Anti-cancer effect of afatinib, dual inhibitor of HER2 and EGFR, on novel mutation HER2 E401G in models of patient-derived cancer.

BACKGROUND: Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. METHODS: We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. RESULTS: We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. CONCLUSIONS: Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.

Adenoid Basal Carcinoma with Adenoid Cystic Carcinoma Component of the Uterine Cervix: A Case Report and Literature Review.

Adenoid basal carcinoma (ABC) is rare cancer with a favorable prognosis. However, some ABCs are associated with other histological types, such as squamous cell carcinoma. Here, we present a case of a mixed tumor of ABC and adenoid cystic carcinoma (ACC) of the cervix, with a detailed immunohistochemical study and literature review. We describe a case of a 66-year-old woman who underwent cervical cancer screening that led to the detection of a 0.7 cm nodular lesion. Cervical punch biopsies revealed a high-grade squamous intraepithelial lesion. Cervical conization revealed a mixed carcinoma composed of ABC and ACC, showing stromal invasion, lymphovascular invasion, and positive resection margins. Immunohistochemically, the ACC components were positive for KIT and αSMA and negative for NKX3.1. The tumor presented with proficient mismatch repair (MMR) and was negative for HER2, PD-L1, and TRKA (NTRK1). Subsequent radical hysterectomy with pelvic lymph node dissection revealed the presence of residual tumor cells in the cervix. Our literature review identified six similar cases, including one patient who died of disease recurrence. We report a rare tumor comprising both ABC and ACC. Prognostic data on mixed tumors are scarce; however, given the aggressive nature of ACC, attention should be paid to the detection of mixed tumors. Since ABC and ACC histology may overlap, adequate sampling and IHC for detecting ACC would be helpful.

Cytological Comparison between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Image Analysis Software Using Touch Smear Samples of Surgically Resected Specimens.

To investigate useful cytological features for differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), this study cytologically compared HCC to ICC using image analysis software. Touch smear specimens of surgically resected specimens were obtained from a total of 61 nodules of HCC and 16 of ICC. The results indicated that the major/minor axis ratio of ICC is significantly larger than that of HCC (1.67 ± 0.27 vs. 1.32 ± 0.11, p < 0.0001) in Papanicolaou staining. This result means that the nucleus of HCC is close to round and the nucleus of ICC is close to an oval. This significant difference in the major/minor axis ratio between ICC and HCC was consistently observed by the same analyses using clinical samples of cytology (4 cases of HCC and 13 cases of ICC) such a fine-needle aspiration, brushing and ascites (ICC: 1.45 ± 0.13 vs. HCC: 1.18 ± 0.056, p = 0.004). We also confirmed that nuclear position center-positioned nucleus (p < 0.0001) and granular cytoplasm (p < 0.0001) are typical features of HCC tumor cells compared to ICC tumor cells. The research study found a significant difference in the nuclear morphology of HCC (round shape) and ICC (oval shape) in Papanicolaou-stained cytology specimens. This simple and objective finding will be very useful for the differential cytodiagnosis of HCC and ICC.

Effects of Fat Repositioning for Tear Trough Deformity on Eye Movement.

ABSTRACT: Fat repositioning is a common surgical technique for treating tear trough deformity. As this technique is mainly performed for cosmetic purposes, its functional outcomes have rarely been evaluated. The purpose of this study was to evaluate the changes in eye movements that occur after fat repositioning for tear trough deformity. The authors performed fat repositioning on 18 eyelids of 9 patients and evaluated their eye movements and binocular vision before surgery and at 1, 3, and 6 months after surgery. Hess screen and Binocular single vision tests were performed during each follow-up examination and the scores were recorded. The authors observed that fat repositioning did not affect binocular vision; however, vertical and horizontal eye movements worsened at 3 months after surgery. Nevertheless, there was no significant difference between the eye movements recorded before surgery and those recorded 6 months after surgery. Regardless of this finding, it should be noted that vertical or horizontal strabismus might occur after fat repositioning for tear trough deformity.

Cytological Appearances of Ovarian Seromucinous Borderline Tumor in Ascites: Presentation of 2 Cases.

BACKGROUND: Seromucinous borderline tumor (SMBT) is a rare neoplasm which was newly defined in the 2014 WHO classification. Although the clinical and histopathological characteristics of SMBT have been well described, its cytological characteristics have not. We recently experienced 2 cases of SMBT which were defined by cytological findings of ascites. CASE PRESENTATION: Case 1 was a 65-year-old Japanese woman. Preoperative imaging studies revealed abundant ascites and a cystic tumor, with a solid component measuring 13 cm on the left ovary. Radical surgery was performed during the intraoperative diagnosis of ovarian borderline tumor, made by histological examinations of frozen tumor sections. The cytological smears of preoperatively and intraoperatively collected ascites showed many atypical cells resembling reactive mesothelial cells. Alcian-blue staining of cell block sections revealed intracytoplasmic mucin, and the results of immunohistochemistry were consistent with SMBT. The final pathological diagnosis of tumor was SMBT. Case 2 was a 28-year-old Japanese woman. Preoperative imaging studies revealed a small amount of ascites and cystic tumors with solid components in the bilateral ovaries. She initially underwent fertility preservation surgery. SMBT was suspected by cytological examination of smears of intraoperatively collected ascites and the findings of cell block. She underwent additional radical surgery based on a final pathological diagnosis of SMBT. CONCLUSION: In our experience, the tumor cells of SMBT in ascites mimicked reactive mesothelial cells. The nuclear atypia of SMBTs was intermediate between that of reactive mesothelial cells and serous carcinoma. The immunohistochemistry and mucin staining using cell block were very helpful for facilitating the cytodiagnosis of SMBT.

