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Abstract Hemolytic anemia is a rare and unique complication of alectinib, not observed with other anaplastic lymphoma kinase (ALK) inhibitors. Here, we present a case of an ALK fusion‐positive non‐small‐cell lung cancer (NSCLC) patient who developed liver failure due to diffuse liver metastasis at initial diagnosis. Treatment was initiated with low‐dose alectinib, but the patient developed severe hemolytic anemia. Switching to lorlatinib allowed for the continuation of ALK inhibitor therapy and successful tumor reduction. ALK inhibitors are crucial for ALK fusion‐positive NSCLC patients. Managing severe side effects by switching medications is essential to maintain effective therapy. In this case, lorlatinib effectively controlled the tumor and improved the patient's liver function and performance status. This case highlights the importance of adapting treatment strategies to manage adverse effects while ensuring the continued use of ALK inhibitors for optimal patient outcomes.

Abstract Introduction Comprehensive genome profiling (CGP) has revolutionized healthcare by offering personalized medicine opportunities. However, its real‐world utility and impact remain incompletely understood. This study examined the extent to which CGP leads to genomically matched therapy and its effectiveness. Methods We analyzed data from advanced solid tumor patients who underwent CGP panel between December 2019 and May 2023 at the Osaka International Cancer Institute. Patient demographics, specimen details, and expert panel assessments were collected. Turnaround time (TAT) and genomically matched therapy outcomes were analyzed. Gene alterations and their co‐occurrence patterns were also assessed. Results Among 1437 patients, 1096 results were available for analysis. The median TAT was 63 [28–182] days. There were 667 (60.9%) cases wherein recommended clinical trials were presented and there were 12 (1.1%) cases that could be enrolled in the trial and 25 (2.3%) cases that could lead to therapies under insurance reimbursement. The median progression free survival of the trial treatment was 1.58 months (95% CI: 0.66–4.37) in clinical trials and 3.66 months (95% CI: 2.14–7.13) in treatment under insurance. Pathologic germline variants were confirmed in 15 patients (1.3%). Co‐alteration of CDKN2A, CDKN2B, and MTAP was significantly observed in overall population. Conclusion The effectiveness of the genomically matched therapy based on the CGP panel was unsatisfactory. Expansion of clinical trials and utilization of remote clinical trials are required to ensure that the results of the CGP panel can be fully returned to patients.

Abstract Background It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. Methods We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. Results Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. Conclusions For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

Abstract In this study, we investigated the association between PD‐L1 expression in tumor cells and underlying genetic mutations, which was analyzed in detail using laser microdissection and next‐generation sequencing analysis. To investigate whether driver mutations are involved in the background of PD‐L1 expression, the EGFR major activating mutation was selected as the most frequent driver mutation. Surgical resection specimens were used to extract sufficient amounts of nucleic acids for analysis, and the high tumor proportion score (TPS:100%) and low (TPS: 0%) PD‐L1‐expressing parts of the tumor were each laser microdissected to examine the association between PD‐L1 expression heterogeneity and genetic mutations within the same tumor. The association between PD‐L1 heterogeneity and gene mutations within the same tumor was investigated. Analysis showed no association between PD‐L1 expression heterogeneity and genetic variants, which were found to be almost identical. However, PD‐L1 expression was found to be associated with the number of tumor infiltrating lymphocytes (TILs) present in the tumor, which may be related to whether or not lymphocytes can infiltrate into the tumor depending on the tumor histological type (solid pattern, lepidic pattern, etc.) and other factors.

Abstract Background Cytology is a fast and simple modality for identifying malignancies and tumor histology. In this study, we analyzed the sensitivity of cytology for liver tumor biopsy and evaluated its potential for prompt clinical diagnosis. Methods This retrospective study included patients who had concurrently undergone conventional cytology, on‐site cytology, and histopathology for ultrasound‐guided liver tumor biopsies. In the case of malignant tumors, malignancy was first diagnosed, then preliminary clinical diagnosis was established using histology based on cytology and clinical information, followed by histopathological diagnosis. Sensitivity of malignancy detection was evaluated by comparison with histopathological diagnosis. Results Of the 191 tumors, 164 (85.9%) were malignant. The sensitivity of conventional cytology for malignancy detection was 97.6%. The sensitivity of non‐hepatocellular carcinoma (non‐HCC) (99.3%) detection was higher than that of the HCCs (87.5%; p = 0.001). The sensitivity of on‐site cytology for malignancy detection was as high as that of conventional cytology. Similar to conventional cytology, the sensitivity of on‐site cytology for non‐HCC detection (99.3%) was higher than that for HCCs (79.2%; p

