Pityriasis Rosea With Multiple Herald Patches Resulting in a V-shaped Pattern and a Christmas Tree Distribution.

Pityriasis rosea (PR), a benign and self-limiting skin disorder, typically manifests as a single initial lesion known as the herald patch. The herald patch is commonly followed by the development of secondary erythematous papules and plaques, aligning with Langer's lines to form a specific distribution pattern, resembling a Christmas tree on the back and a V-shaped pattern on the upper chest. Therefore, diagnosing PR may not be difficult based on its typical clinical presentation. In contrast, cases of atypical PR presentation have been reported, encompassing several differential diagnoses. Here, we present a case with multiple herald patches that needed differentiation from ringworm, syphilis, and erythema annular centrifugum. Subsequently, our case was diagnosed with PR, as the patches formed a V-shaped pattern and a Christmas-tree distribution.

Identification of target cells of human papillomavirus 18 using squamocolumnar junction organoids.

Human papillomavirus 18 (HPV18) is a highly malignant HPV genotype among high-risk HPVs, characterized by the difficulty of detecting it in precancerous lesions and its high prevalence in adenocarcinomas. The cellular targets and molecular mechanisms underlying its infection remain unclear. In this study, we aimed to identify the cells targeted by HPV18 and elucidate the molecular mechanisms underlying HPV18 replication. Initially, we established a lentiviral vector (HPV18LCR-GFP vector) containing the HPV18 long control region promoter located upstream of EGFP. Subsequently, HPV18LCR-GFP vectors were transduced into patient-derived squamocolumnar junction organoids, and the presence of GFP-positive cells was evaluated. Single-cell RNA sequencing of GFP-positive and GFP-negative cells was conducted. Differentially expressed gene analysis revealed that 169 and 484 genes were significantly upregulated in GFP-positive and GFP-negative cells, respectively. Pathway analysis showed that pathways associated with cell cycle and viral carcinogenesis were upregulated in GFP-positive cells, whereas keratinization and mitophagy/autophagy-related pathways were upregulated in GFP-negative cells. siRNA-mediated luciferase reporter assay and HPV18 genome replication assay validated that, among the upregulated genes, ADNP, FHL2, and NPM3 were significantly associated with the activation of the HPV18 early promoter and maintenance of the HPV18 genome. Among them, NPM3 showed substantially higher expression in HPV-related cervical adenocarcinomas than in squamous cell carcinomas, and NPM3 knockdown of HPV18-infected cells downregulated stem cell-related genes. Our new experimental model allows us to identify novel genes involved in HPV18 early promoter activities. These molecules might serve as therapeutic targets in HPV18-infected cervical lesions.

Nuclear proinflammatory cytokine S100A9 enhances expression of human papillomavirus oncogenes via transcription factor TEAD1.

Transcription of the human papillomavirus (HPV) oncogenes, E6 and E7, is regulated by the long control region (LCR) of the viral genome. Although various transcription factors have been reported to bind to the LCR, little is known about the transcriptional cofactors that modulate HPV oncogene expression in association with these transcription factors. Here, we performed in vitro DNA-pulldown purification of nuclear proteins in cervical cancer cells, followed by proteomic analyses to identify transcriptional cofactors that bind to the HPV16 LCR via the transcription factor TEAD1. We detected the proinflammatory cytokine S100A9 that localized to the nucleus of cervical cancer cells and associated with the LCR via direct interaction with TEAD1. Nuclear S100A9 levels and its association with the LCR were increased in cervical cancer cells by treatment with a proinflammatory phorbol ester. Knockdown of S100A9 decreased HPV oncogene expression and reduced the growth of cervical cancer cells and their susceptibility to cisplatin, whereas forced nuclear expression of S100A9 using nuclear localization signals exerted opposite effects. Thus, we conclude that nuclear S100A9 binds to the HPV LCR via TEAD1 and enhances viral oncogene expression by acting as a transcriptional coactivator. IMPORTANCE Human papillomavirus (HPV) infection is the primary cause of cervical cancer, and the viral oncogenes E6 and E7 play crucial roles in carcinogenesis. Although cervical inflammation contributes to the development of cervical cancer, the molecular mechanisms underlying the role of these inflammatory responses in HPV carcinogenesis are not fully understood. Our study shows that S100A9, a proinflammatory cytokine, is induced in the nucleus of cervical cancer cells by inflammatory stimuli, and it enhances HPV oncogene expression by acting as a transcriptional coactivator of TEAD1. These findings provide new molecular insights into the relationship between inflammation and viral carcinogenesis.

