Adenocarcinoma arising in the multiple heterotopic submucosal glands of the intestine in a Satoyoshi syndrome patient: A case report.

Satoyoshi syndrome is a rare multisystemic disorder of unknown etiology characterized by progressive muscle spasms, alopecia and diarrhea. Multiple protruding lesions with cystic glands, namely gastroenterocolitis cystica polyposa, manifest in the gastrointestinal tract. Since the first report of these lesions in 1977, which was unique to Satoyoshi syndrome, few studies have focused on their role, and the associated clinicopathological features are not well understood. Here, we report a 64-year-old Japanese woman with Satoyoshi syndrome who presented with multiple polypoid lesions in the stomach, duodenum, jejunum, ileum and colon. Histologically, the polypoid lesions in the intestine comprised multiple heterotopic submucosal glands containing cystically dilated glands and smooth muscle fibers in the lamina propria mucosa and/or submucosa. Additionally, we observed stromal changes, such as fibrosis, discontinuous and thinning muscularis mucosae, and diffuse neural fiber proliferation in the entire intestinal tract. Furthermore, multiple foci of adenocarcinomas were identified within several heterotopic submucosal glands. We hypothesized that multiple heterotopic submucosal glands in the present case corresponded to previously reported gastroenterocolitis cystica polyposa, suggesting that these lesions are essential in the histopathology and are a unique manifestation of Satoyoshi syndrome.

Telementoring Demonstration in Craniofacial Surgery With HoloLens, Skype, and Three-Layer Facial Models.

BACKGROUND: Telementoring is the technology for providing surgical instruction from a remote place via a network. To demonstrate the use of telementoring in craniofacial surgery, Skype and a mixed reality device HoloLens were adopted, and 3-layer facial models had been developed. METHODS: A resident in hospital A used the model surgery under remote guidance by a mentor surgeon in hospital B 4 times on different dates. The straight-line between hospitals A and B is 250 km. The mentor gave the resident guidance via Skype and HoloLens, communicating by voice, and video of the surgical field, and providing reference data. RESULTS: There was no delay in voice communication and a delay of <0.5 seconds in the video. The resident was able to confirm the main landmarks of the surgical field and to grasp the situation without problems. The mentor could send appropriate instructions by voice, could point out a specific part by telestration function, and could draw lines on the 2-dimentional images pasted on the operator's field of vision. DISCUSSION: With the use of HoloLens, Skype, and the 3-layer models, it was possible to demonstrate telementoring. The risk of personal information leakage due to data interception seems to be very low because its data communication is encrypted with advanced encryption standard. CONCLUSION: This telementoring system has various advantages and many improvable aspects in the field of craniofacial surgery.

Robustness of Clonogenic Assays as a Biomarker for Cancer Cell Radiosensitivity.

Photon radiation therapy is a major curative treatment for cancer. However, the lack of robust predictive biomarkers for radiosensitivity precludes personalized radiation therapy. Clonogenic assays are the gold standard method for measuring the radiosensitivity of cancer cells. Although a large number of publications describe the use of clonogenic assays to measure cancer cell radiosensitivity, the robustness of results from different studies is unclear. To address this, we conducted a comprehensive detailed literature search of 256 common cancer cell lines and identified the eight cell lines most-frequently examined for photon sensitivity using clonogenic assays. Survival endpoints and experimental parameters from all 620 relevant experiments were compiled and analyzed. We found that the coefficients of variation for SF2 (surviving fraction after 2 Gy irradiation) and for D10 (dose that yields a surviving fraction of 10%) were below 30% for all cell lines, indicating that SF2 and D10 have acceptable inter-assay precision. These data support further analysis of published data on clonogenic assays using SF2 and D10 as survival endpoints, which facilitates robust identification of biological profiles representative of cancer cell sensitivity to photons.

Radiosensitivity Differences between EGFR Mutant and Wild-Type Lung Cancer Cells are Larger at Lower Doses.

