The growth rate of the humerus: long-term follow-up of treatment of solitary bone cyst of the proximal humerus using cannulated screws: a case report

Although the growth of the proximal epiphysis of the humerus is thought to contribute 80% of the total increase in humeral length, few articles have provided evidence for this. A 9-year-old boy with a pathological fracture at the humeral neck, owing to a solitary bone cyst, was treated by the decompression method using cannulated screws for 7.5 years. During this period, we measured the longitudinal humeral bone growth. The value obtained for the longitudinal growth contribution of the proximal humerus was 88% in this particular case.     

Comparison of the images in virtual bronchoscopy under different conditions

OBJECTIVE: We report herein the comparison of the virtual bronchoscopy (VB) images which were constructed with 2 different computed tomography (CT) scanners combined with 3 different applications in 2 healthy adult volunteers. METHODS: CT scanners were multi-detector row CT (MDCT) [64 detectors] and MDCT (16 detectors). Applications, by which VB images were made, were Leonardo (Leo), Ziostation (Zio), and Plus XNVZ2 (Plus). The image quality was evaluated by 3 expert bronchoscopists. RESULTS: The change of the threshold value was necessary in Leo for practical use in subsegmental bronchi and more distal area, but unnecessary in Plus or Zio. When Plus was used, the VB images from the data obtained with MDCT (16 detectors) and MDCT (64 detectors) had almost equal quality. CONCLUSIONS: Although the process to construct VB images was different in each application, it was regarded that Plus was not inferior to Zio or Leo in VB image quality.     

Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients

The Japanese guidelines for the testing of KRAS mutations in colorectal cancer have been used for the past 5 years. However, new findings of RAS (KRAS/NRAS) mutations that can further predict the therapeutic effects of anti‐epidermal growth factor receptor (EGFR) antibody therapy necessitated a revision of the guidelines. The revised guidelines included the following five basic requirements for RAS mutation testing to highlight a patient group in which anti‐EGFR antibody therapy may be ineffective: First, anti‐EGFR antibody therapy may not offer survival benefit and/or tumor shrinkage to patients with expanded RAS mutations. Thus, current methods to detect KRAS exon 2 (codons 12 and 13) mutations are insufficient for selecting appropriate candidates for this therapy. Additional testing of extended KRAS/NRAS mutations is recommended. Second, repeated tests are not required for the detection; tissue materials of either primary or metastatic lesions are applicable for RAS mutation testing. Evaluating RAS mutations prior to anti‐EGFR antibody therapy is recommended. Third, direct sequencing with manual dissection or allele‐specific PCR‐based methods is currently applicable for RAS mutation testing. Fourth, thinly sliced sections of formalin‐fixed, paraffin‐embedded tissue blocks are applicable for RAS mutation testing. One section stained with H&E should be provided to histologically determine whether the tissue contains sufficient amount of tumor cells for testing. Finally, RAS mutation testing must be performed in laboratories with appropriate testing procedures and specimen management practices.     

Impacts of the STING‐IFNAR1‐STAT1‐IRF1 pathway on the cellular immune reaction induced by fractionated irradiation

Radiotherapy (RT) combined with immune checkpoint inhibitors has recently produced outstanding results and is expected to be adaptable for various cancers. However, the precise molecular mechanism by which immune reactions are induced by fractionated RT is still controversial. We aimed to investigate the mechanism of the immune response regarding multifractionated, long‐term radiation, which is most often combined with immunotherapy. Two human esophageal cancer cell lines, KYSE‐450 and OE‐21, were irradiated by fractionated irradiation (FIR) daily at a dose of 3 Gy in 5 d/wk for 2 weeks. Western blot analysis and RNA sequencing identified type I interferon (IFN) and the stimulator of IFN genes (STING) pathway as candidates that regulate immune response by FIR. We inhibited STING, IFNAR1, STAT1, and IFN regulatory factor 1 (IRF1) and investigated the effects on the immune response in cancer cells and the invasion of surrounding immune cells. We herein revealed type I IFN‐dependent immune reactions and the positive feedback of STING, IRF1, and phosphorylated STAT1 induced by FIR. Knocking out STING, IFNAR1, STAT1, and IRF1 resulted in a poorer immunological response than that in WT cells. The STING‐KO KYSE‐450 cell line showed significantly less invasion of PBMCs than the WT cell line under FIR. In the analysis of STING‐KO cells and migrated PBMCs, we confirmed the occurrence of STING‐dependent immune activation under FIR. In conclusion, we identified that the STING‐IFNAR1‐STAT1‐IRF1 axis regulates immune reactions in cancer cells triggered by FIR and that the STING pathway also contributes to immune cell invasion of cancer cells.     

RET fusion gene: Translation to personalized lung cancer therapy

Development of lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, depends in many cases on the activation of “driver” oncogenes such as KRAS, epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK). Inhibitors that target the EGFR and ALK tyrosine kinases show therapeutic effects against LADCs containing EGFR gene mutations and ALK gene fusions, respectively. Recently, we and others identified the RET fusion gene as a new targetable driver gene in LADC. The RET fusions occur in 1–2% of LADCs. Existing US Food and Drug Administration‐approved inhibitors of RET tyrosine kinase show promising therapeutic effects both in vitro and in vivo, as well as in a few patients. Clinical trials are underway to investigate the therapeutic effects of RET tyrosine kinase inhibitors, such as vandetanib (ZD6474) and cabozantinib (XL184), in patients with RET fusion‐positive non‐small‐cell lung cancer.     

