Multidisciplinary management of locally recurrent rectal cancer with carbon ion radiotherapy followed by prophylactic removal of the irradiated bowel: a case report.

BACKGROUND: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT. CASE PRESENTATION: A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion. CONCLUSIONS: The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.

Liver resection with thrombectomy for patients with hepatocellular carcinoma and tumour thrombus in the inferior vena cava or right atrium.

BACKGROUND: Hepatocellular carcinoma (HCC) with tumour thrombus (TT) in the inferior vena cava (IVC) or right atrium (RA) is a rare advanced disease state with a poor prognosis. The aim of this study was to examine survival after surgical resection. METHODS: Patients with HCC and TT of either the IVC or RA, who underwent liver resection between February 1997 and July 2017, were included. Their short- and long-term outcomes and surgical details were analysed retrospectively. RESULTS: Thirty-seven patients were included; 16 patients had TT in the IVC below the diaphragm, eight had TT in the IVC above the diaphragm, and 13 had TT entering the RA. Twelve patients had advanced portal vein TT (portal vein invasion (Vp) greater than Vp3 and Vp4), ten had bilobar disease, and 12 had extrahepatic disease. There were no in-hospital deaths, although two patients died within 90 days. Median survival did not differ between patients who had resection with curative intent (18·7 months) and those with residual tumour in the lung only (20·7 months), but survival was poor for patients with residual tumour in the liver (8·3 months). CONCLUSION: Liver resection with thrombectomy for advanced HCC with TT in the IVC or RA is safe and feasible, leading to moderate survival.

ANTECEDENTES: El carcinoma hepatocelular con trombo tumoral (TT) en la vena cava inferior (inferior vena cava, IVC) o en la aurícula derecha (right atrium, RA) es un estado avanzado de la enfermedad raro, con un pronóstico desfavorable. En este estudio analizamos la supervivencia después de la resección quirúrgica. MÉTODOS: Se incluyeron pacientes con carcinoma hepatocelular con TT en la IVC o en la RA, que se sometieron a resección hepática entre febrero de 1997 y julio de 2017. Los resultados a corto y a largo plazo de estos pacientes y los detalles quirúrgicos se analizaron retrospectivamente. RESULTADOS: Se incluyeron 37 pacientes. Entre estos pacientes, se identificaron 16 pacientes con TT en la IVC infradiafragmática, 8 pacientes con TT en la IVC supradiafragmática y 13 pacientes con TT entrando en la AR. Doce pacientes asociaron TT avanzado en la vena porta más allá de vp 3 y 4, 10 pacientes tenían enfermedad bilobar y 12 pacientes tenían enfermedad extrahepática. A pesar de que la tasa de mortalidad hospitalaria fue cero, dos pacientes fallecieron a los 90 días. Aunque la mediana del tiempo de supervivencia no fue diferente entre el grupo al que se le realizó resección con intención curativa (18,7 meses) y aquellos con tumor residual solo en el pulmón (20,7 meses), la supervivencia fue extremadamente pobre para los pacientes con tumor residual en el hígado (8,3 meses). CONCLUSIÓN: La resección hepática con trombectomía para el carcinoma hepatocelular avanzado con trombo tumoral en la vena cava inferior o en la aurícula derecha es segura y factible, asociándose a una supervivencia moderada.

Enolase-1 expression in the stratum corneum is elevated with parakeratosis of atopic dermatitis and disrupts the cellular tight junction barrier in keratinocytes.