Abstract Aim Appropriate sample selection with a tumor fraction ≥20% without necrosis contamination is required for successful cancer genomic profiling (CGP). Rapid on‐site evaluation (ROSE) is performed to assess adequate sampling. Method This retrospective study included 54 patients who underwent CGP using liver tumor biopsy specimen with ROSE. Result The sampling success rate (98.1%) was higher than the previously reported 77.5%–88.9%. ROSE was performed once in 51 patients and twice in three patients; for those undergoing ROSE twice, the first ROSE was negative for malignancy, or showed few tumor cells with necrotic cell contamination, while the second ROSE obtained from another location showed abundant malignant cells. In these patients, the CGP was successful using the second specimen, though the first sample did not meet the required criteria for CGP test. Conclusion Performing ROSE during liver tumor biopsy may be useful for CGP test sampling because ROSE prevents sampling errors and contributes to adequate sampling.

Abstract Rapid and reliable identification of targetable driver mutations in patients with advanced stage lung cancer is essential. Adequate amount of tumor tissue biopsies (i.e., genomic biopsies) are required to successfully analyze the gene panel. In the present case, we performed three pleural fluid investigations, including transbronchial biopsy of the primary tumor, transesophageal endoscopic ultrasound‐guided fine needle aspiration (EUS‐FNA) of lymph node metastasis, and thoracoscopic biopsy of the pleural seeding sites. Among the three investigations, thoracoscopic biopsy alone successfully obtained a sufficient amount of tissue. Thus, it is important to determine the technique and site of biopsy, as multiple biopsies are not only burdensome to the patient, but also lead to significant delays in therapy induction.

Abstract Background The usefulness of comprehensive genomic profiling (CGP) panels for thoracic malignancies after completion of the standard treatment is unclear. Methods The results of CGP panels for malignant thoracic diseases performed at our hospital between December 2019 and June 2022 were collected. We examined whether CGP panel results led to new treatment, correlated with the effectiveness of immune checkpoint inhibitors (ICIs), or revealed secondary findings related to hereditary tumors. Results A total of 60 patients were enrolled, of which 52 (86.6%) had lung cancer. In six (10%) patients, the panel results led to treatment with insurance‐listed molecular‐targeted agents; four patients had EGFR mutations not detected by the real‐time polymerase chain reaction assay and two had MET ex.14 skipping mutations. In small‐cell lung cancer, the tumor mutation burden was high in 4/6 (66.7%) patients and pembrolizumab was available. Another MET ex.14 skipping mutation was detected in two cases with EGFR‐tyrosine kinase inhibitor resistance. ICI efficacy was ≤1 year in patients with STK‐11, KEAP1, and NEF2L2 mutations. A BRCA2 mutation with a high probability of germline mutation was detected in one patient. A thymic carcinoma with no detectable oncogenic mutation responded to second‐line treatment with Tegafur‐Gimeracil‐Oteracil Potassium (TS‐1) for ≥9 years. Conclusions CGP panels are useful in thoracic malignancies, especially lung cancer, because they can detect overlooked driver mutations and genetic alterations. We believe that the significance of conducting a CGP panel prior to treatment may also exist, as it may lead to the prediction of ICI treatment efficacy.

Immune checkpoint inhibitor (ICI)-related myocarditis has been reported to appear in the early phase after ICI initiation. Herein, we report the case of a 78-year-old man with non-small cell lung cancer. Pembrolizumab was introduced as first-line therapy. After 9 months, second-line therapy, including bevacizumab, was initiated. After another 7 months, echocardiography showed diffuse left ventricular dysfunction. Based on the histopathologic examination of the myocardium, the patient was diagnosed with ICI-related myocarditis. Initiation of prednisolone therapy improved cardiac function. This case of late-onset ICI-related myocarditis illustrates that endomyocardial biopsy can be useful in the differential diagnosis of cancer-related left ventricular dysfunction. Résumé: Il a été rapporté qu’une myocardite pouvait survenir peu après l’instauration d’un traitement par des inhibiteurs des points de contrôle immunitaire (ICI). Nous présentons le cas d’un homme de 78 ans atteint d’un cancer du poumon non à petites cellules. Le pembrolizumab a été administré comme traitement de première intention. Neuf mois plus tard, un traitement de deuxième intention par le bévacizumab a été instauré. Après sept autres mois, l’échocardiographie a montré une dysfonction ventriculaire gauche diffuse. À la suite des résultats de l’examen histopathologique du myocarde, une myocardite liée aux ICI a été diagnostiquée. L’instauration d’un traitement par la prednisolone a amélioré la fonction cardiaque du patient. Ce cas de myocardite tardive liée aux ICI montre l’utilité éventuelle de la biopsie de l’endomyocarde dans le diagnostic différentiel d’une dysfonction ventriculaire gauche liée au cancer.

