Association of Loss of Heterozygosity at the p53 Locus with Chemoresistance in Osteosarcomas

Although the osteosarcoma is considered to be among the most chemosensitive malignancies and preoperative chemotherapy is commonly applied, an appreciable proportion of cases are in fact quite insensitive. Predictive markers for chemosensitivity are therefore desirable in order to develop effective treatment strategies. Thirty-two cases of conventional osteosarcomas treated at the Cancer Institute Hospital, Tokyo, were analyzed. The sensitivity to preoperative chemotherapy was investigated with reference to loss of heterozygosity (LOH) at the 17p13 ( p 53) and 13q14 ( Rb ) loci and expression of the cell-cycle associated proteins, p53, Rb, p21/Waf-1, mdm-2 and Ki-67, as detected immunohistochemically. LOH was detected by analyzing polymerase chain reaction products at marker microsatellite loci. The efficacy of chemotherapy was evaluated both radiologically and histologically. LOH at p 53 or Rb loci was seen in 54% (13/24) and 58% (14/24) of cases, respectively. Only 15% of osteosarcomas with LOH at the p 53 locus were sensitive to preoperative chemotherapy, as compared to 64% of tumors without such loss ( P <0.05). A similar but much less distinct tendency was observed with LOH at the Rb locus. No relationship was evident between chemosensitivity and immunohistochemical staining patterns for p53, Rb, p21/Waf-1, mdm-2 or Ki-67. The results suggest that p 53 gene deletion, but not the other parameters investigated, may be useful for predicting chemoresistance of osteosarcomas.     

Hyperlipidemia as a risk factor for Trousseau syndrome-related cerebral infarction in patients with advanced gastrointestinal cancer

Trousseau syndrome-related cerebral infarction rarely occurs during chemotherapy in patients with gastrointestinal (GI) cancer, and its clinical features remain unclear. The present study aimed to examine the clinical features of Trousseau syndrome-related cerebral infarction developed during chemotherapy for GI cancer. The present retrospective cohort study consecutively enrolled 878 patients with unresectable GI cancer who received chemotherapy at the Multidisciplinary Treatment Cancer Center, Kurume University Hospital (Kurume, Japan) between April 2014 and March 2020. Patients with colorectal cancer (n=308) were the most common, followed by those with pancreatic (n=242), gastric (n=222) and biliary tract (n=59) cancer, neuroendocrine tumors (n=34) and duodenal cancer (n=11). Among the 878 patients, Trousseau syndrome-related cerebral infarction occurred in 8 (0.9%) patients with a median age of 70.5 years (range, 58–75 years), and 50% of the patients were male (4/8). In total, 3 patients had gastric cancer, 3 had pancreatic cancer and 2 had biliary tract cancer. A greater percentage of patients with Trousseau syndrome-related cerebral infarction had hyperlipidemia (38.0%) than those without (8.2%; P=0.005). Hyperlipidemia was a risk factor for occurrence of Trousseau syndrome-related cerebral infarction with an odds ratio of 7.009 (95% confidence interval, 1.785-27.513). Trousseau syndrome-related cerebral infarction developed during GI chemotherapy was rare and hyperlipidemia may predict its onset.     

Mortality among persons with a history of Kawasaki disease in Japan: Can paediatricians safely discontinue follow-up of children with a history of the disease but without cardiac sequelae?

Aim: To clarify the question of whether patients with Kawasaki disease suffer a higher mortality rate after the incidence of the disease in comparison with age-matched healthy individuals. Methods: Between July 1982 and December 1992, 52 collaborating hospitals collected data on all patients having a new, definite diagnosis of Kawasaki disease. Patients were followed up until 31 December 2001 or their death. The expected number of deaths was calculated from Japanese vital statistics data and compared with the observed number. Results: Of 6576 patients enrolled, 29 (20 males and 9 females) died. The standardized mortality ratio (SMR: the observed number of deaths divided by the expected number of deaths based on the vital statistics in Japan) was 1.15 (95% CI: 0.77-1.66). In spite of the high SMRs during the acute phase, the mortality rate was not high after the acute phase for the entire group of patients. Although the SMR after the acute phase was 0.75 for those without cardiac sequelae, six males (but none of the females) with cardiac sequelae died during this period; and the SMR for the male group with cardiac sequelae was 1.95 (95% CI: 0.71-4.25). The mortality from congenital anomalies of the circulatory system was elevated, but no increase in cancer deaths was observed.

