Long-term outcomes of stimulated salivary flow and xerostomia after definitive intensity-modulated radiation therapy for patients with head and neck cancer†.

This retrospective study aimed to evaluate the time to recovery from xerostomia and analyze its predictors, along with long-term outcomes of stimulated salivary flow after intensity-modulated radiation therapy (IMRT) for head and neck cancer (HNC). We evaluated patients with HNC who had received IMRT with curative intent between 2012 and 2018 at our institution. The salivary recovery ratio (SRR) was defined as '(the stimulated salivary flow)/(pre-treatment salivary flow)'. The cutoff value of SRR in salivary recovery was estimated via the relationship between SRR and xerostomia grades. The salivary recovery time was defined as the time for SRR to exceed cutoff values from the end of radiotherapy. Fifty-seven patients were analyzed, with a 48-month median follow-up period of stimulated salivary flow. The cutoff value for SRR was 44.8%, and patients with a higher grade of xerostomia had a lower SRR (P < 0.001). The median salivary recovery time was 12 months. The cumulative incidence rates of salivary recovery at two and four years were 84 (95% confidence interval [CI]: 53-79) and 92% (95% CI: 82-97), respectively, and these were significantly lower in patients with a higher mean parotid gland dose, mean oral cavity dose and stimulated salivary flow per parotid gland volume. Stimulated salivary flow and xerostomia recover over a long period after radiotherapy.

Awareness of children's developmental problems and sharing of concerns with parents by preschool teachers and childcare workers: The Japanese context.

BACKGROUND: This study aims to determine the extent to which preschool teachers and childcare workers are aware of the presence of developmental problems among children and to what extent they share information with parents about their concerns regarding a child's development or diagnosis of neurodevelopmental disorders (NDDs). METHODS: We wrote to all 924 preschools and childcare centres in Japan's Nagano and Yamanashi prefectures to request participants. We then sent survey forms to the preschools and childcare centres that agreed to cooperate for three grades comprising 3-, 4- and 5-year-olds in the school year 2020. We asked the staff member in charge of each child to complete the survey. The survey included questions about the teacher's concerns regarding the possibility of an NDD and whether the matter had been shared with the children's parents. RESULTS: We obtained data for 10 354 children from 206 preschools and childcare centres (response rate = 22.3%). Among these children, 457 (4.4%) had an NDD diagnosis that their parents shared with the teachers. However, the teachers of 1274 children (12.3%) had concerns regarding their development but were not informed by the parents about the diagnosis, if any. These 1274 children included 775 (60.8%) cases where the teachers failed to share their concerns with parents because (1) the teachers could not communicate with parents (n = 119), (2) the teachers were not sure if there was a neurodevelopmental problem (n = 360) and (3) the parents were not aware of the problem (n = 296). CONCLUSIONS: Preschool teachers and childcare workers had concerns about the development of a substantial proportion of children in their charge. However, teachers and childcare workers did not share their concerns regarding many children's developmental problems with their parents. The findings suggest that there are challenges in information-sharing between teachers/childcare workers and parents.

Clonal Origin and Lineage Ambiguity in Mixed Neuroendocrine Carcinoma of the Uterine Cervix.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state.

Long-term survival outcomes and recurrence patterns of olfactory neuroblastoma: A 13-year experience at a single institution.