In the era of precision medicine, radiotherapy strategies should be determined based on genetic profiles that predict tumor radiosensitivity. Accordingly, pre-clinical research aimed at discovering clinically applicable genetic profiles is needed. However, how a given genetic profile affects cancer cell radiosensitivity is unclear. To address this issue, we performed a pilot in vitro study by utilizing EGFR mutational status as a model for genetic profile. Clonogenic assays of EGFR mutant (n = 6) and wild-type (n = 9) non-small cell lung carcinoma (NSCLC) cell lines were performed independently by two oncologists. Clonogenic survival parameters SF2, SF4, SF6, SF8, mean inactivation dose (MID), D10, D50, α, and ß were obtained using the linear quadratic model. The differences in the clonogenic survival parameters between the EGFR mutant and wild-type cell lines were assessed using the Mann-Whitney U test. As a result, for both datasets, the p values for SF2, SF4, D50, α, and α/ß were below 0.05, and those for SF2 were lowest. These data indicate that a genetic profile of NSCLC cell lines might be predictive for their radiation response; i.e., EGFR mutant cell lines might be more sensitive to low dose- and low fraction sized-irradiation.

FGFR Signaling as a Candidate Therapeutic Target for Cancers Resistant to Carbon Ion Radiotherapy.

Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.

Macroscopic Localized Subicular Thinning as a Potential Indicator of Amyotrophic Lateral Sclerosis.

Subicular degeneration occurs in amyotrophic lateral sclerosis (ALS) patients. However, it was unknown whether microscopic subicular degeneration could be observed as macroscopic changes and whether these changes were associated with the transactive-response DNA binding protein 43 kDa (TDP-43) pathology. Topographic differences between subicular degeneration caused by ALS and Alzheimer disease (AD) had also not been characterized. Here we investigated the subiculum and related areas in autopsied brains from 3 ALS and 3 AD patients. Macroscopic subicular thinning and corresponding astrocytosis were pronounced in ALS compared to AD. This thinning was frequently accompanied by TDP-43 pathology in the transentorhinal cortex and nucleus accumbens. The preferential susceptibility of the perforant pathway to TDP-43 deposition may be an underlying cause of subicular thinning in ALS.

Novel Finding of an Excess Bone in Postaxial Polydactyly of the Foot.

Background: Postaxial polydactyly is a common congenital foot anomaly. However, the severity of the anomaly varies from simple cases with only soft tissue duplication to complex cases with bone and joint disorders. In our clinical practice, we found a new morphological anomaly of postaxial polydactyly. We encountered several cases of postaxial polydactyly with bone fragments located between the fourth and fifth toes. The bone fragments were independent of the joint cavity. The mechanisms underlying its development remain unknown because it is a novel disorder. In the present study, we investigated the characteristics of the excess bone to formulate an embryological hypothesis. Methods: We examined the frequency and trends in the occurrence of excess bone using data from photographs and radiographs of these cases. An example of a disorder similar to excess bone is mosaic-like alignment, as reported by Iba et al. We also compared the characteristics of the mosaic-like alignment with those of the excess bone. Based on these data and existing embryological knowledge, we hypothesized the origin of the excess bone. Results: Excess bone and mosaic-like alignments showed different characteristics. Therefore, both were considered completely different disorders. We hypothesized that excess bone was caused by damage to the interdigital ectoderm immediately before interdigital programmed cell death. Conclusions: We encountered a new form of postaxial polydactyly. This can be a factor influencing the treatment strategy because it can affect alignment and stability.

Bronchogenic cysts in rare sites (retroperitoneum, skin, spinal cord and pericardial cavity): A case series and characterization of epithelial phenotypes.

Bronchogenic cysts are congenital malformations of the bronchial tree, detected as a cystic and/or mass lesion in the thoracic cavity. Although it occurs in distant locations, such as skin and retroperitoneum, to the best of our knowledge, little is known about the components and phenotypes of the epithelium that line a bronchogenic cyst in rare sites. The present study reviewed 34 bronchogenic cysts that were surgically resected at Osaka Medical and Pharmaceutical University Hospital (Osaka, Japan) from January 1998 to December 2020. Bronchogenic cysts in rare sites were detected and diagnosis was confirmed based on the presence of pseudostratified, ciliated and/or columnar epithelium together with at least one of the following: Cartilage, smooth muscle or seromucous glands. The phenotypes of epithelium lining the cyst were characterized using immunohistochemical analysis. A total of six bronchogenic cysts in rare sites (two cases each in the retroperitoneum and skin and one case each in the cervical spinal cord and pericardial cavity) met the criteria for confirmation of the diagnoses. The epithelium lining the cyst stained positive for cytokeratin CK7 and thyroid transcription factor 1 (a marker expressed in thyroid follicles and bronchial epithelium) and negative for CK20, indicating that the phenotypes were similar to those of the respiratory epithelium. The present study demonstrated that a bronchogenic cyst can occur in rare sites, such as the retroperitoneum, skin, spinal cord and pericardial cavity, suggesting that it should be considered as a differential diagnosis before surgical approach to implement relevant management modalities such as follow-up, simple or radical resection.

