Performance of oral HPV DNA, oral HPV mRNA and circulating tumor HPV DNA in the detection of HPV-related oropharyngeal cancer and cancer of unknown primary.

A biomarker that is useful for the detection of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) and cancer of unknown primary (CUP) is indispensable. We evaluated the diagnostic performance of HPV DNA and mRNA in oral gargle samples and circulating tumor HPV16 DNA (ctHPV16DNA) in blood samples. Oral HPV DNA and mRNA were analyzed using commercially available HPV assays of the GENOSEARCH HPV31 and Aptima, respectively. ctHPV16DNA was analyzed using in-house droplet digital polymerase chain reaction. Seventy-four patients with OPC and eight patients with CUP were included. The sensitivity and specificity of oral HPV DNA, oral HPV mRNA, and ctHPV16DNA were 82% (95% confidence interval [CI] = 66-92) and 100% (95% CI = 88-100), 85% (95% CI = 69-94) and 94% (95% CI = 73-100), and 93% (95% CI = 81-99) and 97% (95% CI = 84-100), respectively, for HPV16-related OPC, while those were 20% (95% CI = 1-72) and 100% (95% CI = 3-100), 0% (95% CI = 0-52) and 100% (95% CI = 3-100), and 100% (95% CI = 54-100) and 100% (95% CI = 16-100), respectively, for HPV16-related CUP. The sensitivity of ctHPV16DNA for HPV16-related OPC was higher than that of oral biomarkers, though the difference was not statistically significant. ctHPV16DNA remarkably correlated with the anatomic extent of disease, total metabolic tumor volume and HPV16 copy number per tumor genome in patients with HPV16-related OPC/CUP, whereas oral biomarkers did not. In conclusion, ctHPV16DNA is a potentially promising biomarker for HPV16-related OPC, while further studies are required for HPV16-related CUP.

Carcinoma of unknown primary origin with isolated adrenal metastasis: a report of two cases.

The adrenal glands are one of the most common sites of malignant tumor metastasis. However, metastatic adrenal carcinoma of unknown primary origin with localized adrenal gland involvement is an extremely rare condition. Herein, we reported two cases of carcinoma of unknown primary origin with isolated adrenal metastasis. In the first case, back pain was the trigger; while in the second case, the triggers were low fever and weight loss. Metabolic abnormalities such as hypertension and obesity were not detected in either case. Neither patient had relevant previous medical histories, including malignancy. However, both had a long-term history of smoking. Systemic imaging studies revealed only adrenal tumors and surrounding lesions. Primary adrenocortical carcinoma was initially suspected, and chemotherapy including mitotane was considered. However, due to difficulty in complete resection of the tumor, core needle tumor biopsies were performed. Histopathological examination of biopsy specimens led to the diagnosis of carcinoma of unknown primary origin with isolated adrenal metastasis. In both cases, additional laboratory testing showed high levels of serum squamous cell carcinoma-related antigen and serum cytokeratin fragment. Malignant lesions confined to the adrenal glands are rare. As in our cases, it could be occasionally difficult to differentiate non-functioning primary adrenocortical carcinoma from metastatic adrenal carcinoma of unknown primary origin localized to the adrenal gland. If the lesion is unresectable and there are elevated levels of several tumor markers with no apparent hormonal excess, core needle tumor biopsy should be considered to differentiate the primary tumor from the metastatic tumor.

Prospective Study of Chromogranin A as a Predictor of Progression in Patients with Pancreatic, Small-Intestinal, and Unknown Primary Neuroendocrine Tumors.