OBJECTIVES: Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare malignant neoplasm of the nasal vault and anterior skull base. The results of treatment for ONB are relatively good; however, regional and distant metastases can develop several years after definitive treatment. This study aimed to validate the treatment modality of ONB for oncological outcomes, especially for regional recurrence. METHODS: We retrospectively reviewed the medical records of 22 patients diagnosed with ONB at Kyoto University Hospital between 2009 and 2020. Descriptive statistics were calculated, and Kaplan-Meier curves were used. RESULTS: The median follow-up time was 58.2 months. One (4.5%) patient was clinically node positive, (cN+) and the remaining 21 (95.5%) were clinically node negative (cN0) at presentation. Eighteen patients underwent an endoscopic endonasal approach (EEA) for primary resection, and the remaining four patients underwent a combined EEA and transcranial approach. Elective neck dissection was not performed for 21 patients with cN0 ONB, whereas unilateral neck dissection with removal of ipsilateral lateral retropharyngeal node was performed for one patient with cN+ ONB. Postoperative radiotherapy without concurrent chemotherapy was performed only at the primary tumor bed for 21 patients with cN0 ONB, and at the primary tumor bed and bilateral neck for one patient with cN+ ONB. The 5-year overall, disease-specific, and disease-free survival rates were 94.1%, 100%, and 69.6%, respectively. No patients developed local recurrence, but 6 (27.2%) patients experienced recurrence with a median time to recurrence of 36.4 months, including four and two patients who initially developed regional recurrences and bone metastases, respectively. Five (22.7%) patients had delayed neck recurrence. The salvage rate was only 60.0% in the five patients who had delayed neck recurrence. Regarding the level of delayed neck recurrence, 4 (18.2%) patients had lateral retropharyngeal lymph node metastases. CONCLUSION: Patients with ONB have excellent survival outcomes after endoscopic surgical resection of the primary lesion with postoperative radiotherapy only to the primary tumor bed. Despite excellent survival, delayed neck recurrence, including the lateral retropharyngeal lymph node, remains high. Because salvage surgery for lateral retropharyngeal lymph node recurrence is sometimes technically difficult, it may be better to extend the field of postoperative radiotherapy from the primary tumor bed only to include bilateral lateral retropharyngeal lymph node regions in patients with clinically N0 ONB. Further prospective studies with a large number of patients are needed to determine the extent of postoperative radiotherapy.

Application of a Flexible PET Scanner Combined with 3 T MRI Using Non-local Means Reconstruction: Qualitative and Quantitative Comparison with Whole-Body PET/CT.

PURPOSE: Flexible positron emission tomography (fxPET) employing a non-local means reconstruction algorithm was designed to fit existing magnetic resonance imaging (MRI) systems. We aimed to compare the qualitative and quantitative performance of fxPET among fxPET with MR-based attenuation correction (MRAC), fxPET with CT-based attenuation correction (CTAC) using CT as a part of WB PET/CT, and whole-body (WB) PET/CT. PROCEDURES: Sixteen patients with suspected head and neck cancer underwent 2-deoxy-2-[18F]fluoro-D-glucose WB PET/CT scans, followed by fxPET and 3 T MRI scans. Phantom data were compared among the three datasets. For registration accuracy, we measured the distance between the center of the tumor determined by fxPET and that in MRI. We compared image quality, detection rates, and quantitative values including maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and tumor-to-muscle ratio (TMR) among the three datasets. RESULTS: The phantom data in fxPET, except the percent contrast recoveries of 17-mm and 22-mm hot spheres, were inferior to those in WB PET/CT. The mean registration accuracy was 4.4 mm between fxPET using MRAC and MRI. The image quality was comparable between two fxPET datasets, but significantly inferior to WB PET/CT (p < 0.0001). In contrast, detection rates were comparable among the three datasets. SUVmax was significantly higher, and MTV and TLG were significantly lower in the two fxPET datasets compared with the WB PET/CT dataset (p < 0.005). There were no significant differences in SUVmax, MTV, and TLG between the two fxPET datasets or in TMR among the three datasets. All quantitative values had significantly positive correlations. CONCLUSIONS: Compared with WB PET/CT, the phantom data and image quality were inferior in fxPET. However, the results of the detection rates and quantitative values suggested the clinical feasibility of fxPET.

Efficacy of local salvage therapy for recurrent uterine cervical cancer after definitive radiotherapy.

BACKGROUND: The prognosis of patients with recurrence of uterine cervical cancer after definitive radiotherapy and the efficacy of local salvage therapy for recurrence were evaluated. METHODS: We retrospectively reviewed 110 patients who were treated with definitive radiotherapy/chemoradiotherapy for uterine cervical cancer between 2008 and 2017 at our institution. Local salvage therapy was defined as any surgery or radiotherapy described in the medical record as intended for local control or cure. RESULTS: We identified 25 patients who developed recurrence after definitive radiotherapy/chemoradiotherapy. The median follow-up time post-recurrence was 18.9 months. Thirteen patients (52%) reported recurrence in the isolated extra-pelvic lymph node (EPLN). The 2-year overall survival after first recurrence (OSr) for patients with isolated EPLN recurrence was 83.1%, compared to that of 31.2% for patients with other patterns of recurrence (p < 0.001). The 2-year OSr for patients who underwent local salvage therapy was 75.2%, whereas that for patients who did not undergo therapy was 41.6% (p = 0.04). Among patients who had recurrence in the isolated EPLN and received local salvage therapy, 20% of the patients reported recurrence in visceral and/or bone metastases after local salvage therapy, and 50% of the patients experienced another EPLN recurrence, which was salvaged with repeating local therapy. CONCLUSIONS: Patients with uterine cervical cancer with isolated EPLN recurrence had favorable prognoses. The indications of local salvage therapy should be considered, especially for patients with isolated EPLN recurrence.