Useful Genioplasty for Repeated Recurrent Sleep Apnea of Congenital Anomalies and Its Evaluation.

Congenital facial anomalies with hypoplasia of the midface or lower face are associated with obstructive apnea syndrome. Although such patients underwent bone advancement surgery and their sleep apnea improved in the short term, it often recurred several years after surgery. It is difficult to perform another major osteotomy because of impairment of the facial contour or prior orthodontic treatment. Genioplasty was performed for genioglossus muscle advancement in patients with congenital anomalies and repeated sleep apnea. In this study, we evaluated the usefulness of this procedure and the mechanism for the improvement of sleep apnea. Methods: Six patients were included: three with syndromic craniosynostosis, two with Treacher-Collins syndrome, and one with micrognathia by Goldenhar syndrome. Patients who had recurrence of sleep apnea after previous maxillomandibular osteotomies, or advancement and orthodontic treatment, received genioplasty for genioglossus muscle advancement. The patients were evaluated by body mass index, simple polysomnography, hyoid bone position on cephalogram, and the airway area on computed tomography images pre- and postoperatively. Results: Polysomnography showed a significant improvement in the apnea-hypopnea index. Cephalometric measurement showed significant results of the hyoid bone position from point B and the ramus plane. However, no significant results were obtained in the airway area assessment. Conclusions: Genioplasty for genioglossus muscle advancement can improve apnea-hypopnea index by moving the hyoid bone forward. Genioplasty was useful in patients with congenital anomalies who had a recurrence of sleep apnea after several procedures.

Left testicular and pulmonary metastases of mucinous adenocarcinoma of the prostate after robot-assisted radical prostatectomy.

Introduction: We present a case of mucinous adenocarcinoma of the prostate with testicular and lung metastases following robot-assisted radical prostatectomy, androgen deprivation therapy, and radiotherapy. Case presentation: A 73-year-old man with a prostate-specific antigen level of 4.3 ng/mL was diagnosed with prostate cancer. Following the robot-assisted radical prostatectomy, the pathological diagnosis was mucinous adenocarcinoma of the prostate (pT3bpN0, Gleason score of 4 + 4). Salvage hormonal therapy and irradiation were performed after the prostatectomy. Enlargement of the left testis was noted, and 28 months after prostatectomy, computed tomography detected a left testicular tumor and nodular lesions in the bilateral lungs. The histopathological diagnosis of left high orchiectomy was metastasis of a mucinous adenocarcinoma of the prostate. Chemotherapy with docetaxel followed by cabazitaxel was initiated. Conclusion: Mucinous prostate adenocarcinoma with distal metastases following prostatectomy has been managed for longer than 3 years with multiple treatments.

Glove-shaped Foam with Negative Pressure Wound Therapy for Skin Graft Fixation on the Hand.

Tie-over bolster dressing has been the gold standard for skin graft immobilization. However, skin grafting onto the hand remains challenging. To prevent shearing of the skin, joint fixation with Kirschner wire and casting is often required. However, wire fixation through the joint can disrupt finger growth and cause joint contracture, especially in pediatric patients. So, we performed graft fixation with negative pressure wound therapy (NPWT). The use of NPWT with skin grafting has recently been reported. Previous studies have reported that NPWT can provide even pressure on irregular wounds and in highly mobile areas. However, application of NPWT in the digital region often results in air leaks. This report includes four patients who required skin grafting on the hand. All patients received skin grafts in the affected area. Graft fixation was performed with NPWT. A glove-shaped form was designed. The hand was encased on the ventral and dorsal sides and small pieces of foam were placed between the fingers. The fixation was maintained for 7 days at a pressure of -50 to -80 mmHg. None of the cases had air leak requiring reattachment of the system and graft take was successful in all cases without any complications. The NPWT "glove-shape" technique enabled maintenance of average negative pressure for all skin grafts on the hand. This technique does not require joint fixation and may help to prevent growth disturbance and joint contracture.

