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Crizotinib, a first-generation anaplastic lymphoma kinase ( ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 ( EML4)- ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925 LPE3- CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925 LPE3 cell line, which harbors the EML4- ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925 LPE3- CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor ( EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti- EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin ( AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4- ALK lung cancer. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) improve the outcomes of several types of cancer. However, they are also associated with various immune-related adverse events including myocarditis. ICI-induced myocarditis is a rare, potentially life-threatening adverse event. We herein report two cases of corticosteroid-refractory ICI-induced myocarditis. In both cases, additional immunosuppressive therapies, such as intravenous immunoglobulin and tacrolimus, successfully resolved myocarditis. Given the corticosteroid-refractory nature of these cases, we suggest that prompt addition of other immunosuppressive drugs to corticosteroid therapy should be considered in the treatment of ICI-induced myocarditis.

We report a case of limited effectiveness of dabrafenib and trametinib in a 59-year-old man with poorly differentiated lung carcinoma and a rare BRAF K601E mutation. The patient, unresponsive to chemotherapy and immunotherapy, received these targeted agents as second-line treatment. Despite a notable initial response, tumor regression lasted only 52 days. A subsequent liquid biopsy revealed additional alterations ( BRAF amplification, KIT amplification, TP53 S241F), indicating a complex resistance mechanism. This case underscores the challenges in treating BRAF K601E-mutant lung carcinoma, emphasizing the need for advanced molecular diagnostics, personalized approaches, and further research into more effective therapies for unique genetic profiles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nishiyama, Sato, Sakaguchi, Kotani, Yamashita, Ohtsubo, Nanjo, Yano, Mizuguchi, Ikeda and Takeuchi.)

Leptomeningeal carcinomatosis (LMC) remarkably decreases the quality of life of EGFR-mutant lung cancer patients. In contrast to the lesions outside the central nervous system (CNS), molecular mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance in CNS lesions including LMC are largely unknown. In this study, we established an in vivo imaging model for LMC with EGFR mutant lung cancer cell lines harboring an exon 19 deletion in EGFR and evaluated the effect of first generation EGFR-TKIs, erlotinib, second generation afatinib, and third generation AZD9291. In PC-9/ffluc model, erlotinib treatment slowed the development of LMC. Importantly, treatment with afatinib or AZD9291 apparently delayed the development of LMC. Moreover, treatment with a higher dose of AZD9291, also associated with inhibited phosphorylation of EGFR downstream molecule S6, regressed LMC refractory to the aforementioned EGFR-TKI treatments. These observations suggest that the third generation EGFR-TKI AZD9291 may be an effective treatment for first or second generation EGFR-TKI resistant LMC caused by EGFR-mutant lung cancer.

Context: Pancreatic cancer is frequently complicated by malignancies in other organs. However, synchronous triple cancers including pancreatic cancer have been seldom reported in the English language literature., Case Report: We describe the rare case of a 77-year-old man with triple cancers of the pancreas, stomach, and cecum. Biopsies revealed that all three tumors were adenocarcinomas. The pancreatic and gastric tumors were positive for cytokeratin 7 and negative for cytokeratin 20, whereas the cecal tumor was negative for cytokeratin 7 and positive for cytokeratin 20. K-ras mutations were present at codon 12 in the pancreatic tumor and at codon 13 in the cecal tumor, but were absent from the gastric tumor. Since the three tumors had different characteristics, the patient was diagnosed with synchronous triple cancers. Because invasive surgery was required to remove all three tumors and the patient had risk factors for surgery, we elected to treat him with chemotherapy. All three cancers were markedly reduced in size by treatment with cycles of 100 mg/day S-1 for 2 weeks, followed by a 1-week rest. The patient later developed hypoproteinemia and anasarca, which was diagnosed as pancreatic exocrine insufficiency due to pancreatic head cancer. Treatment with pancrelipase resulted in dramatic improvements in hypoproteinemia and anasarca., Conclusions: This is the first case report in which S-1 was effective in triple cancers of the pancreas, stomach, and cecum. Patients with pancreatic head cancer should be monitored for pancreatic exocrine insufficiency.

Safety of pemetrexed mono-therapy in elderly patients with non-small-cell lung cancer was examined between May 2009 and April 2010 at Kobe City Medical Center General Hospital . The numbers of non-elderly and elderly(over 70 years old)patients were 14 and 19, respectively. Rates of neutropenia over Grade 3 were 14. 3% in the non-elderly group, and 36. 8% in the elderly group(p=0. 297). However, febrile neutropenia was only seen in one case in each group(p=0. 606), and no treatment-related death was observed. Although the rates of rash appearance were 28. 6% and 36. 8%(p=0. 347)for the non-elderly and the elderly, respectively, most rashes were relieved by steroids. From these results, pemetrexed mono-therapy is considered one of the applicable regimens for elderly patients.