Reducing variability among treatment machines using knowledge-based planning for head and neck, pancreatic, and rectal cancer.

PURPOSE: This study aimed to assess dosimetric indices of RapidPlan model-based plans for different energies (6, 8, 10, and 15 MV; 6- and 10-MV flattening filter-free), multileaf collimator (MLC) types (Millennium 120, High Definition 120, dual-layer MLC), and disease sites (head and neck, pancreatic, and rectal cancer) and compare these parameters with those of clinical plans. METHODS: RapidPlan models in the Eclipse version 15.6 were used with the data of 28, 42, and 20 patients with head and neck, pancreatic, and rectal cancer, respectively. RapidPlan models of head and neck, pancreatic, and rectal cancer were created for TrueBeam STx (High Definition 120) with 6 MV, TrueBeam STx with 10-MV flattening filter-free, and Clinac iX (Millennium 120) with 15 MV, respectively. The models were used to create volumetric-modulated arc therapy plans for a 10-patient test dataset using all energy and MLC types at all disease sites. The Holm test was used to compare multiple dosimetric indices in different treatment machines and energy types. RESULTS: The dosimetric indices for planning target volume and organs at risk in RapidPlan model-based plans were comparable to those in the clinical plan. Furthermore, no dose difference was observed among the RapidPlan models. The variability among RapidPlan models was consistent regardless of the treatment machines, MLC types, and energy. CONCLUSIONS: Dosimetric indices of RapidPlan model-based plans appear to be comparable to the ones based on clinical plans regardless of energies, MLC types, and disease sites. The results suggest that the RapidPlan model can generate treatment plans independent of the type of treatment machine.

Treadmill Exercise after Controlled Abnormal Joint Movement Inhibits Cartilage Degeneration and Synovitis.

Cartilage degeneration is the main pathological component of knee osteoarthritis (OA), but no effective treatment for its control exists. Although exercise can inhibit OA, the abnormal joint movement with knee OA must be managed to perform exercise. Our aims were to determine how controlling abnormal joint movement and treadmill exercise can suppress cartilage degeneration, to analyze the tissues surrounding articular cartilage, and to clarify the effect of treatment. Twelve-week-old ICR mice (n = 24) underwent anterior cruciate ligament transection (ACL-T) surgery on their right knees and were divided into three groups as follows: ACL-T, animals in the walking group subjected to ACL-T; controlled abnormal joint movement (CAJM), and CAJM with exercise (CAJM + Ex) (n = 8/group). Walking-group animals were subjected to treadmill exercise 6 weeks after surgery, including walking for 18 m/min, 30 min/day, 3 days/week for 8 weeks. Safranin-O staining, hematoxylin-eosin staining, and immunohistochemical staining were performed. The OARSI (Osteoarthritis research Society international) score was lower in the CAJM group than in the ACL-T group and was even lower in the CAJM + Ex group. The CAJM group had a lower meniscal injury score than the ACL-T group, and the CAJM + Ex group demonstrated a less severe synovitis than the ACL-T and CAJM groups. The observed difference in the perichondrium tissue damage score depending on the intervention method suggests different therapeutic effects, that normalizing joint motion can solve local problems in the knee joint, and that the anti-inflammatory effect of treadmill exercise can suppress cartilage degeneration.

Effects of exercise therapy on joint instability in patients with osteoarthritis of the knee: A systematic review.