Long-term oncological outcome of reduced-port laparoscopic surgery (single-incision plus one port) as a technical option for rectal cancer.

BACKGROUND: The purpose of this study was to clarify the oncological safety of reduced-port laparoscopic surgery (single-incision plus one port) (RPS) for patients with rectal cancer. METHODS: The clinicopathological data of 63 selected patients with clinical Stage I-III (T1-3 and N0-2) rectal cancer who underwent RPS of radical anterior resection between 2012 and 2017 were retrospectively analyzed. The median distance of tumor from anal verge was 11 cm. Ordinarily, a multiport platform with three channels was placed in the 3-cm umbilical incision, and another 5- or 12-mm port was placed in the right lower abdomen. RESULTS: The median operative time, amount of intraoperative bleeding, number of harvested lymph nodes, and length of distal margin were 272 min, 10 mL, 22 nodes, and 4.0 cm, respectively, and there was one (2%) patient with involvement of the radial margin. There were eight patients (13%) who required additional ports, and one patient (2%) who converted to open surgery. Intra- and postoperative complications occurred in one (2%) and 12 patients (19%), respectively. The median length of postoperative hospital stay was 8 days. The median follow-up period was 79 months, and incisional hernia was observed in 3 (5%) patients at the platform site not the port site, and cancer recurrence occurred in four patients (6%). The 5-year relapse-free and overall survival rates were 100% and 100% in the patients with pathological Stage I disease, 94% and 100% in the patients with pathological Stage II disease, and 83% and 89% in the patients with pathological Stage III disease, respectively. CONCLUSION: RPS in the selected patients with rectal cancer, performed by an expert laparoscopic surgeon, may be technically safe and oncologically acceptable as well as multiport laparoscopic surgery.

Folliculin Prevents Lysosomal Degradation of Human Papillomavirus To Support Infectious Cell Entry.

Human papillomavirus (HPV) infects epithelial basal cells in the mucosa and either proliferates with the differentiation of the basal cells or persists in them. Multiple host factors are required to support the HPV life cycle; however, the molecular mechanisms involved in cell entry are not yet fully understood. In this study, we performed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) knockout (KO) screen in HeLa cells and identified folliculin (FLCN), a GTPase-activating protein for Rag GTPases, as an important host factor for HPV infection. The introduction of single guide RNAs for the FLCN gene into HeLa, HaCaT, and ectocervical Ect1 cells reduced infection by HPV18 pseudovirions (18PsVs) and 16PsVs. FLCN KO HeLa cells also exhibited strong resistance to infection with 18PsVs and 16PsVs; nevertheless, they remained highly susceptible to infections with vesicular stomatitis virus glycoprotein-pseudotyped lentivirus and adeno-associated virus. Immunofluorescence microscopy revealed that the numbers of virions binding to the cell surface were slightly increased in FLCN KO cells. However, virion internalization analysis showed that the internalized virions were rapidly degraded in FLCN KO cells. This degradation was blocked by treatment with the lysosome inhibitor bafilomycin A1. Furthermore, the virion degradation phenotype was also observed in Ras-related GTP-binding protein C (RagC) KO cells. These results suggest that FLCN prevents the lysosomal degradation of incoming HPV virions by enhancing lysosomal RagC activity. IMPORTANCE Cell entry by human papillomavirus (HPV) involves a cellular retrograde transport pathway from the endosome to the trans-Golgi network/Golgi apparatus. However, the mechanism by which this viral trafficking is safeguarded is poorly understood. This is the first study showing that the GTPase-activating protein folliculin (FLCN) protects incoming HPV virions from lysosomal degradation and supports infectious cell entry by activating the Rag GTPases, presumably through the suppression of excessive lysosomal biosynthesis. These findings provide new insights into the effects of small GTPase activity regulation on HPV cell entry and enhance our understanding of the HPV degradation pathway.

Blood Perfusion Assessment by Indocyanine Green Fluorescence Imaging for Minimally Invasive Rectal Cancer Surgery (EssentiAL trial): A Randomized Clinical Trial.