A 74-year-old woman diagnosed with poorly-differentiated neuroendocrine carcinoma originating from the ascending colon was referred to our hospital. She had felt anorexia, abdominal pains and her (ECOG) performance status was 3. Her CT scan showed that some abdominal lymph nodes were swelling and that there were many metastatic lesions occupying most of the liver. We started chemotherapy with cisplatin and irinotecan according to a regimen for small cell lung cancer. Considering her poor PS, both of the drugs were administered at 30mg/m² twice 4 weeks in the first course of chemotherapy. Her anorexia and abdominal pains immediately disappeared, and CT scan showed that all of the metastases were decreased in size. After 4 courses, however, some of the metastatic lesions were increased in size. She died 8 months after diagnosis. The tumor marker doubling time was 17 days.

We report a 53-year-old man with cancer of an unknown primary site with an epidermal growth factor receptor mutation for which gefitinib was effective. In 2007, he complained of left gluteal pain and right cervical lymph node swelling. He was given a diagnosis of adenocarcinoma at the biopsy of the right cervical lymph node. Although metastases of multiple lymph nodes, bone, and bilateral adrenal glands were found, the primary site could not be determined on close examination, resulting in a diagnosis of cancer of unknown primary site(poor prognosis group). He was then treated with systemic chemotherapy. After he showed resistance to chemotherapy, he received gefitinib as third-line therapy because the tumor harbored an epidermal growth factor receptor(EGFR)mutation. Subsequently, multiple metastatic tumors gradually reduced and clinical benefit was observed for a long time.

Background: The administration of opioids to outpatients with cancer pain can be difficult because the constant dose modification and treatments of side effects involved are occasionally impossible. Therefore, more effective and safer drugs with better patients compliance are needed to complete a successful opioid introduction. Compared with other opioids, low-dose fentanyl has been suggested to produce milder side effects such as nausea, constipation, and somnolence. Further more, compliance can be improved because the drug is a patch,administered transdermally., Methods: Between July 2008 and December 2009, we investigated the safety and analgesic effect of a fentanyl patch (2.1 mg) as a direct opioid introduction for 36 outpatients with cancer pain without titrations of other opioids., Results: Side effects of constipation, nausea, somnolence, and dizziness were observed in 17 (47%), 6 (17%), 4 (11%), and 3 (8%) patients, respectively, and no respiratory suppression was observed. Regarding the analgesic effect, 23 (64%) patients reported improvement on pain scales one week after the initiation of the fentanyl patch., Conclusions: Opioid introduction to opioid-naÏve outpatients with cancer pain using the low-dose fentanyl patch (2.1 mg) may be effective.

Clinically amyopathic dermatomyositis (CADM) is a subgroup of dermatomyositis that manifests with characteristic cutaneous lesions and mild or no muscle involvement. It is known that rapidly progressive interstitial pneumonia with a poor prognosis can occur in patients with CADM. The anti-CADM-140 antibody is thought to be useful as a specific serological marker for CADM. We encountered 4 patients with the anti-CADM-140 antibody. All patients complained of cutaneous lesions and dyspnea. Chest X-ray films and CT scans showed ground-glass opacities (GGO) and consolidation in the lower lobes. All cases were treated with pulse methylprednisolone, cyclophosphamide therapy and cyclosporine. Three patients died of respiratory failure and 1 improved. Anti-CADM-140 antibody-positive cases are likely to have poor prognoses and should be treated by intensive therapy as soon as possible.

Case one was a 76-year-old woman. She was diagnosed as having lung adenocarcinoma with multiple metastases (cT4N0M1, stage IV, mucinous BAC)in June, 2004. Starting in July, 2004, she received various modalities of chemotherapy( cisplatin+vinorelbine, gefitinib, pemetrexed, gemcitabine, docetaxel, paclitaxel). S-1 monotherapy given to her starting April, 2006 achieved a partial response(PR)as a seventh-line treatment. Case two was a 60-year-old woman. She was diagnosed as having lung adenocarcinoma with multiple metastases(cT4N3M1, stage IV)in October, 2004. That month, her chemotherapy began. After various treatments(cisplatin+vinorelbine, docetaxel, gefitinib), S-1 monotherapy was initiated in February, 2007 as the fourth-line treatment; as a result, PR was achieved. Even though chemotherapies were performed in succession, in the condition of good general status, salvage chemotherapy can be affected by the rotation of drugs. In such cases, S-1 monotherapy can be a reasonable choice from the standpoint of feasibility and effectiveness.