Novel interleukin-33 and its soluble ST2 receptor as potential serum biomarkers in parotid gland tumors.

An increasing number of patients with parotid gland tumors have been observed in recent years. The relationship between the immune system and tumor formation is thoroughly investigated. However, newly discovered molecules offer a new insight into the pathophysiology of malignancies. It would be ideal to find an easily determinable biomarker of tumor existence, its malignant potential or a biomarker suggesting the probability of disease recurrence. Our study is the first to examine serum concentrations of IL-33 and its sST2 receptor in patients with various types of parotid gland tumors. Serum IL33, sST2, IL-4 and IL-10 concentrations were determined in patients with benign and malignant parotid gland tumors (pleomorphic adenoma, Warthin's tumor, myoepithelioma and acinic cell carcinoma). We observed for the first time that serum IL-33 level was significantly elevated in patients with various types of parotid gland tumors and sST2 levels were significantly higher in pleomorphic adenoma and acinic cell carcinoma patients compared to the controls. Our results demonstrate for the first time that serum IL-33 and its sST2 receptor may be important factors in the pathology of parotid gland tumors. Although our results are promising, further investigations are required to detect if serum concentrations of those molecules may be a biomarker in parotid gland tumors. Impact statement Parotid gland tumors seem to be an increasingly important medical challenge, mostly due to a noticeable increase in the incidence. It would be crucial to find an easily determinable biomarker of tumor existence, its recurrence or malignant potential. We observed for the first time that serum IL-33 level was significantly elevated in patients with various types of parotid gland tumors and its sST2 receptor levels were significantly higher in pleomorphic adenoma and acinic cell carcinoma patients compared to the controls. We believe that our study helps to understand the biology of the tumors and a potential role of a relatively newly identified cytokine IL-33 in the pathophysiology of the parotid gland tumors.

Cytologic characteristics of circulating epithelioid cells in pancreatic disease.

BACKGROUND: Circulating epithelioid cells (CECs), also known as circulating tumor, circulating cancer, circulating epithelial, or circulating nonhematologic cells, are a prognostic factor in various malignancies that can be isolated via various protocols. In the current study, the authors analyzed the cytomorphologic characteristics of CECs isolated by size in a cohort of patients with benign and malignant pancreatic diseases to determine whether cytomorphological features could predict CEC origin. METHODS: Blood samples were collected from 9 healthy controls and 171 patients with pancreatic disease who were presenting for surgical evaluation before treatment. Blood was processed with the ScreenCell size-based filtration device. Evaluable CECs were analyzed in a blinded fashion for cytomorphologic characteristics, including cellularity; nucleoli; nuclear size, irregularity, variability, and hyperchromasia; and nuclear-to-cytoplasmic ratio. Statistical differences between variables were analyzed via the Fisher exact test. RESULTS: No CECs were identified among the 9 normal healthy controls. Of the 115 patients with CECs (positive or suspicious for), 25 had nonmalignant disease and 90 had malignancy. There were no significant differences in any of the cytologic criteria noted between groups divided by benign versus malignant, neoplastic versus nonneoplastic, or pancreatic ductal adenocarcinoma versus neuroendocrine tumor. CONCLUSIONS: CECs were observed in patients with malignant and nonmalignant pancreatic disease, but not in healthy controls. There were no morphologic differences observed between cells from different pancreatic diseases, suggesting that numerous conditions may be associated with CECs in the circulation and that care must be taken not to overinterpret cells identified by cytomorphology as indicative of circulating tumor cells of pancreatic cancer. Additional studies are required to determine the origin and clinical significance of these cells. Cancer Cytopathol 2017;125:332-340. © 2017 American Cancer Society.

Metastatic pancreatic acinar cell carcinoma in a younger male with marked AFP production: A potential pitfall on fine needle aspiration biopsy.

A 30-year-old male presented to his doctor with complaints of abdominal pain and was found to have retroperitoneal as well as multiple hepatic masses. A serum alpha-fetoprotein (AFP) level was significantly elevated (17,373 ng mL-1 ), raising suspicions for a metastatic germ cell tumor. Fine needle aspiration biopsy of the pancreatic lesion revealed atypical epithelioid cells with round nuclei, large prominent nucleoli, and granular cytoplasm. The morphologic differential diagnosis included pancreatic neoplasm, metastatic germ cell tumor, other metastatic carcinoma, and melanoma. An extensive panel of immunohistochemical stains confirmed the diagnosis of acinar cell carcinoma. The diagnosis of acinar cell carcinoma could be confounded by the markedly increased AFP level, particularly in the setting of a retroperitoneal mass in a younger male. The increased AFP level in the setting of an acinar cell tumor is a potential pitfall to correct diagnosis by cytology. As the treatment for these two entities differs considerably, acute awareness of the phenomenon is important. We present a case of pancreatic ACC with an increased AFP level diagnosed on a cytology specimen. Diagn. Cytopathol. 2017;45:133-136. © 2016 Wiley Periodicals, Inc.

Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin.

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare malignancy, accounting for <1 % of all pancreatic neoplasms. Very few retrospective studies are available to help guide management. We previously reported the case of a patient with metastatic PACC who achieved prolonged survival following doxorubicin treatment. Personalized treatment was based on molecular and in vitro data collected from primary cells developed from their liver metastasis. We now report the characterization of a patient derived tumor xenograft (PDTX) mouse model that originated from this patient's PACC liver metastasis. METHODS: Fragments of biopsy tissue (5 mm(3)) from PACC liver metastasis were implanted into athymic nude mice. Tumors were grown and passaged from the host mice into new mice to be tested for therapeutic response. Immuno-histochemical (IHC) biomarkers were used to confirm that the PDTX model represents human PACC. The antitumor activities of multiple drugs (5-FU, irinotecan, oxaliplatin, gemcitabine, bevacizumab, erlotinib, doxorubicin and imatinib) were tested. Tumor size was measured over 74 days or until they reached an endpoint volume of ~800 mm(3). Tests to measure serum lipase levels and histological analyses of tumor tissues were also conducted to assess PACC progression and re-differentiation. RESULTS: The model presented here expresses the same IHC markers found in human PACC. In the chemotherapy study, oxaliplatin produced a prolonged durable growth response associated with increased apoptosis, decreased serum lipase levels and increased healthy acinar cells. Bevacizumab also produced a significant growth response, but the effect was not prolonged as demonstrated by oxaliplatin treatment. The other chemotherapies had moderate to little effect, particularly after treatment ceased. Mutations in DNA repair genes are common in PACC and increase tumor susceptibility to oxaliplatin. To explore this we performed IHC and found no nuclear expression of BRCA2 in our model, indicating a mutation affecting nuclear localization. Gene sequencing confirms BRCA2 has a homozygous gene deletion on Exon 10, which frequently causes a protein truncation. CONCLUSIONS: In summary, we report the development and characterization of the first and only preclinical PACC PDTX model. Here we show sustained anti-tumor activity of single agent oxaliplatin, a compound that is more effective in tumors that harbor mutations in DNA repair genes. Our data shows that BRCA2 is mutated in our PACC model, which could contribute to the oxaliplatin sensitivity observed. Further studies on this rare PACC model can serve to elucidate other novel therapies, biomarkers, and molecular mechanisms of signaling and drug resistance.

A novel serum metabolomics-based diagnostic approach to pancreatic cancer.

BACKGROUND: To improve the prognosis of patients with pancreatic cancer, more accurate serum diagnostic methods are required. We used serum metabolomics as a diagnostic method for pancreatic cancer. METHODS: Sera from patients with pancreatic cancer, healthy volunteers, and chronic pancreatitis were collected at multiple institutions. The pancreatic cancer and healthy volunteers were randomly allocated to the training or the validation set. All of the chronic pancreatitis cases were included in the validation set. In each study, the subjects' serum metabolites were analyzed by gas chromatography mass spectrometry (GC/MS) and a data processing system using an in-house library. The diagnostic model constructed via multiple logistic regression analysis in the training set study was evaluated on the basis of its sensitivity and specificity, and the results were confirmed by the validation set study. RESULTS: In the training set study, which included 43 patients with pancreatic cancer and 42 healthy volunteers, the model possessed high sensitivity (86.0%) and specificity (88.1%) for pancreatic cancer. The use of the model was confirmed in the validation set study, which included 42 pancreatic cancer, 41 healthy volunteers, and 23 chronic pancreatitis; that is, it displayed high sensitivity (71.4%) and specificity (78.1%); and furthermore, it displayed higher sensitivity (77.8%) in resectable pancreatic cancer and lower false-positive rate (17.4%) in chronic pancreatitis than conventional markers. CONCLUSIONS: Our model possessed higher accuracy than conventional tumor markers at detecting the resectable patients with pancreatic cancer in cohort including patients with chronic pancreatitis. IMPACT: It is a promising method for improving the prognosis of pancreatic cancer via its early detection and accurate discrimination from chronic pancreatitis.

