Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma.

Nicotinamide phosphoribosyltransferase (NAMPT) plays a major role in NAD biosynthesis in many cancers and is an attractive potential cancer target. However, factors dictating therapeutic efficacy of NAMPT inhibitors (NAMPTi) are unclear. We report that neuroendocrine phenotypes predict lung and prostate carcinoma vulnerability to NAMPTi, and that NAMPTi therapy against those cancers is enhanced by dietary modification. Neuroendocrine differentiation of tumor cells is associated with down-regulation of genes relevant to quinolinate phosphoribosyltransferase-dependent de novo NAD synthesis, promoting NAMPTi susceptibility in vitro. We also report that circulating nicotinic acid riboside (NAR), a non-canonical niacin absent in culture media, antagonizes NAMPTi efficacy as it fuels NAMPT-independent but nicotinamide riboside kinase 1-dependent NAD synthesis in tumors. In mouse transplantation models, depleting blood NAR by nutritional or genetic manipulations is synthetic lethal to tumors when combined with NAMPTi. Our findings provide a rationale for simultaneous targeting of NAR metabolism and NAMPT therapeutically in neuroendocrine carcinoma.

[A case of anaplastic pancreatic cancer with osteoclast-like giant cells during follow-up of a branch-duct pancreatic intraductal papillary mucinous tumor].

In this study, a 76-year-old man initially diagnosed with branch-duct pancreatic intraductal papillary mucinous tumor is presented. During follow-up, stenosis was discovered in the main pancreatic duct of the tail. A nodular lesion was found in the pancreatic duct consistent with the stenosis. Distal pancreatectomy was performed since it was suspected to be malignant. Histopathology revealed polymorphic mononuclear cells proliferated with osteoclast-like giant cells in the nodule. The patient was finally diagnosed with anaplastic pancreatic cancer with osteoclast-like giant cells, a relatively rare tumor. It is reported herein with a review of the literature.

A Case of Ectopic Thyroid Presenting as a Superior Mediastinal Mass.

We report a very rare case of an ectopic thyroid in the superior mediastinum, which was detected incidentally using imaging. The case was a 50-year-old woman patient. She had an orthotopic thyroid and normal thyroid function. This superior mediastinum mass obviously lacked continuity with the orthotopic thyroid. Its computed tomography density was lower than that of the orthotopic thyroid, and an enhancement was heterogeneously observed. In the cytodiagnosis, only large and small lymphocytes were observed, and malignant diseases such as malignant lymphoma could not be ruled out, so surgical resection was performed through a cervical incision. Combined resection of the thyroid was unnecessary, and ligation of the feeding vessels from the thorax side was able to be carried out without incident.

Divergent metabolic responses dictate vulnerability to NAMPT inhibition in ovarian cancer.

It is of current interest to target cancer metabolism as treatment for many malignancies, including ovarian cancer (OVC), in which few druggable driver mutations have been identified. Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD salvage pathway, is a potential therapeutic target in OVC. However, factors that determine responsiveness to NAMPT inhibition are not fully understood. Here, we report that OVC cell lines can be divided into subgroups exhibiting NAMPT-dependent or NAMPT-independent glycolysis, and these metabolic differences correlate with vulnerability to NAMPT inhibition. Interestingly, cells showing NAMPT-dependent glycolysis were enriched in a group of cells lacking BRCA1/2 gene mutations. Our findings suggest the importance of selecting appropriate patients for NAMPT-targeting therapy in OVC.

Risk factors for cervical lymph node metastasis in endoscopically resected superficial hypopharyngeal cancers.

