Locally advanced rectal cancer in a young adult affected with dyskeratosis congenita (Zinsser-Cole-Engman syndrome): a case report.

BACKGROUND: Dyskeratosis congenita (DKC), also known as Zinsser-Cole-Engman syndrome, is a progressive genetic disease with a triad of reticulate skin pigmentation, nail dystrophy, and leukoplakia. Approximately 8-10% of patients with DKC develop malignancies, and cases of colorectal cancer with DKC in young people have been reported previously. CASE PRESENTATION: A 25-year-old man with DKC since approximately 10 years of age developed fever and lower abdominal discomfort. Diagnostic imaging revealed locally advanced rectal cancer with lymph node metastasis, direct invasion of the prostate, and pelvic abscess due to tumor microperforation (cT4bN2M0 cStage IIIC). Biopsy showed well to moderately differentiated ductal adenocarcinoma. Genetic testing was negative for RAS and BRAF gene mutations, and microsatellite instability (MSI) testing was also negative. After sigmoid colostomy, the patient was treated with total neoadjuvant therapy (TNT) with systemic chemotherapy (six courses of FOLFOX + panitumumab) followed by chemoradiation therapy (50.4 Gy with capecitabine). After TNT, the primary tumor and metastatic lymph nodes shrank. According to the findings of colonoscopy and magnetic resonance image (MRI), we diagnosed near complete response (near-CR) and decided to follow the patient without surgery by every 3 months re-evaluation. However, 5 months after TNT, tumor regrowth was detected on colonoscopy and imaging, and the patient underwent total pelvic exenteration. He developed paralytic ileus as a postoperative complication, and was discharged on the 38th postoperative day. Pathological examination revealed a residual tumor with invasion of the periprostatic tissue. There was no metastasis in the pararectal and lateral pelvic lymph nodes, but one extramural non-contiguous cancerous extension (tumor deposit) was observed (ypT4bN1cM0 ypStage IIIC). The patient has been free of recurrence for one year after surgery. CONCLUSIONS: DKC often develops into various tumors in the digestive system at an early age; therefore, appropriate surveillance may be required. In addition, considering that cancers in patients with DKC occur at a young age, fertility preservation and survivorship are also important, and adequate explanations and care should be provided to patients before and after treatment.

Genetic intratumour heterogeneity and clonal evolution in extramammary Paget's disease.

All tumour cells in a patient have shared and non-shared genetic alterations, and the diversity of mutations is described as intratumoural heterogeneity (ITH). Multiregion sequencing is a genome sequencing analytical technique used for multiple, spatially-separated biopsy tissues that may further our understanding of ITH and tumour evolution. Although genetic mutations in extramammary Paget's disease (EMPD) have recently been detected by next-generation sequencing analysis, there have been no reports of ITH based on multiregion sequencing in EMPD. Thus, we clarified the landscape of ITH and tumour evolution in EMPD. We performed whole-exome sequencing on 35 tissues (30 tumour tissues and five normal skin samples as a paired control), collected from five patients with EMPD. The rate of private mutations was significantly higher than that of ubiquitous and shared mutations. Ubiquitous mutations were not present in driver genes, and most driver genes exhibited private and shared mutations. The most frequent base substitution was C>T in almost all lesions, and most mutational signatures corresponded to signature 1, 2, 3, and 8. The types of proposed aetiology in most lesions were based on age and AID/APOBEC family and BRCA1/BRCA2 mutations. Evolutionary trees were characterized by short trunks and long branches due to the extremely high ratio of private mutations. In contrast, pathogenic factors, such as base substitutions, mutational signatures, and proposed aetiology, were shared. Tumour evolution in EMPD appears to be characterized by a high level of genetic ITH with shared background factors.

Elevation of circulating DNAs of disease-associated cytokines in serum cell-free DNA from patients with alopecia areata.

Alopecia areata (AA) is an autoimmune disease characterized by damage to hair follicles and hair loss. Cell-free DNA (cfDNA) has recently received attention as a biomarker of various disorders including inflammatory skin diseases. In this study, we aimed to investigate the clinical significance of cfDNA and the circulating DNAs of disease-associated cytokines in AA patients. Serum samples were obtained from 63 patients with AA and 32 healthy controls (HC). Using droplet digital polymerase chain reaction, circulating C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL11, C-X-C motif chemokine receptor 3, interferon (IFN)-γ, interleukin (IL) -7, IL-15, and Janus kinase (JAK) 2 were detectable in both HC and AA patients. Among the detectable DNAs, copies of circulating CXCL9, CXCL11, IL-15, IFN-γ, and JAK2 were significantly higher in AA patients than in HC. These results suggest that increased circulating DNA levels may reflect damage to hair follicles in AA patients.