Objective: Abnormal load stress caused by joint instability has been reported to be one of the factors responsible for the development of osteoarthritis (OA). However, few studies have investigated the efficacy of exercise therapy for patients with knee instability-induced OA, and there are no specific treatment guidelines or effects for this form of OA. Therefore, the purpose of this study was to examine the effect of exercise treatments for joint instability in patients with knee OA by a systematic review. Design: Systematic review. Results: Searches in three databases, PubMed, Cochrane, and the Physiotherapy Evidence Database, yielded 14 articles that were scrutinized, and 6 articles that met the inclusion criteria were selected. Conclusions: Exercise therapy focusing on joint instability, including muscle maintenance and strength training, and specific training targeting knee instability have no additional beneficial effects on knee joint instability. However, because of the benefits of treatment protocols based on patient attributes in exercise treatment focused on joint instability, it is necessary to investigate the effects in more detail in the future.

Effects of Controlling Abnormal Joint Movement on Expression of MMP13 and TIMP-1 in Osteoarthritis.

OBJECTIVE: Abnormal joint movement is associated with osteoarthritis (OA). Previous studies using the controlling abnormal joint movement (CAJM) model of OA reported delayed cartilage degeneration; however, none of them focused on gait performance and the localization of matrix metalloproteinase 13 (MMP13) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in chondrocytes. Therefore, we aimed to investigate the effect of controlling abnormal joint movement on gait performance and the localization of MMP13 and TIMP-1, using kinematic and histological analyses. DESIGN: Rats were assigned to 2 groups: anterior cruciate ligament transection (ACL-T) group and CAJM group (n = 5/group); contralateral hind limbs of ACL-T rats were designated as intact. After 1, 2, and 4 weeks, step length was analyzed, and after 2, 4, and 8 weeks, Safranin O-Fast Green staining and immunohistochemical staining for MMP13 and TIMP-1 were performed. RESULTS: Step length did not differ significantly between the groups. However, degeneration of articular cartilage was higher in the ACL-T group than in the intact group (P < 0.05). There was no significant difference in the CAJM group at all time points. Immunohistochemical analysis of the MMP13/TIMP-1 relationship revealed a significant increase in the expression ratio of MMP13 after 4 weeks in the ACL-T group compared to the CAJM group (P < 0.05). CONCLUSIONS: Controlling abnormal joint movement may reduce mechanical stress owing to kinematic elements of small articulation including joint instability and delayed cartilage degeneration, despite the lack of kinematic change in step length.

Blood pressure control in chronic kidney disease according to underlying renal disease: the Fukushima CKD cohort.

BACKGROUND: Inadequate blood pressure control is one of the important causes of chronic kidney disease (CKD), but only a limited number of reports have examined blood pressure control in Japanese patients with pre-dialysis CKD. Differences in blood pressure control due to underlying renal disease in pre-dialysis patients with CKD were investigated in the present study using the baseline data of the Fukushima CKD cohort study. METHODS: The study involved 1351 CKD patients, classified by underlying disease of primary renal disease, hypertensive nephropathy, diabetic nephropathy, other nephropathies, or unknown. Target blood pressure of CKD patients was defined as < 130/80 mmHg in patients under 75 years old with diabetes and/or proteinuria, and < 140/90 mmHg in other patients. RESULTS: The achievement rate of target systolic blood pressure was lower in the diabetic and hypertensive nephropathy groups than in the primary renal disease group (33.3%, 46.0% vs. 68.1%, p < 0.001). However, the number of antihypertensive medications increased in the diabetic and hypertensive nephropathy groups compared to the primary renal disease group (2.16, 2.04 vs. 1.55, p < 0.001). Inadequate blood pressure control was independently related to the underlying renal disease, with a significant difference between diabetic nephropathy and primary renal disease (odds ratio 3.19; 95% confidence interval, 2.16-4.69; p < 0.001). CONCLUSION: This study showed that blood pressure control differs by the underlying renal disease. Blood pressure control was poor especially in diabetic nephropathy despite multidrug combination antihypertensive treatment. It is necessary to verify whether strict blood pressure control improves patients' prognosis in diabetic nephropathy.

MicroRNA-205-5p inhibits three-dimensional spheroid proliferation of ErbB2-overexpressing breast epithelial cells through direct targeting of CLCN3.