OBJECTIVE: Hypopharyngeal cancer is a head and neck cancer with a poor prognosis, and most cases show metastases on diagnosis. Cervical lymph node (LN) metastasis is a poor prognostic factor in hypopharyngeal cancer patients. The identification of risk factors for LN metastasis can help guide surgical treatment strategies for these patients. METHODS: This retrospective study included 93 superficial hypopharyngeal cancer patients with 109 histopathologically examined lesions treated by endoscopic resection between January 2007 and December 2017. Tumor thickness quantification, quantification of budding nests, immunostaining and other histopathological analyses in paraffin-embedded, formalin-fixed tissue sections (3-µm) of surgical specimens were performed by a certified pathologist. RESULTS: Cervical LN metastasis was positive in 18 out of 93 cases (19.3%) and 18 out of 109 lesions (16.5%). No differences were detected in patient characteristics between LN-positive and LN-negative cases, except for tumor thickness, which was significantly larger in LN-positive cases (3119.4±602.2µm vs. 1015.5±129.6µm, respectively; p<0.0001). Univariate analysis showed that tumor thickness ≥1000µm (odds ratio: 5.559, p=0.003), lesions with high budding grade (odds ratio: 5.188, p=0.01) and vascular invasion (odds ratio: 12.710, p=0.007) were significantly associated with cervical LN metastasis. Multivariate analysis revealed tumor thickness≥1000µm as the most significant risk factor for cervical LN metastasis in superficial hypopharyngeal cancer (odds ratio: 3.639, p=0.04). CONCLUSIONS: We demonstrate for the first time that high budding grade may serve as powerful predictors of LN metastasis and tumor thickness ≥1000µm is a significant risk factor for LN metastasis of superficial hypopharyngeal cancer. These results should be further examined in future larger scale studies.

PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth.

Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRASG12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs.

Ex vivo model of non-small cell lung cancer using mouse lung epithelial cells.

Lung cancer is the most common cause of cancer mortality, however, efficient methods to culture, expand and transform lung epithelial (LE) cells have not been established. In the present study, an efficient ex vivo method was applied to recapitulate lung carcinogenesis using mouse LE cells. A Matrigel-assisted three-dimensional culture was used to isolate and selectively expand LE cells from mouse lungs. Purified LE cells were passaged and expanded for at least 2 to 3 months while maintaining epidermal growth factor-dependence. LE cells were also easily transformed by genetic manipulations using retroviral vectors. A SV40 large-T antigen, suppressing p53 and pRB, plus an activated oncogene, such as KrasG12V or EGFRex19del, were required to transform LE cells. Transformed cells formed tumors resembling non-small cell lung cancer (NSCLC) in allograft models and exhibited strong oncogene addiction. This experimental system provided a unique model system to study lung tumorigenesis and develop novel therapeutics against NSCLC.

Mixed squamous cell and glandular papilloma of the lung resembling early adenocarcinoma: A case report.

INTRODUCTION: An extremely rare case of mixed squamous cell and glandular papilloma of the lung is reported. The correlation between the radiological and the pathological features as well as the clinical pitfall in making a diagnosis is discussed. PRESENTATION OF CASE: An asymptomatic 68-year-old female with a cigarette smoking habit presented with a small nodule in her peripheral lung. A wedge resection was performed though it failed on-site diagnosis which was instead obtained following pathological scrutiny. The postsurgical course was excellent with no recurrence of disease. DISCUSSION: A small ground glass nodule gradually enlarged and transformed to a partially solid nodule a year and a half later. This transformation falsely made us suspect an early adenocarcinoma development. Eventually, the extremely rare subtype of pulmonary papilloma, with biphasic glandular and squamous cells, had been demonstrated to obstruct the peripheral bronchiole; and the adjoining alveoli had filled with a large volume of mucus. These pathological features seemed to have constituted the inner solid portion and the marginal ground glass portion respectively in the CT images, mimicking invasive lepidic adenocarcinoma. CONCLUSION: Both pre- and intra-operative diagnoses are difficult mainly because of the rareness of the disease, however, mixed squamous cell and glandular papilloma may be considered in case the presence of primary adenocarcinoma is not validated.

Clear cell carcinoma of the nasal cavity: A case report from histopathological viewpoint.

We report an extremely rare case of primary clear cell carcinoma (CCC), not otherwise specified (NOS) of the nasal cavity. An 80-year-old woman was referred to our hospital with left nasal obstruction caused by a nasal cavity tumor. The tumor was resected completely with lateral rhinotomy approach. Histopathological examination revealed CCC. CCC metastasis from renal cell carcinoma (RCC), which is at the top of differential diagnosis, was ruled out by the absence of renal tumor at computed tomography (CT). Also, immunohistochemical results of the specimen with vimentin negative and CK7 focally positive excluded the possibility of RCC metastasis. The patient is free from recurrence 1 year after the surgery, and there is no evidence of RCC. In this report histopathological characteristics, especially immunohistochemical properties of primary CCC, NOS of the nasal cavity are presented together with some clinical features of this rare tumor. Also, we refer to histopathogenesis of primary CCC of nasal cavity in relation to myoepithelial carcinoma. Histopathological discussion is further extended to include other CCC and CCC-resembling histologies to confirm the uniqueness of the present case.