Abstract Introduction Success of next generation sequencing (NGS) analysis is becoming indispensable in the treatment of advanced lung cancer. However, the advantages and disadvantages of each sampling method in the NGS analysis have not yet been clarified. Methods We compared the success rates of NGS analysis, and DNA and RNA yields for transbronchial biopsy (TBB), endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA), computed tomography (CT)‐guided biopsy, fluid sample, and surgical biopsy for NGS analysis in patients through the lung cancer genomic screening project for individualized medicine (LC‐SCRUM)‐Asia, a nationwide NGS screening project. In case, sufficient samples could not be collected by TBB and EBUS‐TBNA, re‐biopsy (genome re‐biopsy) was performed. Results A total of 223 patients were enrolled and success rates of NGS analysis were not different between samples obtained through TBB, EBUS‐TBNA, and CT‐guided biopsy; however, success rates for fluid samples and surgical biopsy samples were significantly higher than those of other methods. The risk of genome re‐biopsy was higher with TBB for centrally located lesions. CT‐guided biopsy yielded more samples but had a lower success rate for analysis of RNA‐based NGS than TBB. Conclusions TBB is the mainstay of sampling methods, but for centrally located lesions, EBUS‐TBNA may be a better strategy. For CT‐guided biopsy, the success rate of RNA‐based NGS analysis is low. Fluid samples are expected to yield successful results as surgical biopsy samples, but the latter are better for sample preservation. Determining the optimal method for genome biopsy for each case is important.

Abstract Background Type A thymomas comprise a homogenous population of neoplastic epithelial cells that are characterized by a spindle/oval shape without nuclear atypia. They may be accompanied by few non-neoplastic lymphocytes. Most type A thymomas are detected in the earlier Masaoka stages. Compared to other thymoma subtypes, they rarely metastasize or recur. There have been some reports of patients with type A thymomas with pulmonary metastasis; however, these thymomas were 20 mm or more in size. Herein, we report the case of a patient who underwent surgical resection for a small-sized type A thymoma (12 mm) with pulmonary metastasis. Case presentation A 62-year-old patient presented with an abnormal shadow in the left lung on plain chest radiography during a medical checkup. Chest computed tomography revealed a 12-mm tumor in the anterior mediastinum and a 13-mm nodule in the left lower lobe. 18F-fluorodeoxyglucose positron emission tomography/computed tomography revealed uptake in the anterior mediastinal tumor, but did not show a significant uptake in the pulmonary nodule. The patient underwent surgical resection on two separate occasions, and was diagnosed with an atypical type A thymoma and pulmonary metastasis. The TNM classification was p-T1aN0M1b stage IVb, and it was stage IVb according to the Masaoka staging system. No recurrence was observed during the follow-up. Conclusions We report a case of the smallest type A thymoma with pulmonary metastasis. Pulmonary metastasis secondary to a type A thymoma should be considered even if the thymoma is small in size (

Abstract Background We report a patient with thymic squamous cell carcinoma who underwent multiple rounds of surgical resection and definitive radiotherapy for both primary tumor and postoperative recurrence. However, the patient remains well and healthy 18 years after initial diagnosis. Since long-term survival after postoperative recurrence of thymic carcinoma is extremely rare, we also present her immunohistochemical staining results, which suggested indolent disease. Case presentation A 42-year-old woman with thymic squamous cell carcinoma underwent en bloc resection of the tumor and thymus gland. Pleural dissemination was noted in the right thoracic cavity 3, 10, and 16 years postoperatively. Where possible, the nodules were resected surgically: during the postoperative 3rd and 16th years. Definitive radiotherapy was administered for all nodules that could not be excised during the postoperative 3rd and 10th years. Disease-free survival is 25 months. Conclusions Local control of pleural dissemination may be beneficial in the treatment of postoperative recurrence of thymic carcinoma in limited cases of indolent disease.