We previously reported that microRNA-205-5p (miR-205-5p) is significantly decreased in the ErbB2-overexpressing breast epithelial cell line MCF10A-ErbB2 compared with control cells. In this study, we identified a direct target of miR-205-5p, chloride voltage-gated channel 3 (CLCN3). CLCN3 expression was induced by ErbB2 overexpression; this induced expression was then reduced to control levels by the transfection of the miR-205-5p precursor. In RNA-binding protein immunoprecipitation with Ago1/2/3 antibody, CLCN3 was significantly enriched in 293T embryonic kidney cells with miR-205-5p mimic transfection compared with negative control mimic transfection. In luciferase reporter assays using CLCN3 3'-UTR constructs, the miR-205-5p mimic significantly decreased reporter activity of both wild-type and partial mutant constructs in MCF10A-ErbB2 cells. In contrast, no inhibitory effects of the miR-205-5p mimic were detected using the complete mutant constructs. Since miR-205-5p expression in exosomes derived from MCF10A-neo cells was substantially higher than in exosomes derived from MCF10A-ErbB2 cells, we next investigated whether an exosome-mediated miR-205-5p transfer could control CLCN3 expression. To this end, exosomal miR-205-5p derived from MCF10A-neo cells was functionally transferred to MCF10A-ErbB2 cells, which served to decrease the expression of CLCN3. To assess the roles of CLCN3 in breast cancer, we next performed three-dimensional (3D) spheroid proliferation analyses using MCF10A-ErbB2 cells treated with MCF10A-neo-derived exosomes or CLCN3 shRNA stably expressing SKBR3 and MDA-MB-453 breast cancer cells. Our results showed that both treatment with MCF10A-neo-derived exosome and CLCN3 shRNA expression suppressed 3D spheroid proliferation. Collectively, these novel findings suggest that CLCN3 may be a novel direct target of miR-205-5p and this CLCN3/miR-205-5p interaction may serve a pivotal role in regulating breast cancer cellular proliferation under physiological conditions.

Epidermal loss of phospholipase Cδ1 attenuates irritant contact dermatitis.

Irritant contact dermatitis (ICD) is one of the most common inflammatory skin diseases caused by exposure to chemical irritants. Since chemical irritants primarily damage keratinocytes, these cells play a pivotal role in ICD. One of the phosphoinositide-metabolizing enzymes, phospholipase C (PLC) δ1, is abundantly expressed in keratinocytes. However, the role of PLCδ1 in ICD remains to be clarified. Here, we found that croton oil (CrO)-induced ear swelling, a feature of ICD, was attenuated in keratinocyte-specific PLCδ1 knockout mice (PLCδ1 cKO mice). Dendritic epidermal T cells (DETCs), which have a protective role against ICD, were activated in the epidermis of the PLCδ1 cKO mice. In addition, the skin of CrO-treated PLCδ1 cKO mice showed increased infiltration of Gr1+CD11b+ myeloid cells. Of note, elimination of Gr1+CD11b+ myeloid cells restored CrO-induced ear swelling in PLCδ1 cKO mice to a similar level as that in control mice. Taken together, our results strongly suggest that epidermal loss of PLCδ1 protects mice from ICD through induction of Gr1+CD11b+ myeloid cells and activation of DETCs.

Small Cell Carcinomas of the Uterine Cervix and Lung: Proteomics Reveals Similar Protein Expression Profiles.

OBJECTIVE: The phenotypic and pathological features of small cell cervical carcinoma (SMCC) and small small cell lung cancer (SCLC) are very similar; thus, the chemotherapy regimens used for the rare SMCC have been routinely based on regimens used for common SCLC. We set out to explore the protein expression profile similarities between these 2 cancers to prove that linking their therapeutic regimens is justified, with a secondary aim of finding tumor-specific proteins to use as additional biomarkers for more accurate diagnosis of SMCC, and potentially to use as therapeutic targets. METHODS: Protein expression analysis was performed for 3 cases of SMCC and 1 example each of SCLC, mucinous adenocarcinoma of the cervix (MACC), lung mucinous adenocarcinoma (MACL), and squamous cell carcinoma of the cervix (SCC). We used cancer tissue-originated spheroids (CTOS) and isobaric tags for relative and absolute quantitation (iTRAQ)-based comprehensive and quantitative protein expression profile analysis. Expression in corresponding clinical samples was verified by immunohistochemistry. RESULTS: Rather than organ of origin-specific patterns, the SMCC and SCLC samples revealed remarkably similar protein expression profiles-in agreement with their matching tumor pathology phenotypes. Sixteen proteins were expressed at least 2-fold higher in both small cell carcinomas (SMCC and SCLC) than in MACC or SCC. Immunohistochemical analysis confirmed higher expression of creatine kinase B-type in SMCC, compared with MACC and SCC. CONCLUSIONS: We demonstrate a significant overlapping similarity of protein expression profiles of lung and cervical small cell carcinomas despite the significant differences in their organs of origin.