Conclusion: Although it was not statistically significant, the mortality rate among males with cardiac sequelae due to Kawasaki disease appeared to be higher than in the general population. On the other hand, the mortality rates for females with the sequelae and both males and females without sequelae were not elevated.     

A novel hepatic-targeting system for therapeutic cytokines that delivers to the hepatic asialoglycoprotein receptor,but avoids receptor-mediated endocytosis

Purpose. To demonstrate the utilities of a synthetic low-affinity ligand ((Gal)₃) for the asialoglycoprotein receptor (ASGP-R) as a hepatic targeting device for therapeutic cytokines. Methods. The site-specific incorporation of (Gal)₃ or a typical high-affinity ligand (GalNAc)₃ into IL-2 was catalyzed by microbial transglutaminase. The anti-tumor activities, pharmacokinetic profiles and receptor-mediated endocytosis in hepatocytes of the ligand-IL-2 conjugates were examined in mouse. Results. The (Gal)₃ has approximately 50 times lower affinity to ASGP-R than (GalNAc)₃. Nevertheless, the antitumor effects were in the order of (Gal)₃—IL-2 > unmodified IL-2 > (GalNAc)₃—IL-2. The systemic elimination and the hepatic uptake of (GalNAc)₃—IL-2 were more rapid than (Gal)₃—IL-2. The ratio of the rate constant representing dissociation from the cell-surface receptor (k_off) to that representing endocytosis of the ligand (k_int) was greater for (Gal)₃—IL-2 than (GalNAc)₃—IL-2, suggesting that (Gal)₃—IL-2 preferably avoids internalization due to its lower affinity to the receptor. The simulation studies demonstrated that (Gal)₃—IL-2 was present in the hepatic extracellular space for a longer period than (GalNAc)₃ IL-2. Conclusions. The (Gal)₃ ligand increases the therapeutic efficacy of IL-2 by enhancing its exposure to the cell-surface. The k_off/k_int affects the targeting efficacy of the conjugates to ASGP-R.     

Double stapling method for closure of intraoperative alveolar air leakage adjacent to the staple line: a randomized experimental study on ex vivo porcine lungs

BackgroundAlveolar air leakage from a pleural defect around the staple line is one of the complications after wedge resection of the lung. An intraoperative closure of the pleural defect by suturing can cause additional pleural rupture due to tension of the pleura adjacent to staple lines. Therefore, we have introduced a novel closure method for pleural defect adjacent to the staple line, named the double stapling method. This study compared the efficacy of two closure methods; the double stapling method and conventional suturing method with pledgets using ex vivo porcine lungs.MethodsThe double stapling method involves closing the pleural defect by suturing the two parallel staple lines at both sides of the pleural defect. This method was developed to distribute the pleural tension around the needle holes of suturing. As a model of pleural defect adjacent to the staple line after wedge resection, wedge resection of the caudal lobe of left porcine lungs was performed, and a superficial square pleural defect (10 mm × 10 mm) adjacent to the staple line was made by scalpel. The defect was closed using the following two methods: (I) suturing with pledgets (n=10); and (II) double stapling method (n=10). The lobe was inflated in water at an airway pressure of 20, 25, and 30 cmH₂O; closure success or failure was judged by the absence or presence of air leakage.ResultsThe closure success was confirmed in 2 (20%) out of 10 cases in the suturing with pledgets group and 9 (90%) out of 10 in the double stapling method group (P=0.007). In 4 out of 10 cases in the suturing with pledgets group, new pleural clefts longer than 3 mm were created around the needle holes of suturing.ConclusionsEx vivo experiments have suggested the superiority of the double stapling method for the intraoperative closure of alveolar air leakage adjacent to the staple line after wedge resection, compared to conventional suturing with the pledget method.     