BACKGROUND: Retrospective studies are conflicting but most of them report that an increase in plasma chromogranin A (CgA) predicts tumor progression in neuroendocrine tumor (NET) patients. Prospectively, we investigated if a change in plasma CgA is associated with tumor burden changes in NET patients with disseminated disease. METHODS: We included 239 patients treated at 5 NET centers from December 2010 to December 2013. CgA was measured within 6 weeks of a CT or MRI in a patient undergoing at least 2 scan examinations performed over a period of 1-24 months. In a post hoc analysis, CgA measured 3-6 months prior to the CT/MRI was analyzed. Changes in tumor size were evaluated by RECIST1.1. A 25% change in CgA was chosen to discriminate between increased, decreased, or unchanged levels. RESULTS: In 671 events (2 CT/MRI scans and 2 corresponding CgA measurements), we found a weak positive correlation between the RECIST 1.1 responses and change in plasma CgA from baseline (Spearman's rank correlation coefficient: 0.15; p < 0.05). Of 304 events in the post hoc analysis, 58 showed progression, 228 showed stable disease, and 18 showed regression, with a median change in CgA of 19% (IQR: 57 to -20%), -12% (23 to -38%), and -73% (-55 to -83%), respectively. The correlation coefficient for all sites was 0.17 (p = 0.003), and it was 0.16 (p = 0.07), 0.18 (p = 0.04), and 0.20 (p = 0.21) for small-intestinal (n = 137), pancreatic (n = 123), and unknown primary NET (n = 40), respectively. In the 58 patients showing tumor progression, the sensitivity and specificity of an increased CgA concentration were 36 and 82%, respectively, with positive and negative predictive values of 32 and 85%. CONCLUSIONS: In this prospective study of gastroenteropancreatic NET patients, we observed only a weak association between a change in plasma CgA and changes in tumor burden. CgA as a single biomarker was thus inadequate to predict tumor progression.

Molecular characterisation and liquid biomarkers in Carcinoma of Unknown Primary (CUP): taking the 'U' out of 'CUP'.

Cancers of Unknown Primary (CUP) comprise a heterogeneous clinical entity of confirmed metastatic cancer where the primary site of origin is undetectable. It has a poor prognosis with limited treatment options. CUP is historically under-researched; however, understanding its biology has the potential to not only improve treatment and survival by implementation of biomarkers for patient management, but also to greatly contribute to our understanding of carcinogenesis and metastasis across all cancer types. Here we review the current advances in CUP research and explore the debated hypotheses underlying its biology. The evolution of molecular profiling and tissue-of-origin classifiers have the potential to transform the diagnosis, classification and therapeutic management of patients with CUP but robust evidence to support widespread use is lacking. Precision medicine has transformed treatment strategy in known tumour types; in CUP, however, there remains a clinical need for a better understanding of molecular characteristics to establish the potential role of novel or existing therapeutics. The emergence of liquid biopsies as a source of predictive and prognostic biomarkers within known tumour types is gaining rapid ground and this review explores the potential utility of liquid biopsies in CUP.

Roles of Ki-67 and p16 as biomarkers for unknown primary head and neck squamous cell carcinoma.

PURPOSE: Treatment guidelines have not been established for unknown primary head and neck squamous cell carcinoma (SCC). For these patients, chemoradiotherapy (CRT) can provide a better prognosis than that for patients with other head and neck cancers. The presence of HPV in the tumor is associated with a better outcome. However, not all patients with HPV-positive unknown primary head and neck SCC experience good treatment outcomes in actual clinical settings. METHODS: We thus retrospectively determined the Ki-67 proliferation index and p16 expression status to assess the associations of these parameters with treatment outcomes of patients with unknown primary head and neck SCC. RESULTS: The subjects were 13 patients who underwent CRT after surgery or excision biopsy between 1999 and 2016. The 2- and 5-year overall survival (OS) rate was 76.9% and 68.4%, respectively. The prognostic factor was age. There was no significant difference in survival between patients with a high Ki-67 vs. low Ki-67 or between patients with p16-positive vs. p16-negative metastases OS. However, all p16-positive patients with low Ki-67 showed good locoregional control. CONCLUSIONS: The combination of ki67 expression and p16 expression status may allow prediction of local control more accurately than p16 expression status alone.

Plasma D-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke.