OBJECTIVE: Previous studies have shown that enolase-1 (ENO1) in the stratum corneum (SC) is more highly expressed in patients with atopic dermatitis (AD) than in healthy individuals, suggesting that it is a novel biomarker for evaluating skin condition in patients with AD. However, the mechanism underlying high ENO1 expression in the SC and its pathological relevance in AD are unclear. In this study, the relationship between ENO1 expression and keratinization of epidermis was investigated, and the role of high ENO1 expression in keratinocytes was characterized. METHODS: ENO1 expression and morphological characteristics were examined in SC from the cheeks of 24 patients with AD. Additionally, the localization of ENO1 in the excised human epidermis was observed. Moreover, to analyse the role of ENO1 in cellular barrier function, tight junction proteins (TJs) and transepithelial electrical resistance (TEER) in keratinocytes with ENO1 overexpression were evaluated. Furthermore, the localization of ENO1 and plasminogen in keratinocytes was evaluated by immunostaining, and the cellular barrier function in keratinocytes was examined after treatment with tranexamic acid (TXA). RESULTS: ENO1 expression was substantially correlated with the rate of nucleated corneocytes in AD. In addition, ENO1 localized in the basal to spinous layers, but was its expression dramatically decreased in healthy human SC. ENO1 overexpression in human epidermal keratinocytes reduced the expression of TJs (claudin-4, E-cadherin, tricellulin, and occludin) and TEER, and treatment with anti-ENO1 IgG reversed these effects. ENO1 colocalized with plasminogen in keratinocytes. Treatment with TXA rescued the ENO1-induced reductions in TJ and TEER expression. CONCLUSION: We found a substantial correlation between ENO1 expression and the rate of nucleated corneocytes in AD and decreased ENO1 expression with nuclear disappearance. These results suggest that high ENO1 expression in the SC of AD is caused by deficient keratinization, which is an AD characteristic. Moreover, ENO1 overexpression in keratinocytes promoted dysfunction of TJ dynamics, leading to reduced integrity of the cellular barrier, and these effects might be mediated by plasmin activity. We propose that ENO1 is a useful indicator of parakeratosis and might have a potential role in cellular TJ barrier function in the epidermis.

Galectin-7 in the stratum corneum: a biomarker of the skin barrier function.

OBJECTIVE: Skin barrier disruption often occurs in diseased and damaged skin conditions such as atopic dermatitis (AD). We focused the galectin-7 protein (Gal-7) as a biomarker of skin condition and assessed whether the content of Gal-7 in stratum corneum (scGal-7) could be used as an indicator of skin barrier disruption and as an index of local skin symptoms in AD patients. METHODS: Alteration of Gal-7 expression levels in keratinocyte and scGal-7 contents after barrier disruption by sodium dodecyl sulphate were evaluated in vitro and in vivo, respectively. Correlation between scGal-7 content and transepidermal water loss (TEWL) was examined in 126 healthy subjects. We performed single measurements of scGal-7 contents in 34 AD patients and serial measurements of 15 inpatients among them. SC samples were collected by the tape-stripping method, and scGal-7 content was determined using enzyme-linked immunosorbent assay. RESULTS: Gal-7 expression in keratinocytes increased after barrier disruption. The scGal-7 content reflected the disruption of the skin barrier. The scGal-7 contents and TEWL values correlated in healthy subjects. The scGal-7 level was higher in AD patients than in healthy subjects. The scGal-7 contents in the cheek and neck of AD patients significantly correlated with the total and local skin lesion severity scores. Serial measurements in the inpatients showed that the scGal-7 contents in the cheek and neck decreased in tandem with local severity scores in response to treatment. CONCLUSION: Measurement of scGal-7 content in tape-stripped samples was useful for the evaluation of the skin barrier function in dry skin conditions such as AD.

[Advanced thymic carcinoma effectively treated by surgical resection and postoperative radiation therapy: report of a case].

Thymic carcinomas are rare neoplasms, and standard treatment has not yet been established. We reported a case of advanced thymic carcinoma effectively treated by surgical resection and postoperative radiation therapy. A 71-year-old man was pointed out an abnormal shadow on chest X-ray. Chest computed tomography (CT) scan demonstrated an anterior mediastinal tumor. The tumor was diagnosed as carcinoma by CT-guided tumor biopsy and was extirpated completely with combined partial resection of the left lung. Microscopically, the tumor was diagnosed as thymic carcinoma with direct invasion to the left lung. Following postoperative radiation therapy, the patient is doing well without apparent recurrence 5 years after surgery.

Emergence of complex rearrangements at translocation breakpoints in a transgenic mouse; implications for mechanisms involved in the formation of chromosome rearrangements.

Cryptic complex rearrangements as a result of a reciprocal chromosome translocation have been characterised in a transgenic mouse strain. Analysis of the breakpoint junctions in our previous studies showed that the ada transgene was integrated at the breakpoint forming a fusion gene with Golga3 (Mea2). In this study, further detailed analysis around the translocation junctions revealed that the surrounding regions were composed of 13 fragments of defined transgenic chromosome origins over approximately 1.9-Mb areas. Exactly the same cluster structure of these 13 breakpoint fragments already existed in the second generation of the transgenic mice. Our results show that this highly complex rearrangement has been conserved as the incipient form without any additional changes for 18 years up to the present generation, suggesting simultaneous occurrence of multiple events in the founder mouse.

Effects of methyl paraben on skin keratinocytes.