SLC39A7 upregulation links to skin fibrosis in systemic sclerosis via TGF-ß/SMAD pathway.

Systemic sclerosis (SSc) is a multisystem connective tissue disease. Skin fibrosis, the hallmark of this disease, is defined as the excess deposition and accumulation of extracellular matrix, mainly type 1 collagen, in the dermis. SLC39A7 is an intracellular zinc transporter that plays a unique role in connective tissue formation. Therefore, we investigated the expression and role of SLC39A7 in SSc. Using immunohistochemical staining we demonstrated the overexpression of SLC39A7 in the skin of SSc patients. Quantitative real-time PCR and western blot data analysis showed that both SLC39A7 mRNA and protein levels were significantly upregulated in dermal fibroblasts from SSc patients compared to healthy controls. We used the shRNA lentiviral particle transduction system to stably knockdown the expression of SLC39A7 in SSc fibroblasts. The results showed that knockdown of SLC39A7 suppressed the production of type 1 collagen. These findings provide evidence that SLC39A7 is involved in the pathogenesis of SSc and that SLC39A7 plays a positive role in its progression.

PIK3CA mutations in cutaneous squamous cell carcinoma.

Oncogenic PIK3CA mutation activates phosphoinositide 3-kinase (PI3K) enzyme, and PI3K-AKT signaling activation induces several growth-regulatory transcription factors. PIK3CA mutations have attracted attention as biomarker in clinical trials of various inhibitors including PI3K inhibitors. About 80% of PIK3CA mutations in human cancers are observed in 'hot spot' regions: exon 9 (E542K and E545K) and exon 20 (H1047R). There were few reports about clinical significance of PIK3CA mutations in cutaneous cell carcinoma (cSCC). Thus, we investigate the prevalence of three PIK3CA hot spot mutations in 143 cases with cSCC and evaluate the correlation between the presence of these mutations and clinical characteristics by using ddPCR. The frequency of each E542K, E545K and H1047R PIK3CA mutations was 1.4% (2/143), 2.8% (4/143), and 0.7% (1/143) respectively. No significant correlation was found between PIK3CA mutations and clinical characteristics. Although additional basic researches and clinical trials are necessary, various inhibitors may be effective therapeutics for PIK3CA mutation-positive cSCC. Our study revealed the prevalence of PIK3CA mutations in cSCC.

Overexpression of heat shock protein 90 through the downregulation of miR-9-5p in extramammary Paget's disease.

Heat shock protein 90 (HSP90) facilitates diverse cellular processes by interacting process with more than 200 client proteins. Overexpression of HSP90 contributes to the pathogenesis of various malignant tumors, and HSP90 inhibitors attenuate the progression of malignant tumors in vitro/vivo. Numerous clinical trials have used HSP90 inhibitors to treat several cancers, and pimitespib (an HSP90 inhibitor) is covered by insurance for advanced gastrointestinal stromal tumor in Japan. In this study, we investigated the expression pattern of HSP90 and analyzed its clinical significance in extramammary Paget's disease (EMPD). All 77 EMPD tissues investigated were positive for HSP90 expression. The immunoreactivity of HSP90 in fetal cases due to EMPD tended to be highly stained. Although there was no significant difference in HSP90 mRNA levels between 24 paired lesional and nonlesional tissues, microRNA-inhibiting HSP90 levels in tumor tissues were significantly decreased compared with those in normal tissues. Thus, HSP90 may play an important role in the pathogenesis of EMPD and may be a novel therapeutic target for EMPD.

A study of 95 infantile hemangiomas treated with propranolol: A potentially efficacious combination with laser therapy.