Huge pancreatic acinar cell carcinoma with high levels of AFP and fucosylated AFP (AFP-L3).

A 25-year-old Japanese woman with a large abdominal tumor (10 cm in diameter) and high level of serum alpha-fetoprotein (AFP, 1,222.4 ng/mL) was introduced and admitted to our hospital in January 2011. Pre-operative imaging modalities could not identify the tumor origin. There was no chronic hepatic viral disease, however, the elevated level of fucosylated AFP (87.8%) and connection with the left hepatic lobe led us to diagnose the tumor as a hepatocellular carcinoma. Surgical resection was performed in February. Histological findings revealed a pancreatic acinar cell carcinoma (ACC). Herein, we provide details of this difficulty to diagnose a case of ACC.

Prognostic relevance of CA 19-9, CEA, CRP, and LDH kinetics in patients treated with palliative second-line therapy for advanced pancreatic cancer.

The objective of this study was to define prognostic serum biomarkers that could serve as surrogate survival endpoints during second-line treatment for advanced pancreatic cancer. This retrospective single-center study included patients treated with second-line therapy for advanced exocrine pancreatic cancer. A pretreatment value and at least one serial measurement during the first two cycles of second-line chemotherapy for CA 19-9, CEA, CRP, and LDH had to be available in order to evaluate the prognostic role of kinetics on overall survival. A cutoff of a >20% increase from baseline during treatment was defined in order to form groups with suspected different outcomes. The effect of serial biomarker changes on survival was modeled by Cox proportional hazards regression in univariate and multivariate analyses. Overall, 70 patients treated with second-line therapy for advanced disease were included; 94% had distant metastases at treatment initiation. Median time to progression was 2.7 months and median survival 5.4 months. Univariate analysis found that an increase of >20% during treatment was significantly associated with a worse overall survival for CA 19-9 (HR 2.00, p = 0.018), CEA (HR 2.38, p = 0.004), and CRP (HR 3.06, p < 0.001). These associations remained significant within multivariate analysis for CEA (HR 2.86, p = 0.001) and CRP (HR 3.20, p = 0.001). Serum biomarker kinetics might serve as useful prognostic tools during second-line chemotherapy in advanced pancreatic cancer.

Prostate cancer distribution in patients diagnosed by transperineal template-guided saturation biopsy.

OBJECTIVES: To determine the prostate cancer incidence, anatomic distribution, Gleason score profile, and tumor burden in patients diagnosed by transperineal template-guided saturation biopsy (TTSB). MATERIALS AND METHODS: One hundred and two patients underwent TTSB; all but one patient had undergone at least one prior negative TRUS biopsy. Criteria for inclusion included an elevated PSA and/or the diagnosis of ASAP or high-grade PIN on prior biopsy. The prostate gland was divided into 24 regional biopsy locations. The median number of biopsy cores was 50. Multiple clinical parameters were evaluated as predictors for prostate cancer diagnosis. RESULTS: The mean patient age was 64.8 yr with a mean PSA of 9.1 ng/ml and a prostate volume of 78.6 cm(3). On average, patients had undergone 2.1 prior negative TRUS biopsies with a mean of 22.4 core biopsies. Prostate cancer was diagnosed in 43 patients (42.2%) with a Gleason score distribution of 6-9. No anatomic region of the prostate gland was spared of cancer. In patients with prostate cancer, an average of 9.9 cores were involved. In multivariate analysis, prostate volume was the best predictor for prostate cancer diagnosis. CONCLUSIONS: TTBS diagnosed prostate cancer in 42.2% of patients. Considerable anatomic variability in prostate cancer distribution was documented. On the basis of this and other reports, cancer eradication will depend on treatment of the entire prostate gland.

Multiple loss of heterozygosity without K-ras mutation identified by molecular analysis on fine-needle aspiration cytology specimen of acinar cell carcinoma of pancreas.

