patients with idiopathic multicentric Castleman disease: A report of four cases.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease often associated with pulmonary involvement. Recently, transbronchial lung cryobiopsy (TBLC) has been reported to be useful for the diagnosis of diffuse interstitial lung disease. However, there have been no reports of pathological assessment of TBLC for iMCD. METHOD: To clarify the efficacy of TBLC in the diagnosis of iMCD, we retrospectively reviewed four iMCD patients who had undergone both TBLC and surgical lung biopsy (SLB). RESULTS: The median age was 44 years; 2 males and 2 females. Two or three TBLC specimens were taken from each patient. All patients had no complications other than minimal bleeding. The size of the TBLC specimens was approximately 5-6 × 3-4 mm, and the alveolar region, and centrilobular and perilobular areas were adequately sampled. As with SLB, the extent of lung lesions and inflammatory cell infiltration could be sufficiently evaluated by TBLC. The presence of lymphoid follicles could also be assessed by TBLC; however, the germinal centers with lymphoid follicles were difficult to evaluate. The TBLC specimens could also be evaluated for immunostaining, especially IgG4 immunostaining, to rule out IgG4-related lung disease. Pulmonary pathological grading showed a high concordance rate between major pathological findings of TBLC and SLB. The pathologist's confidence level of TBLC for the diagnosis of iMCD was high in all cases. CONCLUSIONS: TBLC exhibits a high concordance rate with SLB in the pathological evaluation of iMCD, which may be useful for the diagnosis of iMCD.

High prevalence of upper lung field pulmonary fibrosis radiologically consistent with pleuroparenchymal fibroelastosis in patients with round atelectasis.

BACKGROUND: Upper-lung field pulmonary fibrosis (upper-PF), radiologically consistent with pleuroparenchymal fibroelastosis (PPFE), was reported to develop in patients with a history of asbestos exposure and tuberculous pleurisy, indicating that chronic pleuritis is correlated with upper-PF development. Round atelectasis reportedly emerges after chronic pleuritis. This study aimed to clarify the association between round atelectasis and upper-PF. METHODS: We examined the radiological reports of all consecutive patients with round atelectasis between 2006 and 2018 and investigated the incidence of upper-PF development. RESULTS: Among 85 patients with round atelectasis, 21 patients (24.7%) were confirmed to finally develop upper-PF lesions. Upper-PF was diagnosed after round atelectasis recognition in more than half of the patients (13/21, 61.9%), whereas upper-PF and round atelectasis were simultaneously detected in the remaining 8 patients. At the time of round atelectasis detection, almost all patients (19/21, 90.5%) had diffuse pleural thickening and round atelectasis was commonly observed in non-upper lobes of 19 patients (90.5%). Fourteen patients had round atelectasis in unilateral lung, and the remaining 7 patients had round atelectasis in bilateral lungs. Among all 14 patients with unilateral round atelectasis, upper-PF developed on the same (n = 11) or both sides (n = 3). Thus, upper-PF emerged on the same side where round atelectasis was present (14/14, 100%). The autopsy of one patient revealed a thickened parietal-visceral pleura suggestive of chronic pleuritis. Subpleural fibroelastosis was also observed. CONCLUSIONS: Upper-PF occasionally develops on the same side of round atelectasis. Upper-PF may develop as a sequela of chronic pleuritis.

Radiological and Pathological Features of Cyst Formation in Idiopathic Multicentric Castleman Disease.

INTRODUCTION: Idiopathic multicentric Castleman disease (MCD) has been reported to form lung cysts at a relatively high rate. However, the radiological and pathological features of cystic formation in MCD are unclear. METHODS: To clarify these questions, we retrospectively investigated the radiological and pathological findings of cysts in MCD patients. Eight consecutive patients who underwent surgical lung biopsies in our center from 2000 to 2019 were included. RESULTS: The median age was 44.5 years, with three males and five females. On the initial computed tomography, cyst formation was found in seven patients (87.5%). All of the cysts were multiple, round, and thin walled, accompanying ground-glass attenuation (GGA) around cysts. In six patients (75%), cysts increased during their clinical courses, and the new cysts had emerged from GGA, although GGA was improved by treatment. In all four cases, whose pulmonary cysts could be pathologically evaluated, a marked plasma cell infiltration around the cyst wall, and loss of elastic fibers of the alveolar wall were observed. CONCLUSIONS: Pulmonary cysts emerged in the area of GGA pathologically consistent with plasma cell infiltration. Cysts in MCD may be formed by the loss of elastic fibers due to marked plasma cell infiltration and may be considered irreversible changes.

Nivolumab-induced Vogt-Koyanagi-Harada-like Syndrome and Adrenocortical Insufficiency with Long-term Survival in a Patient with Non-small-cell Lung Cancer.

A 58-year-old man was diagnosed with lung adenocarcinoma with a tumor proportion score of 10%. After six cycles of second-line chemotherapy with nivolumab, he achieved a complete response (CR) but developed uveitis and sensorineural hearing disorder, which were consistent with Vogt-Koyanagi-Harada (VKH)-like syndrome. Simultaneously, pituitary adrenocortical insufficiency was identified. Nivolumab discontinuation and systemic corticosteroid administration resolved these immune-related adverse events (irAEs). The patient has maintained a CR without any chemotherapy for approximately two years. We herein report a patient with a long-term progression-free survival despite chemotherapy discontinuation due to irAEs, including VKH-like syndrome, which were appropriately managed.

Effect of preoperative administration of methylpredonisolone and ulinastatin on tumor cell metastasis after surgical stress.