Anti-SARS CoV-2 IgG in COVID-19 Patients with Hematological Diseases: A Single-center,Retrospective Study in Japan

Objective Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally. Although the relationship between anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies and COVID-19 severity has been reported, information is lacking regarding the seropositivity of patients with particular types of diseases, including hematological diseases. Methods In this single-center, retrospective study, we compared SARS-CoV-2 IgG positivity between patients with hematological diseases and those with non-hematological diseases. Results In total, 77 adult COVID-19 patients were enrolled. Of these, 30 had hematological disorders, and 47 had non-hematological disorders. The IgG antibody against the receptor-binding domain of the spike protein was detected less frequently in patients with hematological diseases (60.0%) than in those with non-hematological diseases (91.5%; p=0.029). Rituximab use was significantly associated with seronegativity (p=0.010). Conclusion Patients with hematological diseases are less likely to develop anti-SARS-CoV-2 antibodies than those with non-hematological diseases, which may explain the poor outcomes of COVID-19 patients in this high-risk group.     

Quantitative Assay of Epidermal Growth Factor Receptor in Human Squamous Cell Carcinomas of the Oral Region by an Avidin-Biotin Method

A quantitative assay method for epidermal growth factor receptors (EGFRs) of human tumor tissues was established, based on enzyme-labeled avidin-biotin (LAB) interaction with anti-human EGFR monoclonal antibody 52SIgG. A standard calibration curve for EGFR estimation in human tumor tissues was obtained with A431#8 cells cloned from A431 human epidermoid carcinoma cell line. The coefficient of variance for the standard curve was below 35% in the application to tumor tissues from nude mice implanted with human tumor cell lines. The minimum tissue amount required for the quantitative assay was around 0.1 g (wet weight). Using the LAB method, the correlation between the level of EGFR number and tumor malignancy was examined for 14 human squamous cell carcinomas (SCCs) from the oral region. Seven of the SCCs showed a more than two-fold higher EGFR number compared to normal gingival tissues. Three highly aggressive carcinomas with poor prognosis possessed five to ten times higher levels of EGFR number than normal tissues. The elevated EGFR level in the SCCs seems to correlate to increasing tumor size and the stage of SCCs as clinically classified according to the 1987 UICC TNM system.     

Torsion of the normal ovary and oviduct in a pre-pubertal girl

We encountered a 10-year-old prepubertal girl with a normal ovary and oviduct torsion. Hemorrhagic infarction of the ovary and oviduct occurred, and these structures were laparoscopically removed. Torsion of the normal ovary and oviduct in a prepubertal girl is discussed.     

Isolated adenomyotic cyst associated with severe dysmenorrhea

A case of a 23-year-old, nulliparous female with a very rare isolated adenomyotic cyst inducing severe dysmenorrhea was seen. Transvaginal ultrasonographic tomography and magnetic resonance imaging (MRI) showed a 3 x 3-cm cystic mass within the left anterior wall of the uterine corpus. The cystic space was filled with hyperintense fluid on T1-weighted images, which was surrounded by hypointense tissue beside the right uterine corpus on T2-weighted images. The case was preliminarily diagnosed using MRI as having cavitated rudimentary uterine horn. However, hysterosalpingography excluded the possibility of uterine anomaly. A hemorrhagic adenomyotic cyst measuring 3 cm within the left anterior wall of the uterine corpus was surgically removed. There was no evidence of diffuse adenomyosis uteri. Dysmenorrhea completely disappeared postoperatively.