Some ingredients of dermatological formulations result in skin irritation and allergy. In particular, preservatives have been reported extensively as a cause of allergic contact dermatitis. The study focused on parabens which have been used extensively as antimicrobial preservatives in foods, drugs and cosmetics. The aim of this study was to clarify the effects of the daily use of methyl paraben (MP) on human skin. The concentrations of MP in the stratum corneum (SC) of the human forearm were measured using the cup method and GC-MS after daily applications of MP containing formulations. The study also investigated the effects of long-term exposure to MP on keratinocytes in vitro. Normal human keratinocytes and the skin equivalents were cultured in the medium containing MP. The following changes were analysed: proliferating ability, apoptotic cells, morphological changes, mRNA and protein expressions. After 1 month of daily applications of MP containing formulations, MP remained unmetabolized and persisted slightly in the SC. MP decreased the proliferating ability of keratinocytes and changed the cell morphology. MP also decreased the expressions of hyaluronan synthase 1 and 2 mRNAs and type IV collagen. In contrast, it increased the expressions of involucrin and HSP27. Furthermore, MP influenced the epidermal differentiation of the skin equivalent. These results suggest that MP exposure through application of dermatological formulations results in MP persistence and accumulation in the SC, and that MP might influence the aging and differentiation of keratinocytes.

Novel heteroduplex method using small cytology specimens with a remarkably high success rate for analysing EGFR gene mutations with a significant correlation to gefitinib efficacy in non-small-cell lung cancer.

We conducted a feasibility study to examine whether small numbers of cancer cells could be utilised for analysis of the EGFR gene status using the loop-hybrid mobility shift assay, which is a modified heteroduplex technique. Cytology specimens obtained by transbronchial abrasion were successfully used for analysis of the EGFR gene status in 50 of 52 (96.2%) patients diagnosed with class V non-small-cell carcinoma. Furthermore, the relationship between the EGFR gene status and clinical outcome was analysed in 25 patients treated with gefitinib. Overall, 10 of 11 patients with EGFR mutations in exon 19 or 21 showed tumour regression with gefitinib treatment, compared to only two of 14 patients with wild-type EGFR. The response rate was significantly higher in the EGFR mutation group than in the wild-type EGFR group (90.9 vs 14.3%, P=0.00014). Logistic regression analysis revealed that EGFR mutations in cytology specimens represented an independent predictor of the gefitinib response. The overall and progression-free survivals were significantly longer in the EGFR mutation group than in the wild-type EGFR group (P<0.05). In conclusion, cytology specimens could be useful for analysing the EGFR status in the majority of patients with non-small-cell lung cancer to determine whether they are likely to benefit from gefitinib treatment.

CD34+ stromal cells and hyalinized vascular changes in the anal fibroepithelial polyps.

AIMS: To elucidate the pathogenesis of the anal fibroepithelial polyp, we examined surgically resected lesions histopathologically. METHODS AND RESULTS: Twenty-seven surgically resected anal fibroepithelial polyps were investigated histologically with an additional immunohistochemical examination using anti-CD34. For a control study, the surgical specimens of the anal canal showing non-polypoid lesions, obtained from haemorrhoidectomy (18 specimens) and rectectomy (five specimens) due to rectal cancer without anal canal involvement, were also analysed. We demonstrated characteristic spindle or stellate cells immunohistochemically positive for CD34 in the anal fibroepithelial polyps (24/27, 89%). The number of CD34+ cells was statistically related to the size of anal fibroepithelial polyps, although CD34+ stromal cells were recognized in the non-polypoid anal submucosa and haemorrhoids. We also found hyalinized vascular changes in the base of six anal fibroepithelial polyps examined. These features were not detected in the non-polypoid anal canal. CONCLUSIONS: An increase in CD34+ stromal cells may play a role in the enlargement of anal fibroepithelial polyps. CD34+ stromal cells are suggested to be distinctive mesenchymal cells with a capability for tissue repair and overgrowth. The vascular impairment could be secondary change associated with localized tissue damage by abnormal traction.

Protection against malignant progression of spontaneously developing liver tumors in transgenic mice expressing O(6)-methylguanine-DNA methyltransferase.