Using a rat laparotomy stress model, we conducted a comparative analysis of postoperative organ metastasis after administration of ulinastatin (UTI) or methylprednisolone (MP), which have an inhibitory effect on cytokine production. The subjects were classified into 4 groups: 1) minimal laparotomy group (C group), 2) major laparotomy group (L group), 3) preoperative MP intravenous administration + major laparotomy group (MP group), and 4) preoperative UTI intravenous administration + major laparotomy group (UTI group). Either MP or UTI was administered intravenously before surgery, and RI-labeled cells were injected into the portal vein immediately after laparotomy to collect tissue specimens in order to measure radiation dosage. Then, the concentrations of serum IL-2 and IL-6, liver interleukin 1 beta (IL-1ß) and interleukin 10 (IL-10), and liver E-selectin were measured. In addition natural killer cell, (NK cell) activation and neoplastic nodules on the liver surface at 3 weeks after surgery were also measured. The adhesion rate of malignant cells to the liver was higher in the L group than in the C group, higher in the MP group than the L group, and lower overall in the UTI group. The concentration of IL-1ß and IL-6 were decreased in the MP and UTI groups compared to the L group. IL-2 was decreased significantly in the MP group compared with the C and L groups. E-selectin expression level decreased in the UTI group compared with the L group. NK cell activation decreased in the MP group compared with the C group and L group, but no differences were observed between the UTI and L groups. The number of tumor nodules on the surface of the liver increased in the MP group compared with the L group, and decreased in the UTI group compared with the L group. Postoperative alleviation of invasive reaction was suggested in both the MP and UTI groups. However, preoperative administration of MP increased metastasis while that of UTI inhibited metastasis. MP was considered to have decreased anti-tumor immunocompetence and promoted metastasis, while UTI was considered to have inhibited the expression of adhesive molecules and decreased metastasis.

The effect of starvation on blood stream cancer cell metastasis to the liver in rat after laparotomy.

BACKGROUND: Preoperative malnutrition worsens the prognosis of cancer patients. However, it is not certain how preoperative malnutrition affects postoperative hematogenous metastasis. We examined the influence of preoperative starvation on liver metastasis in rats using intra-vascular injection of AH109A hepatoma cells. METHODS: Male donryu rats were divided into Fasting and Control groups. Rats received laparotomy and (125)I-iodo-deoxyuridine labeled AH109A hepatoma cells were inoculated via superior mesenteric vein. Radioactivity in the organs, macroscopic liver metastasis, white blood cell count, leukocyte count, NK cell activity, endogenous serum corticosterone and ACTH concentration and mRNA expression of cytokine in the liver and brain were evaluated at certain time points. RESULTS: 48hours preoperative starvation reduced body weight and induced a state of malnutrition. Accumulation of radioactivity in the liver was more than 4 times higher, and the number of liver metastases was 3.5 times higher in the Fasting than in the Control group. Preoperative starvation caused an almost 2 fold increase in plasma endogenous corticosterone levels and a 66% reduction in white blood cell and lymphocyte counts. Postoperative hypothalamus pituitary adrenal axis response was preserved. In addition, inflammatory cytokine expression in the liver was suppressed in the starved animals, suggesting that preoperative starvation led to a state of cellular immunosuppression, which would be an important factor for liver metastasis. CONCLUSION: Preoperative malnutrition by 48 hours starvation reduced inflammatory cytokine response and cellular immunity, resulting in an increase in hematogenous liver metastasis.

Effect of prophylactic intracerebroventricular injection of methylprednisolone on nitrogen and catecholamine excretion in the urine after laparotomy in rats.

BACKGROUND: This study was carried out to determine whether the prophylactic injection of glucocorticoid into the intracerebroventricular (i.c.v.) space reduced TNF-alpha and IL-1beta mRNA synthesis in the brain after laparotomy, resulting in a reduction of nitrogen excretion in the urine. PATIENTS AND METHODS: Male SD rats (body wt., 225-250 g, n = 114) were catheterized into the i.c.v. space on day 0. On day 4, the rats were assigned to four groups: (1) Control, (2) laparotomy (Trauma), (3) intraperitoneal (i.p.) injection of methylprednisolone (MP) plus laparotomy (IPMP), and (4) i.c.v. injection of MP plus laparotomy (ICVMP). Either 3 or 24 h after surgery, the animals were sacrificed. TNF-alpha and IL-1beta mRNA levels in tissues, including the brain cortex and hypothalamus, were measured by RT-PCR. The amounts of nitrogen and catecholamine excretion in the 24-h urine were determined. RESULTS: The i.p. injection of MP reduced TNF-alpha and IL-1beta mRNA levels in all the tissues 3 h after laparotomy compared with those of the Trauma group. The icv injection of MP prevented elevation of the TNF-alpha and IL-1beta mRNA levels in the brain (cortex, TNF-alpha, ICVMP 0.43 +/- 0.06, P < 0.05, vs Trauma; cortex, IL-1beta, ICVMP 0.25 +/- 0.09, P < 0.05, vs. Trauma; hypothalamus, TNF-alpha, ICVMP 0.31 +/- 0.04, P < 0.05, vs. Trauma; hypothalamus, IL-1beta, ICVMP 0.25 +/- 0.14, P < 0.05, vs. Trauma), but did not inhibit an increase in TNF-alpha and IL-1beta mRNA levels in the liver and skeletal muscle. Both nitrogen and catecholamine excretions in the urine were decreased by ip and by i.c.v. injection of MP compared to those of the Trauma group (nitrogen, ICVMP 559.3 +/- 52.0 mg/day, P < 0.05, vs. Trauma; catecholamine, ICVMP 13.8 +/- 1.8 microg/day, P < 0.05, vs. Trauma). CONCLUSION: A reduction in TNF-alpha and IL-1beta mRNA synthesis in the brain due to prophylactic injection of MP into the icv space reduced the catabolic response after laparotomy.