We studied 95 patients with infantile hemangioma (IH) treated with propranolol at the Department of Dermatology, Kumamoto University Hospital, from November 2016 to January 2022, based on sex, site, clinical classification, duration of treatment, and residual lesions after treatment. Four of the 95 patients discontinued propranolol due to side effects, and 55 completed follow-ups at our hospital. We observed that 30.1% showed complete resolution of the skin rash, while the remaining 69.8% had erythema or atrophic scarring. Complete resolution occurred in 70% of the cases with the subcutaneous type but only in 15% with the tumor type. Seventeen of the 55 patients who completed follow-ups were treated with propranolol combined with laser therapy. Combined use of propranolol and laser therapy significantly reduced severe erythema compared to the propranolol monotherapy. These results suggest that propranolol therapy in IH often leaves erythema except in the subcutaneous type and that an improvement in erythema can be expected when propranolol is combined with laser therapy.

A Japanese case of melanoma of unknown origin with a rare BRAFV600R mutation was successfully treated with BRAF/MEK inhibitors.

Combination therapy with BRAF and MEK inhibitors (BRAF/MEKi) has shown significantly prolonged progression-free survival (PFS) and overall survival (OS) for BRAF mutated melanoma. Over 90% of the activating mutations are BRAFV600E or BRAFV600K changes. There are no reports of BRAFV600R in Japanese patients with melanoma. The third most common BRAF mutation is BRAFV600R. In this case, we detected the BRAFV600R mutation with FoundationOne CDx in a Japanese patient with melanoma.. The patient was treated with BRAF/MEKi and maintained stable disease status for 1 year.

Elevated Alpha 1(I) to Alpha 2(I) Collagen Ratio in Dermal Fibroblasts Possibly Contributes to Fibrosis in Systemic Sclerosis.

Systemic sclerosis (SSc) is characterized by excessive collagen deposition in the skin and internal organs. Activated fibroblasts are the key effector cells for the overproduction of type I collagen, which comprises the α1(I) and α2(I) chains encoded by COL1A1 and COL1A2, respectively. In this study, we examined the expression patterns of α1(I) and α2(I) collagen in SSc fibroblasts, as well as their co-regulation with each other. The relative expression ratio of COL1A1 to COL1A2 in SSc fibroblasts was significantly higher than that in control fibroblasts. The same result was observed for type I collagen protein levels, indicating that α2(I) collagen is more elevated than α2(I) collagen. Inhibition or overexpression of α1(I) collagen in control fibroblasts affected the α2(I) collagen levels, suggesting that α1(I) collagen might act as an upstream regulator of α2(I) collagen. The local injection of COL1A1 small interfering RNA in a bleomycin-induced SSc mouse model was found to attenuate skin fibrosis. Overall, our data indicate that α2(I) collagen is a potent regulator of type I collagen in SSc; further investigations of the overall regulatory mechanisms of type I collagen may help understand the aberrant collagen metabolism in SSc.

Intertumor and intratumor heterogeneity of PIK3CA mutations in extramammary Paget's disease.

Although the prognosis of patients with extramammary Paget's disease (EMPD) treated with radical resection is good, the prognosis of EMPD with distant metastasis is very poor. PIK3CA mutations predict a good response to PIK3CA inhibitors. The aim of this study was to investigate the occurrence rate of PIK3CA mutations (including multiple mutations [MM]) related to the intertumor and intratumor heterogeneity in EMPD and to evaluate the correlation between these mutations and clinical parameters of EMPD. We performed droplet digital polymerase chain reaction to detect PIK3CA mutations (E542K, E545K, H1047R, and MM) in 68 patients with EMPD. In addition, we investigated the presence of PIK3CA mutations at multiple sites in 16 patients with PIK3CA mutations to assess the intratumor heterogeneity of PIK3CA mutations in EMPD. The frequency of one or more PIK3CA mutations in patients with EMPD was 30.8% (21/68). The frequency of E542K, E545K, H1047R, and MM were 10.2% (7/68), 13.2% (9/68), 11.7% (8/68), and 4.4% (3/68), respectively. No significant correlation was found between PIK3CA mutation patterns and clinical parameters. Of the 21 patients with PIK3CA mutations, 16 with tissue samples that could be analyzed at multiple sites were examined. The proportion of patients with the same PIK3CA mutations at all sites was 12.5% (2/16). The proportion of patients with the same PIK3CA mutations at least two or more sites, but not at all sites, was 31.2% (5/16). The proportion of patients with no PIK3CA mutations at other sites was 37.5% (6/16). The proportion of patients with other PIK3CA mutations at other sites was 18.7% (3/16). There is intertumor and intratumor heterogeneity of PIK3CA mutations. PIK3CA mutations in EMPD may be progressor mutations in EMPD.