Fine-needle aspiration diagnosis of pancreatic acinar cell carcinoma (PAC) is challenging. Typically, the cytologic findings in PAC are described as a cellular population of loosely cohesive clusters and single neoplastic cells. The individual cells have granular cytoplasm, uniform nuclei, a fine chromatin pattern, and occasional prominent nucleoli. These features are suggestive of PAC but not diagnostic. We illustrate a case in which the combination of cytopathologic findings, clinical information, and molecular analysis enabled us to arrive at the diagnosis of PAC. Although the cytomorphologic features alone were not specific, the presence of a markedly elevated serum lipase level, cutaneous lesions of fat necrosis, and loss of heterozygosity at 1p, 5q25 at the APC locus, 9p21 at the p16 locus, and 17p13 at the p53 locus were essential in excluding the main differential diagnostic entities including pancreatic ductal carcinoma, pancreatic endocrine tumor, and pancreatoblastoma.

[Changes in prostate-specific antigen in casodex (bicalutamide) monotherapy in a dose 150 mg/day given to patients with locally advanced and/or advanced prostatic cancer]. / Dinamika prostatspetsificheskogo antigena pri monoterapii kasodeksom (bikalutamidom) v doze 150 mg v den' u bol'nykh mestno-rasprostranennym i (ili) rasprostranennym rakom predstatel'noi zhelezy.

Three-month treatment with casodex (150 mg/day) of untreated patients with locally advanced and/or advanced cancer of the prostate is well tolerated. The only side effect encountered in 9(60%) patients was temporary breast painfulness and swelling. Subjective effects consisted of higher activity (in 40% of patients), pain relief (in 33.3%), improved urination (in 80%). Objective effects comprise: reduction of prostate-specific antigen in 14(93.3%) patients by 150.4 ng/ml at the average; a rise in testosterone concentration in 12(80%) patients; regression of the tumor by more than 50% in 5(33.3%) patients; stabilization and partial regression of regional metastases (1 case); stabilization of distant metastases (3 of 4 cases). One patient showed progression of bone metastasizing in partial local regression of the tumor.

Large acinar cell carcinoma of the pancreas in a patient with elevated serum AFP level.

A pancreatic carcinoma, associated with elevated serum alpha-fetoprotein level, was resected from a 67-year-old man. The tumor was strongly suggested to be an acinar cell carcinoma of the pancreas, based on the histological findings of the resected specimen. The tumor measured 12 x 10 x 9 cm, and the cut surface was soft, whitish-yellow, focally necrotic, and hemorrhagic. Under a light microscope, the tumor cells were not arranged in a tubular and trabecular pattern, but rather, showed a tendency toward an acinar structure. Immunohistochemically, alpha 1-antitrypsin- and alpha 1-antichymotrypsin-positive reactions were diffusely positive in most of the tumor cells, while staining for chromogranin, neuron-specific enolase, Grimelius, glucagon, insulin, and alpha-fetoprotein was negative in the tumor cells. We report a large acinar cell carcinoma (associated with elevated serum alpha-fetoprotein level), which had been misdiagnosed as hepatocellular carcinoma preoperatively.

Acinar-islet cell carcinoma presenting as insulinoma.

A case of acinar-islet cell carcinoma presenting as insulinoma is reported. The patient was a 28-year-old man who presented with two convulsive episodes. Fajans' index [immunoreactive insulin (IRI; microU/ml/ glucose mg/dl)] and Turner's [IRI (microU/ml) x 100/glucose (mg/dl) - 30] index were high (2.8 and 308, respectively), as were serum proinsulin levels (550 pg/ml). Abdominal computed tomography and angiography revealed a highly vascular tumor in the pancreatic tail and several similar tumors in the liver. Histologic features of a biopsy specimen from a hepatic tumor were those of a malignant pancreatic endocrine tumor. Insulin secretion by the liver metastases was confirmed by venous sampling after arterial stimulation with calcium. These findings led us to diagnose malignant insulinoma with liver metastases. Serum levels of alpha-fetoprotein and trypsin were markedly elevated, to 2234 ng/ml (normal < 10) and 22,000 ng/ml (normal < 460) respectively, and these levels continued to rise with further growth of the liver metastases. Immunohistochemically, the metastatic liver tumor specimen was positive for alpha-fetoprotein, alpha 1-antichymotrypsin, chromogranin A, and neuron-specific enolase. These findings of amphicrine features in the tumor were indicative of acinar-islet cell carcinoma that produced alpha-fetoprotein and trypsin in addition to insulin.

Fat necrosis with features of erythema nodosum in a patient with metastatic pancreatic carcinoma.