OBJECTIVE: The aim of the present randomized controlled trial was to evaluate the superiority of indocyanine green fluorescence imaging (ICG-FI) in reducing the rate of anastomotic leakage in minimally invasive rectal cancer surgery. BACKGROUND: The role of ICG-FI in anastomotic leakage in minimally invasive rectal cancer surgery is controversial according to the published literature. METHODS: This randomized, open-label, phase 3, trial was performed at 41 hospitals in Japan. Patients with clinically stage 0-III rectal carcinoma less than 12 cm from the anal verge, scheduled for minimally invasive sphincter-preserving surgery were preoperatively randomly assigned to receive a blood flow evaluation by ICG-FI (ICG+ group) or no blood flow evaluation by ICG-FI (ICG- group). The primary endpoint was the anastomotic leakage rate (grade A+B+C, expected reduction rate of 6%) analyzed in the modified intention-to-treat population. RESULTS: Between December 2018 and February 2021, a total of 850 patients were enrolled and randomized. After the exclusion of 11 patients, 839 were subject to the modified intention-to-treat population (422 in the ICG+ group and 417 in the ICG- group). The rate of anastomotic leakage (grade A+B+C) was significantly lower in the ICG+ group (7.6%) than in the ICG- group (11.8%) (relative risk, 0.645; 95% confidence interval 0.422-0.987; P =0.041). The rate of anastomotic leakage (grade B+C) was 4.7% in the ICG+ group and 8.2% in the ICG- group ( P =0.044), and the respective reoperation rates were 0.5% and 2.4% ( P =0.021). CONCLUSIONS: Although the actual reduction rate of anastomotic leakage in the ICG+ group was lower than the expected reduction rate and ICG-FI was not superior to white light, ICG-FI significantly reduced the anastomotic leakage rate by 4.2%.

[Laparoscopic Abdominoperineal Resection of the Rectum in a Case with Pagetoid Spread of Anal Canal Carcinoma].

The patient, a man in his 60s, first noticed an elevated lesion around the anus 3 years ago. The lesion failed to subside with the topical drug preparations prescribed at a local clinic, and the patient was referred to the Department of Dermatology of our hospital for further workup and treatment. The findings of biopsy from the lesion suggested skin infiltration of anal canal carcinoma, and the patient was referred to the Department of Surgery. Examination here revealed only induration of the anal canal, with no abnormality of the rectal mucosa even when the endoscope was reversed to visualize the rectum. Examination by various imaging modalities failed to reveal any metastases to the lymph nodes or distant organs, and the primary lesion remained unidentified. Laparoscopic abdominoperineal excision of the rectum was performed, beginning with anal manipulation. First, a 15-mm margin was set on the skin from the tumor edge, and the skin stump was divided into 4 equal portions. After confirming by rapid intraoperative frozen-section examination that the margin was negative along the full circumference, anal manipulation was performed, leaving a distance in the vertical direction immediately below the tumor. Upon completion of the anal manipulation, intraperitoneal manipulation was performed in a routine manner. The anal skin was relaxed subcutaneously, as done during mastectomy, and the subsequent suture closure could be done smoothly. The tumor was classified as pT1bN0M0, pStage Ⅰ. The experience with this case indicates that biopsy should be proactively employed for the diagnosis in such cases, and that proactive skin biopsy is useful when dealing with intractable anal skin lesions.

[A Case of Recurrent Gastric GIST Who Survived for Long after Laparoscopic Resection and Imatinib Therapy].

A man patient in his 70s underwent left nephrectomy and laparoscopic partial gastrectomy for the treatment of a left renal cell carcinoma and gastrointestinal stromal tumor(GIST)arising from the stomach. Histopathologically, both the renal cell carcinoma and GIST were kit-positive, CD34-positive, and S-100 protein-negative, and the Ki-67 index was about 40% as determined by the hot spot method, so that it was diagnosed as an intermediate-group GIST. After surgery, the patient was followed without adjuvant therapy, as he did not wish to receive postoperative chemotherapy. A computed tomography(CT)conducted 3 years after the surgery revealed tumorous shadows in the abdominal wall, inferior periesophageal region, and dorsal aspect of the pancreas. Positron emission tomography(PET)-CT showed fluorodeoxyglucose(FDG) accumulation in these lesions. Therefore, based on a suspicion of recurrent renal cell carcinoma or GIST, we carried out abdominal wall tumor resection for both exploratory and diagnostic purposes, which yielded histopathological diagnosis of GIST, with features similar to those observed at the time of the initial operation. Because the number of tumors remained unchanged during the subsequent follow-up period, the tumorous lesions in the periesophageal region and on the dorsal aspect of the pancreas were resected laparoscopically. Each of the resected tumors showed histological features consistent with GIST. The patient was started on oral imatinib therapy after this operation. To date(5 years after the surgery for the recurrent tumors and 8 years after the initial operation), the patient has remained free of recurrence. The pattern of tumor recurrence noted in the present case(ie, metastasis/dissemination to the skeletal muscles)is relatively rare, and few reports have been published concerning long-term survivors through multidisciplinary treatment (surgical treatment and others). We report this case with a review of the literature.