To study the effect of O(6)-methylguanine-DNA methyltransferase (MGMT) on carcinogenesis, we have previously generated MGMT transgenic mice overexpressing the bacterial MGMT gene, ada, and demonstrated that high MGMT levels in the liver suppress induction of liver tumors after treatment with an alkylating hepatocarcinogen. To examine the effects of life-long elevation of MGMT activity on mouse spontaneous liver tumor development, ada-transgenic and control non-transgenic mice were compared. We also examined mutations at codon 61 of the H-ras oncogene, reported as a hot spot in mouse liver tumors, using a direct DNA sequencing method. The results revealed no significant difference in tumor incidence or mutation spectrum, but interestingly, ada-transgenic mice were found to have fewer malignant tumors and survived longer, indicating a possible protective role of MGMT against malignant conversion.

Primary malignant lymphoma of the cavernous sinus--case report.

A 59-year-old female presented with a very rare case of primary malignant lymphoma of the cavernous sinus manifesting as diplopia and right facial hypesthesia. Magnetic resonance (MR) imaging showed the tumor located in the right cavernous sinus as low intensity with marked enhancement by gadolinium. The tumor was partially removed by the transzygomatic extradural approach. The histological diagnosis was malignant lymphoma. Chest and abdominal computed tomography and gallium-67 scintigraphy revealed no other lesions in the body. The patient received conventional radiotherapy and her diplopia and right facial hypesthesia gradually improved. At 1 month after radiotherapy, MR imaging showed no evidence of residual tumor. Primary cavernous sinus malignant lymphoma is extremely rare, but should be considered in the differential diagnosis of cavernous sinus lesions. Histological confirmation of tumors in this region is essential for choosing the most appropriate treatment to achieve a better outcome.

Histopathologic studies of colorectal postendoscopic resection sites: "skipping electrothermal injury" associated with endoscopic resection procedures.

To elucidate the pathologic changes due to endoscopic resection (ER), 32 post-ER sites in 24 surgically removed colorectal specimens and the previous ER specimens were examined. The depth of all the previous ER specimens was restricted to the submucosa, and all post-ER sites showed submucosal stromal changes of various degrees. Fourteen sites (43.8%) showed muscular or serosal changes. One of these lesions was considered to be a reaction to a tattoo agent, but all the other lesions were considered to represent skipping electrothermal injury caused by electrical current passing through the colorectal wall. The lesions consisted of muscular depletion in the inner layer of the muscularis propria (12 sites, 37.5%), hemorrhage or fibrosis between the inner and outer layers of the muscularis propria (3 sites, 9.4%), and serosal changes (10 sites, 31.3%). These skip regions would be vulnerable to electrical current. These findings suggest that asymptomatic electrothermal injury associated with ER is frequent. Statistically, the electrothermal injury appeared to be related to the size of the previous ER specimens. However. these results also reveal that the ER of tissues <10 mm can cause electrothermal injury and can result in full-thickness necrosis.

Mea2/Golga3 gene is disrupted in a line of transgenic mice with a reciprocal translocation between Chromosomes 5 and 19 and is responsible for a defective spermatogenesis in homozygotes.

A line of transgenic mouse T604 transmitted a transgene to progeny together with a set of chromosomes with a reciprocal translocation. The transgene was integrated at a single site in the translocated chromosomes, as revealed by fluorescence in situ hybridization. The transgenic hemizygous males, also heterozygous for the translocation of chromosomes, showed apparently normal spermatogenesis, while the males homozygous for the transgene as well as for the translocated chromosomes showed a defect in spermatogenesis. Considering that the genetic rearrangement by either insertion of the transgene or the chromosome translocation in the T604 mouse line might have caused a recessive mutation in a gene indispensable for spermatogenesis, we have mapped the transgene integration site and the translocation breakpoints in mouse chromosomes. Linkage analysis with SSLP markers showed that the loci for the transgene and the translocation breakpoints were closely located to D5Mit24 on Chromosome (Chr) 5, and to a region between D19Mit19 and D19Jpk2 on Chr 19. Mea2 gene, mapped only 2 cM from D5Mit24 and known to show male-specific enhanced expression in the testis, was analyzed as a candidate for the gene disrupted in T604 transgenic mice. Southern blot analysis revealed that Mea2 gene was indeed disrupted in T604 mice, and Northern blot analysis of the testis RNA showed that the expression of Mea2 was annihilated in the testis of T604 transgenic homozygotes.

Possible rare involvement of O6-methylguanine formation as a significant mutational factor in mouse urinary bladder carcinogenesis models.