Controlling Abnormal Joint Movement Inhibits Response of Osteophyte Formation.

Objective Osteoarthritis (OA) is induced by accumulated mechanical stress to joints; however, little has been reported regarding the cause among detailed mechanical stress on cartilage degeneration. This study investigated the influence of the control of abnormal joint movement induced by anterior cruciate ligament (ACL) injury in the articular cartilage. Design The animals were divided into 3 experimental groups: CAJM group ( n = 22: controlling abnormal joint movement), ACL-T group ( n = 22: ACL transection or knee anterior instability increased), and INTACT group ( n = 12: no surgery). After 2 and 4 weeks, the knees were harvested for digital microscopic observation, soft X-ray analysis, histological analysis, and synovial membrane molecular evaluation. Results The 4-week OARSI scores showed that cartilage degeneration was significantly inhibited in the CAJM group as compared with the ACL-T group ( P < 0.001). At 4 weeks, the osteophyte formation had also significantly increased in the ACL-T group ( P < 0.001). These results reflected the microscopic scoring and soft X-ray analysis findings at 4 weeks. Real-time synovial membrane polymerase chain reaction analysis for evaluation of the osteophyte formation-associated factors showed that the mRNA expression of BMP-2 and VEGF in the ACL-T group had significantly increased after 2 weeks. Conclusions Typically, abnormal mechanical stress induces osteophyte formation; however, our results demonstrated that CAJM group inhibited osteophyte formation. Therefore, controlling abnormal joint movement may be a beneficial precautionary measure for OA progression in the future.

Dynamic Change of Polarity in Primary Cultured Spheroids of Human Colorectal Adenocarcinoma and Its Role in Metastasis.

Intestinal epithelial cells possess apical-basal polarity, which governs the exchange of nutrients and waste. Perturbation of cell polarity appears to be a general feature of cancers, although most colorectal cancers are differentiated adenocarcinomas, in which polarity is maintained to some extent. Little is known about the role of dysregulated polarity in cancer. The cancer tissue-originated spheroid method was applied to the preparation and culture of spheroids. Spheroids were cultured in suspension or in type I collagen gel. Polarity was assessed by IHC of apical markers and electron microscopy. Two types of polarity status in spheroids were observed: apical-in, with apical membrane located at cavities inside the spheroids in type I collagen gel; and apical-out, with apical membrane located at the outermost layer of spheroids in suspension. These polarities were highly interchangeable. Inhibitors of Src and dynamin attenuated the polarity switch. In patients, clusters of cancer cells that invaded vessels had both apical-in and apical-out morphologic features, whereas primary and metastatic tumors had apical-in features. In a mouse liver metastasis model, apical-out spheroids injected into the portal vein became apical-in spheroids in the liver within a few days. Inhibitors of Src and dynamin significantly decreased liver metastasis. Polarity switching was observed in spheroids and human cancer. The polarity switch was critical in an experimental liver metastasis model.

Radiation sensitivity assay with a panel of patient-derived spheroids of small cell carcinoma of the cervix.

Small cell carcinoma of the uterine cervix (SCCC) is a rare cancer with a poor prognosis for which no standard treatment exists. Here, we successfully established panels of patient-derived spheroid cultures from six SCCC patient samples by cancer tissue-originated spheroids (CTOS) method. To assess the intrinsic radiosensitivity and mechanism of radioresistance in individual SCCC patients, we further developed an in vitro sensitivity assay for radiation. Radiation sensitivity in the CTOS assay varied among individual cases and was consistent with in vivo radiation sensitivity using CTOS-derived xenograft tumors in the examined cases. Furthermore, by comparing gene expression in CTOSs with different radiosensitivity, we found that expression of hypoxia-inducible factor-1α (HIF-1α) target genes was upregulated in resistant CTOSs. HIF-1α protein levels increased several hours after irradiation. In a radioresistant CTOS, an inhibitor of heat shock protein 90 (HSP90) suppressed radiation-induced HIF-1α expression. Suppression of HIF-1α by small hairpin RNA significantly enhanced the effect of radiation, at least in part by promoting radiation-induced apoptosis. HSP90 inhibitor also increased radiation sensitivity. Our results indicate that radiation-induced HIF-1α upregulation was one mechanism of radioresistance in a radioresistant SCCC CTOS. Accumulating CTOS lines may provide a good platform to study characters of rare cancers like SCCC.