BACKGROUND AND PURPOSE: Cancer patients with cryptogenic stroke often have high plasma D-dimer levels and lesions in multiple vascular regions. Hence, if patients with cryptogenic stroke display such characteristics, occult cancer could be predicted. This study aimed to investigate the clinical characteristics of cryptogenic stroke as the first manifestation of occult cancer and to determine whether plasma D-dimer levels and lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. METHODS: Between January 2006 and October 2015, data on 1225 patients with acute ischaemic stroke were extracted from the stroke database of Osaka University Hospital. Among them, 184 patients were classified as having cryptogenic stroke, and 120 patients without a diagnosis of cancer at stroke onset were identified. Clinical variables were analyzed between cryptogenic stroke patients with and without occult cancer. RESULTS: Among 120 cryptogenic stroke patients without a diagnosis of cancer, 12 patients had occult cancer. The body mass index, hemoglobin levels and albumin levels were lower; plasma D-dimer and high-sensitivity C-reactive protein levels were higher; and lesions in multiple vascular regions were more common in patients with than in those without occult cancer. Multiple logistic regression analysis revealed that plasma D-dimer levels (odds ratio, 3.48; 95% confidence interval, 1.68-8.33; P = 0.002) and lesions in multiple vascular regions (odds ratio, 7.40; 95% confidence interval, 1.70-39.45; P = 0.01) independently predicted occult cancer. CONCLUSIONS: High plasma D-dimer levels and lesions in multiple vascular regions can be used to predict occult cancer in patients with cryptogenic stroke.

Inflammation as a validated prognostic determinant in carcinoma of unknown primary site.

BACKGROUND: Carcinoma of unknown primary (CUP) is a clinical presentation with a poor prognosis. Inflammation-based prognostic systems are stage-independent prognostic predictors in various malignancies. We aimed to assess the accuracy of the modified Glasgow Prognostic Score (mGPS), neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) as objective prognostic models in CUP. METHODS: We derived inflammatory scores in 60 consecutive CUP referrals to the Imperial College oncology unit between 1996 and 2011. Patient demographics, treatment and staging data and full blood profiles were collected. An independent cohort of 179 patients presenting to the Taipei Veterens Hospital between 2000 and 2009 were used as a 'validation' data set. Uni- and multivariate survival analysis was used to predict the overall survival (OS). RESULTS: Sixty patients were included: median age 61 (range: 33-86); 51% men; median OS 5.9 months (0.7-42.9); 88% with distant metastases. On univariate analysis NLR >5 (P=0.04) and mGPS (score 1-2) (P=0.03) correlated with OS. Multivariate analysis demonstrated significant hazard ratios for NLR; 2.02 (CI 1.0-4.1) (P=0.04) and mGPS; 1.52 (CI 1.0-2.3) (P=0.03). These findings were reinforced by analysis of the validation data. CONCLUSION: NLR and mGPS are independent, externally validated prognostic markers in CUP, with superior objectivity compared with performance status.

Evaluation of prognosis for carcinoma of unknown origin in elderly patients.

PURPOSE: Carcinoma of unknown origin has a poor outcome and usually occurs in elderly patients. In this article, we analyzed the prognostic factors in elderly patients with cancer of unknown primary site (CUP) for treatment considerations. PATIENTS AND METHODS: Patients >70 years old with histologically proven carcinoma were retrospectively reviewed. The prognostic factors were analyzed with univariate and multivariate Cox regression. RESULTS: We included 63 patients aged 70-79 years and 51 patients ≥80 years old. The results of multivariate Cox regression in the 70-79 years age group revealed white blood cell count ≤10(4)/ml [p = 0.033; hazard ratio (HR) 2.51, range 1.079-5.840] and albumin ≥3.5 g/dl (p = 0.007; HR 3.38, range 1.398-8.177) as independent factors. In the group of patients ≥80 years old, Eastern Cooperative Oncology Group performance status <1 (p = 0.020), white blood cell count ≤10(4)/ml (p = 0.001), albumin ≥3.5 g/dl (p = 0.006), lactate dehydrogenase (LDH) ≤250 U/l (p = 0.002) and non-chest metastasis (p = 0.043) were significantly better with univariate analysis. Multivariate Cox regression revealed albumin ≥3.5 g/dl (p = 0.007; HR 3.28, range 1.389-7.745) and LDH ≤250 U/l (p = 0.045; HR 3.18, range 1.026-9.848) as independent factors. CONCLUSIONS: For elderly patients with CUP, the serum albumin level seems to be a consistently independent prognostic factor. In patients >80 years old, serum LDH plays an important role in prognosis. This study is helpful in predicting the outcome and management for this group of patients.