O6-methylguanine is known as one of the major premutagenic lesions in the human and rodent carcinogenesis process. O6-methylguanine-DNA methyltransferase (MGMT), which repairs methylated guanine bases, might prevent the G:C to A:T transition, and transgenic mice carrying this MGMT gene have been reported to be less sensitive to the carcinogenicity of certain alkylating agents. Here we utilized MGMT transgenic mice to assess the significance of O6-methylguanine formation during urinary bladder carcinogenesis. In experiment 1, 100 and 60 ppm N-butyl-N(4-hydroxybutyl)nitrosamine was given for 20 weeks to transgenic and non-transgenic mice in their drinking water. The incidences of urinary bladder carcinomas were not different between transgenic mice and non-transgenic mice. The mutational spectrum of the p53 gene was evaluated by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing. The pattern of p53 mutations of transgenic and non-transgenic mice did not differ, and the frequencies of mutations were 40% and 42%, respectively. G:C to A:T transition mutations were particularly infrequent (1 of 14 mutations, 7%). In experiment 2, N-methyl-N-nitrosourea, which might induce O6-methylguanine in affected alleles, was given once a week, 3 times (total 5 mg) by direct instillation into the urinary bladder through an abdominal incision. No significant neoplastic lesions were detected, although the experiment was limited by severe toxicity of the treatment. p53 immunostaining was done and there was no difference in transgenic and non-transgenic mice. These results suggest that O6-methylguanine formation might not be a significant mutational factor in these mouse urinary bladder carcinogenesis models.

Histopathological study of pancreatic ischemic lesions induced by cholesterol emboli: fresh and subsequent features of pancreatic ischemia.

To elucidate the histopathological features of pancreatic ischemia, we examined postmortem pancreases in which cholesterol emboli were present. Cholesterol emboli were detected in 17 pancreases (6 of 36 cases of aortic aneurysm and 11 of 223 control cases). Two of the 17 pancreases had well-demarcated patchy lesions composed of degenerating acinar cells showing deeply eosinophilic cytoplasm and pyknotic nuclei, indicating fresh ischemia. In the marginal zone of the larger lesions and in the small lesions, the intralobular ductules had avoided the ischemic changes. Five of the 17 pancreases had patchy fibrotic foci containing small ductules with slightly retraction features. These ductules are considered to be the remnant intralobular ductules that have avoided the previous ischemic damage. We conclude that these patchy fibrotic foci are the healed ischemic lesions. The current findings suggest that the healed ischemic lesions can be differentiated from common pancreatic fibrosis. The existence of remnant intralobular ductules and the patchy retraction features may be useful histological markers for the determination of healed ischemic lesions.

Numerous eosinophilic globules (skeinoid fibers) in a duodenal stromal tumor: an exceptional case showing smooth muscle differentiation.

A unique case of duodenal stromal tumor in a 51-year-old man is reported. The tumor histologically showed spindle cell proliferation and numerous eosinophilic globules. Most globules were composed of tangled 45 nm thick fibrils, which were ultrastructurally identical to 'skeinoid fibers'. The presence of glycogen granules in the tumor cells and the immunoreactivity for alpha-smooth muscle actin suggested smooth muscle differentiation. Focal ultrastructural findings also supported the smooth muscle nature of this tumor. There were no immunohistochemical and ultrastructural features indicating neural differentiation. In previous studies, the presence of such 'skeinoid fibers' was suggested to be a histological marker for neural differentiation in gastrointestinal stromal tumor. However, the findings in the present case suggest that numerous 'skeinoid fibers' can be identified in duodenal stromal tumor with smooth muscle differentiation, although this condition may be rare.

Secretory meningioma with severe perifocal edema--case report.

An 82-year-old male presented with a small parasagittal meningioma associated with disproportionately severe perifocal edema. Histological examination including immunohistochemical staining and electron microscopy resulted in a diagnosis of secretory meningioma. In addition to tumor size, the edema could not be explained by location, growth rate, vascular involvement, or other factors. We conclude that secretory meningiomas may possess an innate ability to cause brain edema.

Cyclothialidine analogs, novel DNA gyrase inhibitors.

DNA gyrase inhibitors, cyclothialidines B, C, D and E were isolated from four Streptomycete strains (NR 0659, NR 0660, NR 0661 and NR 0662). Their structures have been elucidated based on the amino acid analysis of the hydrolysates, NMR and HRFAB-MS experiments and shown to be cyclothialidine analogs. The absolute stereochemistry has been determined by the chiral HPLC analysis of the hydrolysates. Cyclothialidines B, D and E are novel and potent inhibitors of DNA gyrase.