症例は60歳代,女性.20XX年1月に急性膵炎を発症した際に,20mm大の膵頭部腫瘤を指摘された.急性膵炎は保存的治療で改善し,膵頭部腫瘤は膵炎に伴う被包化壊死疑いの診断で経過観察となった.同年7月,9月に再度急性膵炎を発症した際,および同年11月に閉塞性黄疸を発症した際に,膵頭部腫瘤は形態・内部性状が著明に変化した.同年12月に経乳頭的膵管生検が施行され,膵頭部腫瘤は膵腺房細胞癌と診断された.modified FOLFIRINOX(mFFX)による術前補助化学療法施行により奏効が得られ膵頭十二指腸切除術が施行された.画像所見および病理学所見から,腫瘍内部の出血や壊死により腫瘍形態および内部性状が経時的に変化したものと考えられた.また,本症例はBRCA遺伝子検査にてBRCA病的バリアントが確認され,遺伝性乳癌卵巣癌症候群(hereditary breast and ovarian cancer:HBOC)と診断された.
Abstract BackgroundNUT carcinoma (NC) is a rare and extremely aggressive carcinoma that occurs in young individuals. Although NC has a dismal prognosis, recommended therapies have not been established.Case presentationAn 18-year-old man presented with sudden vision loss in his left eye. Magnetic resonance imaging revealed a rapidly growing tumor, which had directly invaded the left optic nerve and epidural space, originating from the left posterior ethmoid sinus. A pathological examination of the tumor revealed a dense proliferation of polygonal-to-round tumor cells with enlarged round nuclei and conspicuous nucleoli, and positive staining for NUT protein in the nuclei of tumor cells. The patient was diagnosed with locally advanced NC. We initiated concurrent chemoradiotherapy (CCRT), consisting of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC), alternating with ifosphamide and etoposide (IE) according to a regimen for Ewing sarcoma, plus radiation therapy (70 Gy/35 Fr). The patient completed CCRT and achieved a complete response.ConclusionsCCRT, comprising a VDC–IE regimen, can be a useful treatment option for adolescent and young adult patients with NC, even when the cancer is at a locally advanced unresectable stage.
Abstract Background Accumulating evidence has demonstrated platinum-based chemotherapy followed by maintenance therapy with a poly Adenosine diphosphate (ADP)-ribose polymerase inhibitor (olaparib) show benefits in unresectable pancreatic cancer with a germline (g)BRCA1/2 mutation. Evaluation of the germline BRCA1 and BRCA2 mutation is essential for making decisions on a treatment strategy for patients with unresectable pancreatic cancer. However, the detection rates of germline BRCA1 and BRCA2 mutations and efficacy of maintenance with olaparib remain undetermined, prospectively, in Japan. Methods & Results In this prospective analysis, the rate of germline BRCA1 and BRCA2 mutations and efficacy of chemotherapy were analyzed in 136 patients with pancreatic cancer who underwent BRACAnalysis® (85 patients) or FoundationOne® CDx (51 patients) between January 2020 and July 2022. A total of six patients (4.4%) had a germline BRCA1 and BRCA2 mutation. Five patients were treated with modified FOLFIRINOX and one with fluorouracil and oxaliplatin. All patients continued platinum-based chemotherapy for ˃4 months and were subsequently treated with olaparib as a maintenance therapy. The response rate to platinum-based chemotherapy in the germline BRCA1 and BRCA2 mutation-positive group was significantly better than that of the germline BRCA1 and BRCA2 mutation-negative group (66% vs 23%, P = 0.04). All patients harbouring a germline BRCA1 and BRCA2 mutation were able to switch to olaparib. The median progression-free survival using olaparib was 5.7 months (range 3.0–9.2). Conclusions The rate of germline BRCA1 and BRCA2 mutations found in patients with unresectable pancreatic cancer was comparable to those of previous studies. An analysis of germline BRCA1 and BRCA2 mutations has benefits for all patients with unresectable pancreatic cancer with regard to decisions on therapeutic strategies in a clinical practice setting.
Abstract Despite continuing advances in the development of effective new therapies, including immunotherapies, the prognosis of pancreatic cancer remains extremely poor. Gap junction proteins have become attractive targets for potential cancer therapy. However, the role of gap junction beta‐4 (GJB4) protein remains unexplored in pancreatic cancer. Through bioinformatic analyses we discovered pancreatic cancer tissues showed higher levels of GJB4 transcripts compared to normal pancreatic tissues and this had a negative effect on overall survival in patients that had pancreatic cancer. The high expression of nuclear GJB4 was identified as a negative prognostic factor in such patients. Knockdown of GJB4 in cultured pancreatic cancer cells resulted in G 0 /G 1 arrest followed by decreased cell proliferation and suppression of metastatic potential. The overexpression of GJB4 accelerated cell proliferation, migration, and invasion in a SUIT‐2 cell line, whereas MET inhibitor canceled the acceleration. GJB4 suppression with siRNA significantly inhibited tumor growth in a mouse xenograft model. Mechanistically, suppression of GJB4 inhibited MET–AKT activities. Such data suggest that targeting the GJB4–MET axis could represent a promising new therapeutic strategy for pancreatic cancer.
A woman in her 70s with main pancreatic duct dilatation was referred to our hospital. Various imaging examinations showed an extensive mass within the lumen of the main pancreatic duct in the head and body of the pancreas. The microscopic examination of a biopsy specimen revealed an adenocarcinoma. She was diagnosed with intraductal tubulopapillary adenocarcinoma of the pancreas;a pylorus-preserving total pancreatectomy was subsequently performed. However, 30 days after surgery, the patient presented with neck pain and left upper arm numbness. Results of magnetic resonance imaging and bone scintigraphy revealed a cervical spinal tumor that was subsequently biopsied. The patient was diagnosed with intraductal tubulopapillary adenocarcinoma with bone metastasis.
To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial –mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than −6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.
An 18-year-old man presented with sudden vision loss in his left eye. Magnetic resonance imaging revealed a tumor that had invaded the left optic nerve, originating from the left posterior ethmoid sinus. Immunohistochemical analyses identified positive staining for NUT protein in the nuclei of tumor cells. We diagnosed locally advanced NUT carcinoma (NC) and initiated concurrent chemoradiotherapy (CCRT), consisting of chemotherapy with vincristine, doxorubicin, and cyclophosphamide, alternating with ifosphamide and etoposide, plus radiation therapy. The patient achieved a complete response. CCRT can be a useful treatment option for adolescent and young-adult patients with locally advanced unresectable NC.