New Notations for Better Morphological Distinction of Postaxial Polydactyly of the Foot.

There have been many reports on the classification and treatment of postaxial polydactyly of the foot. However, despite its being a common congenital anomaly, there is no universal notation about its morphology. Methods: We performed an analysis of 65 postaxial polydactyly cases from 2004 to 2021. Judgment criteria for deciding the surgical procedure were selected, and the points required for notation were decided. Based on them, we devised a new notation. Results: The necessary points required for notation were decided based on the following criteria: (1) the presence and level of syndactyly, (2) bifurcation level of the phalanges, (3) the presence of other deformities, and (4) predominant toes. We came up with a new notation and description method. Different types of syndactyly were represented using a horizontal bar, and predominant toes were represented using equality or inequality symbols. The bifurcation level of the phalanges and accessory deformities were additionally recorded (eg, 4-5>-6, Middle, 5,6: External rotation). From this notation, it is obvious which toe should be resected. Furthermore, syndactyly, accessory deformities, and the condition of the phalanges are also easily understood. Conclusions: Our new notation for postaxial polydactyly consists of some related symbols that are each provided a meaning. This system is simple, especially for easily understanding the morphology, and ideal for daily medical use. We conclude that it could become a universal notation method for cases of postaxial polydactyly of the foot.

First Human Cell Experiments With FLASH Carbon Ions.

BACKGROUND/AIM: This study aimed to establish a setup for ultra-high-dose-rate (FLASH) carbon-ion irradiation, and to conduct the first human cell experiments using FLASH carbon ions. MATERIALS AND METHODS: A system for FLASH carbon-ion irradiation (1-3 Gy at 13 or 50 keV/µm) was developed. The growth and senescence of HFL1 lung fibroblasts were assessed by crystal violet staining assays and senescence-associated ß-galactosidase staining, respectively. Survival of HSGc-C5 cancer cells was assessed by clonogenic assays. RESULTS: The dose rates of carbon ions ranged from 96-195 Gy/s, meeting the definition of FLASH. With both 13 and 50 keV/µm beams, no FLASH sparing effect was observed on the growth suppression and senescence of HFL1 cells, nor on the survival of HSGc-C5 cells. CONCLUSION: We successfully conducted the first human cell experiments with FLASH carbon ions. No FLASH effect was observed under the conditions examined.

Radiosensitization by the Selective Pan-FGFR Inhibitor LY2874455.

Ionizing radiation activates cytoprotective pathways in cancer cells. Fibroblast growth factor receptor (FGFR) is a key player in these pathways. Thus, FGFR signaling is a potential target to induce radiosensitization. LY2874455 is an orally administrable selective pan-FGFR inhibitor. However, the radiosensitizing effects of LY2874455 remain unclear. In this study, we addressed this issue by using radioresistant human cancer cell lines H1703 (FGFR1 mutant), A549 (FGFR1-4 wild-type), and H1299 (FGFR1-4 wild-type). At an X-ray dose corresponding to 50%-clonogenic survival as the endpoint, 100 nM LY2874455 increased the sensitivity of H1703, A549, and H1299 cells by 31%, 62%, and 53%, respectively. The combination of X-rays and LY2874455 led to a marked induction of mitotic catastrophe, a hallmark of radiation-induced cell death. Furthermore, combination treatment suppressed the growth of A549 xenografts to a significantly greater extent than either X-rays or the drug alone without noticeable toxicity. This is the first report to show the radiosensitizing effect of a selective pan-FGFR inhibitor. These data suggest the potential efficacy of LY2874455 as a radiosensitizer, warranting clinical validation.

64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity.

Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.

Simulation Surgery Using 3D 3-layer Models for Congenital Anomaly.