Comparison of postoperative recurrence rates between levator aponeurosis advancement and external Müller's muscle tucking for acquired blepharoptosis.

Treatment options for acquired blepharoptosis include levator resection, levator aponeurosis advancement (LAA), Müller's muscle-conjunctival resection (MMCR), and frontalis suspension. Previously, we reported a technique called external Müller's muscle tucking (EMMT) using the Müller's muscle as a power source. In this study, we compare LAA with EMMT and evaluate the recurrence and reoperation rates. LAA was performed on 96 eyelids in 51 patients. The average follow-up period was 12.2 months, recurrence occurred in four eyelids (4.2%) of three patients, and reoperation was required in one eyelid of one patient (2.0%). EMMT was performed on 94 eyelids in 51 patients, the mean follow-up period was 10.5 months, recurrence occurred in 14 eyelids (15%) of 10 patients, and reoperation was required in three eyelids of two patients (3.9%). A comparison of LAA and EMMT recurrence showed that EMMT was associated with a significantly higher recurrence rate (P = 0.0021). The causes of EMMT recurrence included thinning and fatty degeneration of Müller's muscles, necrosis of ligated Müller's muscles, and less postoperative scar formation. There was no correlation between EMMT recurrence and the severity of the blepharoptosis.

A New Surgical Method for Medial Ectropion Repair: Fixing the Lower Eyelid Retractor to the Back of the Tarsal Plate.

ABSTRACT: Involutional ectropion is a disease in which the eyelids are everted outwards, and because the eyelids move away from the eyeballs, the ocular surface and conjunctiva are exposed causing inflammation, pain, photophobia, foreign body sensation, epiphora, and blurred vision. It is thought to be caused by horizontal and vertical laxity. Various surgical methods have reportedly been used to correct involutional ectropion. Shortening the lower eyelid retractor (LER) is an indispensable surgical operation for medial ectropion. When the LER is shortened, it is usually fixed to the lower edge of the tarsal plate. Herein we describe a new type of surgery that has now been performed on 6 eyes in 4 patients. The procedure involves separating the conjunctiva from the tarsal plate, inserting the LER between the conjunctiva and the tarsal plate, and then fixing it to the back of the tarsal plate. In all 6 eyes, the lower eyelid now contacts the eyeball, and morphological improvements were achieved. This new surgical method is a useful way to raise the tarsal plate.

Gingival Sulcus Incision for Zygomaticomaxillary Complex Fracture.

The usual surgical approaches for zygomaticomaxillary complex fracture are subciliary incision, transconjunctival incision, eyebrow incision, lateral canthal incision, coronal incision, preauricular incision, and superior gingivobuccal incision. In the intraoral approach, a horizontal mucoperiosteal incision is performed at the superior gingivobuccal region, and sometimes, includes the upper labial frenum. This may cause discomfort in the oral cavity because of postoperative scarring and shortening of the upper labial frenum. To avoid these complications, the authors performed a novel approach using gingival sulcus incision instead of oral mucosal incision to treat 5 zygomatic fractures. The authors evaluated the regression of the gingival interdental papillae, gingival swelling, and gingival perception at 2 weeks, 1 month, 3 months, and 6 months after the operation. The regression of the gingival papillae and gingival swelling disappeared 3 months and 1 month after the operation, respectively. No paresthesia was observed in any of the cases. The gingival sulcus approach can lead to scarless results and contribute considerably to the aesthetic appearance of the oral cavity.

In vivo profiling of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced estrogenic/anti-estrogenic effects in female estrogen-responsive reporter transgenic mice.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to simply as "dioxin", is a persistent environmental pollutant. Because of its high environmental persistence and biological accumulation, humans and animals are often exposed to TCDD. Therefore, the harmful effects on humans and animals is a major concern. Although studies have elucidated the adverse estrogenic and anti-estrogenic effects of TCDD, it is unclear in which tissues TCDD exerts these effects in vivo. To investigate the estrogen-related effects of TCDD in various tissues, we generated an improved estrogen-responsive reporter transgenic mouse in which the luciferase gene luc2 is expressed in response to estrogenic signals. Using these mice, we clarified that TCDD inhibits estrogenic signaling in liver and kidney but enhances estrogenic signaling in the pituitary gland in the same individual. Expression of aryl hydrocarbon receptor, aryl hydrocarbon receptor nuclear translocator, and estrogen receptor alpha mRNA was detected in liver, kidney, and pituitary gland, suggesting that the effects of TCDD on estrogenic signaling in these organs is independent of the expression pattern of these receptors. Thus, our results indicate that TCDD exerts both estrogenic and anti-estrogenic tissue-specific effects within the same individual.

Negative Pressure Wound Therapy Followed by Basic Fibroblast Growth Factor Spray as a Recovery Technique in Partial Necrosis of Distally Based Sural Flap for Calcaneal Osteomyelitis: A Case Report.

The distally based sural flap is regarded as the first choice for reconstruction in the distal part of the lower leg because the flap is easy to raise, reliable in its blood supply, and prone to only a few complications. Limited data have investigated the details of treatment in cases of failure of distally based sural flaps. We report a case of calcaneal osteomyelitis in which a successful outcome was finally obtained with a partially necrosed, distally based sural flap using negative pressure wound therapy with basic fibroblast growth factor spray. The 2-year follow-up examination was uneventful. Moreover, the patient was able to walk freely with an ankle-foot orthosis in her house. This technique can be considered as a useful and effective option to recover unfavorable results of distally based sural flaps.