[A Case of Unresectable Advanced Gastric Cancer Successfully Treated with Conversion Surgery].

A man in his 70s consulted a local clinic with a chief complaint of difficulty eating. Upper gastrointestinal endoscopy revealed a type 4 tumor spreading irregularly from immediately below the esophageal cardia to the lower gastric body. The patient was referred to our hospital with a diagnosis of advanced gastric cancer(human epidermal growth factor receptor 2 [HER2]-positive moderately-differentiated adenocarcinoma)accompanied by lymph node enlargement. We planned an open total gastrectomy after staging laparoscopy to rule out dissemination because peritoneal dissemination could not be ruled out using computed tomography(CT). To perform a total gastrectomy, a celiotomy was done after staging laparoscopy results suggested that dissemination was unlikely. However, the border between the pericardial lymph nodes and the pancreas or peritoneal artery was not visible, forcing us to terminate the staging laparotomy based on a judgment of unresectable locally advanced gastric cancer. Therefore, the patient was administered 6 cycles of combined S-1/CDDP plus trastuzumab as the primary therapy. The response to therapy was favorable, and we scheduled a surgical resection. However, the scheduled surgery was rescheduled because of COVID-19 pneumonia, and R0 resection was finally performed after the 7th cycle of S-1/CDDP plus trastuzumab therapy. Histopathologically, the regional lymph node metastasis had disappeared, the viable tumor remained within the mucosal layer, and scarring was evident from the submucosal layer to the serosa. In recent years, conversion surgery for unresectable gastric cancer has been sporadically reported. However, we are unable to definitively opine on whether this kind of surgery may contribute to improving the prognosis, resection remains indispensable for radical treatment. We report this case along with a review of the literature.

[A Case of Triple Negative Breast Cancer with Successful Control of Recurrent Disease Activity for More than Ten Years].

A woman in her 70s underwent mastectomy plus axillary lymph node excision(Bt plus Ax)in December 2011 for left breast cancer classified as pT2N1M0, pStage ⅡB. The tumor was identified as an invasive ductal carcinoma(IDC), neural/ glial antigen 2(NG2), pT2(35 mm), INF γ, ly2, v0, g+, f+, s+, extensive intraductal component(EIC)-negative, ICT- positive, NCAT-positive, n(4/18), estrogen receptor(ER)-negative, progesterone receptor(PgR)-negative, human epidermal growth factor receptor 2(HER2)-negative, Ki-67 30-40%. Postoperative adjuvant fluorouracil plus epirubicin HCl plus cyclophosphamide(FEC)plus paclitaxel(PTX)therapy was administered. The patient refused to undergo postoperative radiation therapy. Two years after the surgery, she was diagnosed as having a lung metastasis and local disease recurrence. Biopsy of the local recurrent lesion revealed the same histopathological diagnosis as before. Capecitabine was selected for treatment of the recurrent lesion. After 2 years of capecitabine treatment, the response was rated as progressive disease (PD). At this time, eribulin mesylate was selected, along with intensity-modulated radiation therapy(IMRT). This resulted in disappearance of the tumor on imaging. However, considering that the histological findings did not suggest complete response(CR)and that the tumor was triple-negative(TN), we adopted a strategy of continuing the drug therapy at reduced dose level. With this strategy, the disease activity could be successfully controlled for 6.5 years. Subsequently, liver metastasis was detected, and the drug was switched to vinorelbine ditartrate(a drug with less non-hematological toxicity). Meanwhile, a breast cancer susceptibility gene(BRCA)analysis was performed in January 2021, which was negative. Subsequently, in September 2021, we obtained a positive result for PDL1-SP142 and negative result for 22C3. About half a year later, ie, in October 2021(11 years after the surgery), we detected an increase in the size of the liver metastasis and selected atezolizumab and nab-PTX for treatment. Applicable regimens of drug therapy are still available at present and drug therapy has been continued based on a discussion and mutual understanding of the adverse reactions, etc. with the patient. Few reports have been published concerning long-term survivors among TN breast cancer cases.