[THREE CASE REPORTS OF METACHRONOUS BILATERAL TESTICULAR TUMOR: INVESTIGATION OF SEXUAL FUNCTION AND FERTILITY].

The sexual dysfunction and infertility after treatment of bilateral germ cell tumors (GCT) becomes the serious problem. Therefore andrological aspects as well as cancer curability should be considered in planning of bilateral GCT treatment. Here we report 3 cases of metachronous bilateral GCT treated with different regimens, and discuss from the viewpoint of preservation of sexual function. Case presentations: (1) A 38-year-old man underwent right-sided orchitectomy for a right testicular tumor at the age of 26 years. Pathological diagnosis was seminoma and clinical stage was T1N0M0S2. 12 years later, contralateral testicular tumor developed. Left-sided orchitectomy was performed. Pathological diagnosis was seminoma and clinical stage was T1N0M0S2. He has been followed up for 4 years after the second operation without any evidence of tumor recurrence. Endocrinological examination show low testosterone level, and high LH and FSH levels. Erection and ejaculation are impossible but he does not request androgen replacement therapy. (2) A 21-year-old man underwent right-sided orchitectomy for a right testicular seminoma at the age of 20 years (T1 N0M0S0). 1 year later, contralateral seminoma (T1N0M0S0) developed and left-sided organ-preserving operation was performed. Histologic specimens showed seminoma and intratubular malignant germ cells (ITMGC) in surrounding seminiferous tubules. 2 cycles of BEP was added after the operation. He has been followed up for 5 years without any evidence of tumor recurrence. Endocrinological examination shows normal levels of testosterone and LH, but FSH is slightly high. Erection and ejaculation are possible. (3) A 36-year-old man underwent right-sided orchitectomy for a right testicular embryonal carcinoma at the age of 30 years. Clinical T1N0M0S1 was confirmed. 6 years later, he noticed the induration at his left testis. The result of fine needle aspiration cytology was embryonal carcinoma. At first, organ-preserving operation after chemotherapy was planned. However, he refused the operation considering the possibility of erectile dysfunction and infertility. As a result, he received only chemotherapy (3 cycles of BEP), and has been free of the disease for 11 years after chemotherapy. The level of testosterone, LH, and FSH are all normal. Erection and ejaculation are possible.

Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis.

We previously reported that deficiency in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) predisposes mouse skin tissue to papilloma formation initiated by DMBA. Here, we demonstrate that Ppp6c loss acts as a tumor promoter in UVB-induced squamous cell carcinogenesis. Following UVB irradiation, mice with Ppp6c-deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice. Time course experiments showed that following UVB irradiation, Ppp6c-deficient keratinocytes upregulated expression of p53, PUMA, BAX, and cleaved caspase-3 proteins. UVB-induced tumors in Ppp6c-deficient keratinocytes exhibited a high frequency of both p53- and γH2AX-positive cells, suggestive of DNA damage. Epidemiological and molecular data strongly suggest that UVB from sunlight induces p53 gene mutations in keratinocytes and is the primary causative agent of human skin cancers. Our analysis suggests that PP6 deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB-induced mutated p53. Understanding PP6 function in preventing UV-induced tumorigenesis could suggest strategies to prevent and treat this condition.

[Paraganglioma of the bladder : two case reports].