A 59-year-old man presented with painful subcutaneous nodules on the anterior surfaces of the legs. He had received oral antibiotics and supportive care for presumed cellulitis and thrombophlebitis, but had minimal improvement. Five months earlier, he had undergone pancreaticoduodenectomy for acinar pancreatic carcinoma; at that time, the serum level of amylase had been normal, but the level of lipase was elevated. The patient denied fever, rigors, arthritis/arthralgia, or pleuritic pain. His medications included aspirin, furosemide, ranitidine, and nortriptyline. He denied any allergies. Physical examination revealed numerous firm, tender, erythematous and violaceous, subcutaneous nodules on the lower extremities, with marked bilateral pitting edema (Fig. 1). Skin biopsy of a representative lesion revealed septal panniculitis, consistent with erythema nodosum (Fig. 2). None of the characteristic changes of pancreatic fat necrosis was present. The patient was treated with aspirin, 650 mg orally, q 6 h, and indomethacin, 50 mg orally, q 12 h, but he continued to develop new nodules; prednisone, 60 mg orally was begun. Although he reported improvement in symptoms, the nodules failed to respond clinically and older nodules ulcerated along the medical aspect of the right leg (Fig. 3). The complete blood count was normal, except for hemoglobin, 10.9 mg per dL. Routine serum biochemical studies were also normal, except for albumin, 3.1 mg per dL, LDH, 312 U per L, and SGOT, 51 U per L. Serum amylase was 14 U per L (normal per 30 to 115 U per L) and serum lipase was 54,160 U per L (normal 0 to 200 U per L). Chest roentgenogram and tuberculin skin test were negative. A CT scan of the abdomen revealed extensive liver metastases. A second biopsy of the skin and subcutis of a necrotic nodule revealed lobular panniculitis with the characteristic picture seen in pancreatic fat necrosis (Fig. 4). The patient was presumed to have metastatic pancreatic carcinoma and pancreatic fat necrosis. Nodules subsequently developed on the thighs, arms, hands, wrists, and fingers. He developed arthritis and arthralgias of the ankles, wrists, and hands, bilaterally, and the right knee. Aspiration of a right knee effusion revealed numerous neutrophils, but no evidence of infection. Treatment was begun with the somatostatin analog, octreotide, in increasing doses. During this therapy, the lesions did not progress and new lesions did not appear. There was no change in the lipase level. Inadvertently, octreotide was omitted at discharge, but reintroduction of octreotide was associated with lack of further progression of the nodules, according to the patient's spouse; however the patient became progressively debilitated and his abdominal pain worsened, requiring continuous sedation. His condition deteriorated and he died several weeks after hospital discharge.

Advanced prostate cancer with normal serum prostate-specific antigen values.

Prostate-specific antigen is a specific and sensitive marker of prostate cancer, and most patients with advanced prostate cancer have elevated serum prostate-specific antigen values. Over a period of 45 months, 976 cases of advanced prostate cancer (stages C and D) were investigated to determine the serum prostate-specific antigen level at presentation. Eight cases of advanced prostate cancer are documented in which the serum prostate-specific antigen values were within normal limits. Six of the eight cases showed the features of invasive moderately differentiated acinar carcinoma; one case of small-cell carcinoma and one of cribriform carcinoma were noted. Direct immunohistochemical assessment of tumor tissue was performed, and the correlation between monoclonal and polyclonal antibody staining was assessed. In seven of the eight cases, monoclonal antibodies showed no convincing staining, while all but one (small cell) were positive for polyclonal stains.

CA 50 compared with CA 19-9 as a serum tumour marker for pancreatic carcinoma.

This study compared the sensitivity and specificity of CA 50 and CA 19-9 as serum tumour markers for pancreatic cancer. One hundred and seventy one subjects were evaluated: 50 healthy controls, 50 patients with pancreatic carcinoma and 71 patients with chronic pancreatitis. Eighty per cent of the pancreatic cancer patients had raised CA 19-9 serum levels and 82% had raised CA 50 serum levels. In the group of patients ith chronic pancreatitis, false positive tests occurred in 8.4% for CA 19-9 and 11.3% for CA 50. For both markers the serum level showed a severe elevation in the advanced stage of cancer disease. Despite the good sensitivity and specificity of CA 50 as a serum tumour marker for pancreatic carcinoma, no major advantage was found compared to CA 19-9. Moreover, if the CA 50 cut-off, level is raised to 85 U/ml to exclude overlap with chronic pancreatitis, sensitivity falls sharply to 46% compared with 72% for CA 19-9 when a 100 U/ml cut-off level is used.