We made realistic, three-dimensional, computer-assisted 3-layered elastic models of the face. The surface layer is made of polyurethane, the intermediate layer is silicone, and the deep layer is salt, representing the skin, subcutaneous tissue, and the bone. We have applied these 3-layer models to congenital anomaly cases and have understood that these models have a lot of advantages for simulation surgery. METHODS: We made 8 models. The models consisted of 2 models of 2 cases with Crouzon disease, 1 model of Binder syndrome, 1 model of facial cleft, 2 models of one case with Goldenhar syndrome, 1 model of cleft lip and palate, and 1 model of the hemifacial macrosomia. RESULTS: We could try several methods, could recognize whether the graft size is adequate, and could visualize the change of the facial contour. We could analyze how to approach the osteotomy line and actually perform osteotomy. The changes of the lower facial contour can be observed. We grafted the models of the graft and confirmed that the incisions could be closed well. We were able to visualize the change in the soft tissue contour by simulating distraction. CONCLUSIONS: The most versatile merit of our models is that we could visualize the change of the soft tissue by movement of the hard tissue with bone graft, distraction osteogenesis, and so on. We must improve the model further to make it more realistic.

Comparison of Clonogenic Survival Data Obtained by Pre- and Post-Irradiation Methods.

Clonogenic assays are the gold standard to measure in vitro radiosensitivity, which use two cell plating methods, before or after irradiation (IR). However, the effect of the plating method on the experimental outcome remains unelucidated. By using common cancer cell lines, here we demonstrate that pre-IR and post-IR plating methods have a negligible effect on the clonogenic assay-derived photon sensitivity as assessed by SF2, SF4, SF6, SF8, D10, or D50 (N.B. SFx indicates the survival at X Gy; Dx indicates the dose providing X% survival). These data provide important biological insight that supports inter-study comparison and integrated analysis of published clonogenic assay data regardless of the plating method used.

Granulocyte colony-stimulating factor-producing squamous cell carcinoma of the tongue exhibiting characteristic fluorine-18 deoxyglucose accumulation on positron emission tomography-computed tomography: A case report.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is a cytokine produced in inflammatory environments that induces differentiation and proliferation of neutrophils in bone marrow. We report a rare case of aggressive G-CSF-producing squamous cell carcinoma of the tongue exhibiting fluorine-18 deoxyglucose (FDG) accumulation in primary lesion, metastatic lymph nodes, spleen, and bone marrow on positron emission tomography-computed tomography (PET/CT). CASE SUMMARY: We report a 58-year-old female with a rapid enlarged lingual mass with partial necrosis. Blood test results from the initial examination revealed a leukocyte count of 21380/µL. On PET/CT, extensive FDG accumulation was observed in the tongue and bilateral cervical lymph nodes, with elevated FDG accumulation in the spleen and bone marrow although no distant metastases were observed. We performed partial glossectomy and bilateral neck dissection. Immunohistochemical staining with G-CSF antibodies on biopsy specimen and resected samples revealed that both specimens were G-CSF positive. This is a rare case of G-CSF producing tongue carcinoma with elevated FDG accumulation in the spleen and bone marrow. CONCLUSION: In patients with the tongue cancer and hyperleukocytosis, where FDG accumulations in the spleen and bone marrow are observed using PET/CT and when these accumulations are not caused by metastasis, G-CSF-producing tumors, with associated poor prognosis, should be considered.

Induction of Micronuclei in Cervical Cancer Treated with Radiotherapy.

Micronuclei (MN) trigger antitumor immune responses via the cyclic GMP-AMP synthase-signaling effector stimulator of interferon genes (cGAS-STING) pathway. Radiotherapy induces MN in peripheral blood lymphocytes. However, data for solid tumors are lacking. Here, we analyzed MN post-radiotherapy in solid tumor samples. Tumor biopsy specimens were obtained from seven prospectively recruited patients with cervical cancer, before treatment and after receiving radiotherapy at a dose of 10 Gy (in five fractions). The samples were stained with 4',6-diamidino-2-phenylindole dihydrochloride, and 200 nuclei per sample were randomly identified and assessed for the presence of MN or apoptosis, based on nuclear morphology. The median number of MN-harboring nuclei was significantly greater in samples from patients treated with radiotherapy than in pre-treatment samples (151 (range, 16-327) versus 28 (range, 0-61); p = 0.015). No significant differences in the number of apoptotic nuclei were observed between pre-treatment and 10 Gy samples (5 (range, 0-30) versus 12 (range, 2-30); p = 0.30). This is the first report to demonstrate MN induction by radiotherapy in solid tumors. The results provide clinical evidence of the activation of antitumor immune responses by radiotherapy.