KRAS mutations detected by the amplification refractory mutation system-Scorpion assays strongly correlate with therapeutic effect of cetuximab

Background:

We aimed to compare the sensitive and quality-controlled KRAS testing with direct sequencing and to assess the impact on decision making of treatment.

Patients and methods:

We analysed genomic DNA isolated from macrodissected formalin-fixed paraffin-embedded specimens by direct sequencing and an amplification refractory mutation system–Scorpion assay (ARMS/S) method. Cetuximab was administered to patients identified as having wild-type (WT) KRAS using direct sequencing. Therapeutic effects were evaluated according to their KRAS status as determined by ARMS/S.

Results:

Among the 159 patients, the overall mutation rate was determined to be 37.0% by direct sequencing and 44.0% by ARMS/S. For the patients diagnosed as WT by direct sequencing and treated with cetuximab (n=47), a response rate of 16.0% was observed for 38 ARMS/S WT patients, whereas 9 ARMS/S mutant (MUT) patients failed to respond. The ARMS/S WT patients showed significant improvement in progression-free survival (PFS) and overall survival (OS) compared with ARMS/S MUT patients (PFS median 5.0 vs 1.7 months, hazards ratio (HR)=0.29, P=0.001; OS median 12.1 vs 3.8 months, HR=0.26, P=0.001).

Conclusion:

Sensitive and quality-controlled KRAS testing may provide improved predictive power to determine the efficacy of anti-epidermal growth factor antibodies.     

Clinicopathological characteristics of EGFR mutated adenosquamous carcinoma of the lung

Adenosquamous carcinoma of the lung (Ad‐Sq) is an uncommon subtype with poor prognosis. We analyzed the clinicopathological characteristics of Ad‐Sq, focusing the correlation between Epidermal Growth Factor Receptor (EGFR) mutation and clinicopathological factors. A total of 67 cases were selected from September 1992 to May 2011. EGFR mutational analysis (n = 59) was performed by direct sequence. We also performed immunohistochemical staining for EGFR mutated cases using the two mutation‐specific antibodies for deletion and L858R. Postoperative 3‐year survival rate of Ad‐Sq was 58.7%, statistically worse in comparison with adenocarcinoma (58.7% vs. 78.1%, P = 0.038). Twenty‐four percent (14/59) were positive for EGFR mutations. Patients who had never been smokers and who were lymphatic permeation positive were seen more frequently in the mutation positive group (P = 0.035, 0.027, respectively). Moreover, the EGFR mutated group tended to have a more positive prognosis than negative. Focusing on the pathological features, the lepidic growth pattern was more frequently seen in the positive group (P = 0.018). Immunoreactivity for the DEL‐specific and L858‐specific antibody were observed in both adenocarcinoma and squamous cell carcinoma components. Our study demonstrated that EGFR mutated Ad‐Sq had similar clinicopathological features as EGFR mutated adenocarcinoma.     

Clinical practice guidance for next‐generation sequencing in cancer diagnosis and treatment (Edition 1.0)

In Japan, the social (medical) health‐care system is on the way to being developed to advance personalized medicine through the implementation of cancer genomic medicine, known as “cancer clinical sequencing,” which uses a next‐generation sequencer. However, no Japanese guidance for cancer genomic testing exists. Gene panel testing can be carried out to help determine patient treatment, confirm diagnosis, and evaluate prognostic predictions of patients with mainly solid cancers for whom no standard treatment is available. This guidance describes how to utilize gene panel testing according to the type of cancer: childhood cancer, rare cancer, carcinoma of unknown primary, and other cancers. The level of evidence classification for unified use in Japan is also detailed. This guidance establishes the basic principles of the quality control of specimens, requirements of medical institutions, informed consent, handling of data during the postanalysis stage, and treatment options based on the evidence level. In Japan, gene panel testing for cancer treatment and diagnosis is recommended to comply with this guidance. This is a collaborative work of the Japanese Society of Medical Oncology, Japan Society of Clinical Oncology, and the Japanese Cancer Association.     

Chronological improvement in precision oncology implementation in Japan

In Japan, comprehensive genomic profiling (CGP) tests for refractory cancer patients have been approved since June 2019, under the requirement that all cases undergoing CGP tests are annotated by the molecular tumor board (MTB) at each government‐designated hospital. To investigate improvement in precision oncology, we evaluated and compared the proportion of cases receiving matched treatments according to CGP results and those recommended to receive genetic counseling at all core hospitals between the first period (11 hospitals, June 2019 to January 2020) and second period (12 hospitals, February 2020 to January 2021). A total of 754 and 2294 cases underwent CGP tests at core hospitals in the first and second periods, respectively; 28 (3.7%) and 176 (7.7%) patients received matched treatments (p < 0.001). Additionally, 25 (3.3%) and 237 (10.3%) cases were recommended to receive genetic counseling in the first and second periods, respectively (p < 0.001). The proportion was associated with the type of CGP test: tumor‐only (N = 2391) vs. tumor‐normal paired (N = 657) analysis (10.0% vs. 3.5%). These results suggest that recommendations regarding available clinical trials in networked MTBs might contribute to increasing the numbers of matched treatments, and that tumor‐normal paired rather than tumor‐only tests can increase the efficiency of patient referrals for genetic counseling.