The prevalence of morphological changes in the thoracolumbar spine on whole-spine computed tomographic images.

OBJECTIVES: This article reviews the prevalence of lumbarisation, sacralisation and lumbar ribs, and their morphological relevance by evaluating multi-slice computed tomography (MSCT) images. These segment variations can cause miscounting of vertebrae at the lumbar spinal level. METHODS: A retrospective radiographic analysis of 226 cases scanned by MSCT prior to forensic autopsy was undertaken. MSCT scans of the entire spine were obtained. Radiological data were evaluated on a three-dimensional image workstation. Vertebral levels were determined by counting downward from the first cervical vertebra, based on the assumption of seven cervical, 12 thoracic and five lumbar vertebrae. The prevalence of lumbarisation, sacralisation and lumbar ribs was assessed. RESULTS: Lumbar ribs were observed in 13 of the 226 cases (5.8 %). Lumbarisation and sacralisation were observed in 14 cases (6.2 %) and six cases (2.7 %), respectively. Lumbar ribs were present in 11 of the 14 cases with lumbarisation, and in two of the 206 cases with normal lumbar vertebral configuration. Lumbarisation had a statistically significant association with lumbar ribs (p < 0.01). CONCLUSIONS: There was a strong association between lumbar ribs and lumbarisation, with a resulting miscount rate for the lumbar spine of slightly less than 10 %. TEACHING POINTS: • Lumbarisation and sacralisation are observed 6.2 % and 2.7 %, respectively. • Thoracolumbar segment variations can cause a miscount rate for the lumbar spine of less than 10 %. • Lumbar rib is significantly associated to lumbarisation.

Cytotoxic prodigiosin family pigments from Pseudoalteromonas sp. 1020R isolated from the Pacific coast of Japan.

Pseudoalteromonas sp. 1020R, isolated from the Pacific coast of Japan, produces prodigiosin family pigments. Structural analysis indicated that these are prodigiosin (2-methyl-3-pentyl-prodiginine) and three other prodigiosin congeners which differ only in the lengths of the alkyl side chains. These compounds exhibited different extents of cytotoxicity against U937 leukemia cells, and cell death was accompanied by typical features of apoptosis.

Defining PET standardized uptake value threshold for tumor delineation with metastatic lymph nodes in head and neck cancer.

OBJECTIVE: Hot spots of F-18 fluorodeoxyglucose positron emission tomograms are variable in size according to window settings of standardized uptake values. The purpose of this study was to determine the standardized uptake value threshold that represents the target volume. METHODS: Sixty-three patients who underwent fluorodeoxyglucose positron emission tomographic computed tomography and were diagnosed as having head and neck cancer with cervical lymphadenopathy were studied. The horizontal and vertical diameters of metastatic lymph nodes (LN-CT) were measured at the center of computed tomographic images. Of the corresponding nodes, the maximal standardized uptake value (SUVmax) and standardized uptake value profiles along the central horizontal and vertical axes were calculated on positron emission tomographic images (LN-PET). On the standardized uptake value profiles, the standardized uptake value levels (SUVeq) where the size of LN-PET was equivalent to the diameters of LN-CT were obtained. The regression formula between SUVeq and SUVmax was obtained. The regression formula of SUVeq was validated in subsequent 30 positron emission tomographic computed tomography studies. RESULTS: The mean horizontal and vertical diameters of LN-CT were 14.9 and 16.4 mm, respectively. SUVmax ranged from 1.88 to 9.07, and SUVeq was between 1.16 and 6.42. The regression formula between SUVeq and SUVmax was as follows: SUVeq = 1.21 + 0.34 × SUVmax (coefficient of correlation: R = 0.69). The validation study resulted in a good correlation between the volume of lymph nodes on computed tomography and positron emission tomographic computed tomography (R(2) = 0.93). CONCLUSIONS: The formula with a relatively high coefficient of correlation is considered to indicate that SUVeq is not constant, but is a complex of an absolute standardized uptake value and is proportional to SUVmax.