Case 1. A 48-year-old man with no history of hypertension was referred to our hospital with a 1 cm bladder tumor. According to cystoscopy, magnetic resonance imaging and 131I-MIBG scintigraphy, we diagnosed it as a paraganglioma of the bladder. Partial cystectomy was performed. The histological findings supported the diagnosis of paraganglioma of the bladder. Six years later, he was free of any evidence of recurrence. Case 2. A 64-year-old woman with hypertension was pointed out to have a 1cm bladder mass by ultrasound in a health examination. She was referred to our hospital for further examination. Cystoscopoy revealed a 1 cm intramural nodule covered by intact urothelium at the right posterior wall. Submucosal bladder tumor was not diagnosed as paraganglioma by cold punch biopsy. So, transurethral resection of the bladder tumor was performed for differential diagnosis. The tumor was hypervascular and involved the muscular layer of the bladder. Although a transient elevation of blood pressure occurred during the procedure, the tumor was resected as completely as possible. The histological diagnosis was paraganglioma of the bladder. She has been followed up for 27 months after operation without any evidence of recurrence.

Gastric-type endocervical glandular neoplasms associated with aberrant p16 expression and K-RAS gene mutation in Peutz-Jeghers syndrome.

In this report, unique endocervical glandular lesions exhibiting gastric differentiation were examined in a patient with Peutz-Jeghers syndrome. The result of the human papillomavirus (HPV) in situ hybridization (ISH) for the hysterectomy specimens was negative, but they demonstrated a papillary mucinous adenocarcinoma at the proximal endocervix continuous to atypical lobular endocervical glandular hyperplasia. Both contained MUC6-positive neutral mucin in cytoplasm, and showed different immunoreactivity to p16, Ki-67, and p53. Moreover, they harbored the identical K-RAS gene mutation suggesting that there was a common origin. Somatic K-RAS mutation and defective function of p16 may have been involved in the tumorigenesis of these unusual mucinous neoplasms.

Case report of Mammary Analog Secretory Carcinoma of the parotid gland.

Mammary Analog Secretory Carcinoma (MASC) is a new entity of malignant salivary gland tumors that morphologically resembles mammary secretory carcinoma and carries the identical ETV6-NTRK3 fusion gene. We report our first case of MASC in Japan occurring in the parotid gland of a 37-year-old female patient with a t (12; 15) (p13; q25) translocation. Histologically, the tumor was composed of monomorphic cuboidal cells with low-grade vesicular nuclei and pale eosinophilic cytoplasm, and formed microcystic and tubular spaces with periodic acid-Schiff-positive secretion. Immunohistochemically, the tumor cells tested positive for cytokeratin, vimentin, and S-100 protein. MASC is a morphological mimicker of acinic cell carcinoma, but is a distinct neoplasm characterized by a specific chromosomal translocation. An accumulation of similar case studies is mandatory in order to clarify biological behaviors.

A Case of Angiosarcoma Arising in Trunk of the Right Pulmonary Artery Clinically Simulating Pulmonary Thromboembolism.

Angiosarcoma arising in the pulmonary artery is extremely rare. We herein report a case of angiosarcoma arising in the pulmonary artery trunk of 71 year-old woman. This case was clinically diagnosed as pulmonary thromboembolism but angiosarcoma of the pulmonary artery should be considered as the differential diagnosis of unusual clinical manifestations of pulmonary thromboembolism because of the extremely poor prognosis of the lesion.

[A case of early cystic duct carcinoma concomitant with xanthogranulomatous cholecystitis (XGC)].

We reported a case of early cystic duct carcinoma concomitant with xanthogranulomatous cholecystitis (XGC). This case was a 72-year-old man in whom thickening of the gallbladder wall was pointed out an abdominal ultrasonography and elevation of the CA19-9 level was detected at a local clinic. Endoscopic ultrasonography and CT demonstrated a mass in the cystic duct. Mapping biopsy using peroral cholangioscopy (POCS) revealed a diagnosis of cystic carcinoma with superficial flat growth, therefore a pylorus-preserving pancreatoduodenectomy was performed. Histopathological diagnosis was well differentiated papillotubular adenocarcinoma with superficial flat spread and the thickening of the gallbladder wall was XGC. A case of early cystic duct carcinoma concomitant with XGC is extremely rare.

A case of cutaneous bronchogenic cyst in the scapular area.

Cutaneous bronchogenic anomalies are rare. We report a 4-year-old boy who presented with a tumour and relapsing infection in the right scapular region. Histopathological examination of this tumour revealed a subcutaneous cystic legion formed by ciliated columnar epithelium with smooth muscle bundles and squamous epithelium with sebaceous glands.