Liver metastasis is not uncommon in various malignant tumors. Most of liver metastases present as discrete masses. However, liver metastases can appear as diffuse infiltrating neoplasms. Infiltration of malignant cells can provoke hepatic fibrosis, which mimics cirrhosis. Progress of diffuse type of liver metastasis remains unclear because of its difficulty in diagnosis or aggressive nature. In this report, we describe a 27-year-old woman with diffuse type of liver metastasis from renal cell carcinoma. The present case showed atypical findings of clinical images on liver examinations, which was histologically diagnosed as a focally spared region in diffuse type of liver metastasis by needle biopsy. Liver fibrosis was not observed in the biopsy specimen. Our case report suggests that liver biopsy is essential for diagnosis of diffuse type of liver metastasis, and the spared region can be observed in the metastatic process of the diffuse type.

Adenosquamous carcinoma of the sinonasal tract is extremely rare. We report a case of such tumor in a 66-year-old Japanese male who presented with a 3.0-cm tumor in the maxillary sinus. The tumor mass filled the maxillary sinus, and part of the maxillary sinus floor was destroyed. Histological analysis showed that tumor cells with a marked atypia and pleomorphism with a high nuclear-cytoplasm ratio infiltrated beneath the mucosa. The tumor formed invasive nests and cribriform structures, and these structures were partially accompanied by marked necrosis. Additionally, tendency toward keratinization and peripheral palisading were present in the nests, and neoplastic cells showed varying cellular morphology including clear cells, where immunohistochemically positive staining for p63, p40 and CK5/6 was observed. While, immunoreactivity for these markers was absent in some of cribriform structures and solid nests, as well as areas showing fine nesting and cells surrounding glandular lumina. p16 was negative throughout the tumor, while p53 positive staining was detected throughout the tumor. CDX2 expression was observed in some solid nests. The tumor could be termed adenosquamous carcinoma, and also simultaneously considered to be essentially an adenocarcinoma derived from the ciliated epithelium of the maxillary sinus mucosa gradually increasing nuclear atypia with partial squamous metaplasia. The morphological transition was more clearly recognized in the p53 immunostaining. The patient died of disease two years after the primary surgery. This tumor is considered a histological type that can be fatal, and clinical attention is especially required when such a tumor encountered.

SCLC transformation in EGFR-mutated lung adenocarcinoma is one of the major phenotypic changes that is observed during the resistance to EGFR tyrosine kinase inhibitors. However, the mechanism of this transformation remains unclear. In this study, we found a small de novo SCLC component in surgically resected specimens of EGFR-mutated lung adenocarcinoma before EGFR tyrosine kinase inhibitor treatment. By using laser microdissection and whole-exome sequencing, TP53 loss of heterozygosity was found to be possibly involved in SCLC transformation.

The recent increase in the number of molecular targeted agents for lung cancer has led to the demand for the simultaneous testing of multiple genes. Although gene panels using next-generation sequencing (NGS) are ideal, conventional panels require a high tumor content, and biopsy samples often do not meet this requirement. We developed a new NGS panel, called compact panel, characterized by high sensitivity, with detection limits for mutations of 0.14%, 0.20%, 0.48%, 0.24%, and 0.20% for EGFR exon 19 deletion, L858R, T790M, BRAF V600E, and KRAS G12C, respectively. Mutation detection also had a high quantitative ability, with correlation coefficients ranging from 0.966 to 0.992. The threshold for fusion detection was 1%. The panel exhibited good concordance with the approved tests. The identity rates were as follows: EGFR positive, 100% (95% confidence interval, 95.5–100); EGFR negative, 90.9 (82.2–96.3); BRAF positive, 100 (59.0–100); BRAF negative, 100 (94.9–100); KRAS G12C positive, 100 (92.7–100); KRAS G12C negative, 100 (93.0–100); ALK positive, 96.7 (83.8–99.9); ALK negative, 98.4 (97.2–99.2); ROS1 positive, 100 (66.4–100); ROS1 negative, 99.0 (94.6–100); MET positive, 98.0 (89.0–99.9); MET negative 100 (92.8–100); RET positive, 93.8 (69.8–100); RET negative, 100 (94.9–100). The analytical performance showed that the panel could handle various types of biopsy samples obtained by routine clinical practice without requiring strict pathological monitoring, as in the case of conventional NGS panels.

Abstract Tirabrutinib (ONO/GS-4059; Ono Pharmaceutical) is a newly developed drug that selectively and irreversibly inhibits Bruton’s tyrosine kinase (BTK) and has been approved in Japan for treating relapsed/refractory primary central nervous system lymphoma (PCNSL). However, its therapeutic effect is yet to be verified at the pathological level in human patients. A 64-year-old patient with recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL. The left cerebellum lesions on magnetic resonance imaging disappeared one month after tirabrutinib treatment. The patient died because of suspected pneumocystis pneumonia and acute exacerbation of interstitial pneumonia 43 days after starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire brain, including the left cerebellum lesion, confirming complete obliteration of tumor cells by tirabrutinib. This letter pathologically confirms the effect of tirabrutinib on relapsed/refractory PCNSL for the first time in humans. Trial registration: JapicCTI-173646. Registered 14 July 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646.

A SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rapidly progressing subtype of lung cancer with a poor prognosis and causes early postoperative recurrence among operable patients. In this study, we present a case of SMARCA4-UT with vertebral and chest wall invasion that successfully underwent conversion surgery after treatment with atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin. The surgical specimen comprised SMARCA4-deficient and SMARCA2-positive adenocarcinoma, confirming intratumor heterogeneity. Gene panel analysis revealed no substantial differences in mutant gene profiles among tumors and no differences in SMARCA2 mutations. Furthermore, no recurrence occurred for 9 months after surgery. Thus, this case illustrates the possibility of multidisciplinary treatment including neoadjuvant therapy with immunotherapy and conversion surgery for SMARCA4-UT.

Abstract Background Hemorrhagic hepatic cysts infrequently involve several iconographic changes requiring a differential diagnosis, primarily with a cystic malignancy. We herein report a case of laparoscopy-assisted extended right hepatectomy for a giant hemorrhagic hepatic cyst with an enhancing mural nodule that was clinically suspected of being biliary cystadenocarcinoma. Case presentation A 73-year-old woman was followed up for giant hepatic cyst occupying the right lobe of the liver. During the follow-up, an enhancing mural nodule was newly noted on computed tomography in 2016. Based on additional clinical examinations, biliary cystadenocarcinoma was undeniable, and laparoscopy-assisted extended right hepatectomy was performed for diagnostic and therapeutic purposes. She had no perioperative complications and was discharged on postoperative day 13. A histological examination of the mural nodule showed neovascularization within an organized hematoma. Conclusion We herein report a rare case of giant hemorrhagic hepatic cyst mimicking biliary cystadenocarcinoma that was successfully treated with laparoscopy-assisted extended right hepatectomy. Laparoscopic surgery in our case was an effective procedure performed with the utmost care.

Recent studies demonstrated that homologous repair deficiency (HRD) score is a useful marker for response to poly (ADP-ribose) polymerase inhibitors or platinum-based chemotherapy. We determined HRD scores and elucidated the clinicopathologic characteristics of HRD-high tumors and their response to non-platinum-based chemotherapy. Primary breast cancer patients (n = 120) were pre-operatively treated with paclitaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide (P-FEC). Germline and somatic homologous recombination related gene mutations (gHRRm and sHRRm, respectively) and HRD scores were analyzed using whole exome sequencing (WES) in tumor tissues obtained before chemotherapy. Of 120 tumors, 30 were determined to be HRD-high tumors, significantly associated with high Ki-67 (P = 0.014), ER negativity (P = 0.007), and PR negativity (P = 0.021). Triple-negative cancers showed significantly higher HRD scores than the luminal, luminal-HER2, and HER2 subtypes (P = 0.023, 0.016, and 0.033, respectively). HRD scores were significantly higher in tumors with gHRRm than in those with sHRRm (P = 0.002) or wild-type HRR genes (P = 1.44e-4), but no significant difference was found in HRD scores between tumors with sHRRm and wild-type HRR genes (P = 0.206). HRD-high tumors had significantly (P = 0.003) higher pCR rates and higher near-pCR rates (P = 0.049) compared with those of the HRD-low tumors in all tumors and the luminal subtype, respectively. HRD-high tumors were associated with aggressive phenotypes and gHRRm, but not sHRRm. Our findings suggested that HRD scores might be useful in predicting response to P-FEC in the luminal subtype.