[Analysis of prognostic factors in 68 patients with cancer of unknown primary site].

OBJECTIVE: The aim of this study was to analyze the clinical characteristics and prognostic factors in patients with cancer of unknown primary site (CUP). METHODS: The clinical and follow-up data of 68 CUP patients (46 adenocarcinoma patients, 22 squamous cell carcinoma patients), were retrospectively analyzed. Univariate and multivariate analysis were conducted to determine the correlation of survival with clinical features, tumor markers, blood test, liver function and so on. RESULTS: The median survival time of the 68 CUP patients was 123 days. The results from univariate Cox regression analysis showed that the prognostic factors were related to a performance status, presence or absence of liver metastases, the number of metastatic sites, carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH), hypoalbuminemia, hypohemoglobinemia and lymphocyte count. Multivariate Cox regression analysis of the clinical factors identified that a performance status (PS) ≥ 2, liver metastasis, elevated serum carcinoembryonic antigen (CEA) and lactate dehydrogenase (LDH) levels, hypoalbuminemia (< 35 g/L) and lymphopenia (≤ 0.7 × 10(9)/L) were significant independent unfavorable predictive factors. Based on the number of the unfavorable predictive factors, we divided all the patients into three subgroups: subgroup involving 0-1 unfavorable factor, subgroup involving 2 - 3 unfavorable factors and subgroup involving 4 - 6 unfavorable factors. The median survival time was 390 days, 138 days and 77 days, respectively, in the 3 subgroups. Compared with the other two groups, the survival of the subgroup involving 0 - 1 unfavorable factor was significantly longer (P < 0.05), the survival between the subgroup involving 2 - 3 unfavorable factors and subgroup involving 4 - 6 unfavorable factors was not significantly different (P > 0.05). CONCLUSIONS: A performance status ≥ 2, liver metastasis, elevated serum carcinoembryonic antigen and lactate dehydrogenase levels, hypoalbuminemia and lymphopenia are independent unfavorable prognostic factors in patients with cancer of unknown primary site. The patients who had more than 2 unfavorable prognostic factors have a worse prognosis.

Differences in outcomes of bilateral adrenalectomy in patients with ectopic ACTH producing tumor of known and unknown origin.

BACKGROUND: Endogenous Cushing syndrome (CS) can be caused by ectopic corticotropin-producing tumors of known (EK) and unknown origin (EU). Bilateral adrenalectomy (BA) can be used as definite treatment of hypercortisolism in such cases. This study compared patients undergoing BA for CS secondary to EK vs EU. METHODS: Retrospective review (1995-2017) of patients undergoing BA due to EK or EU. We analyzed demographic characteristics, laboratory values, intraoperative variables, surgical outcomes, and survival. RESULTS: 48 patients (26 EU, 22 EK) were identified. Serum cortisol and ACTH concentrations were similar. 92% of BA for EU were performed minimally invasively vs 77% for EK, P = 0.22. Complications occurred in 19% of EU and 4.5% EK, P = 0.2. Mean survival was 4.3 years for EU and 4.0 years for EK without difference in all-cause mortality P = 0.63. CONCLUSION: BA cure rate was 100% for CS in EU and EK. Morbidity, long term and all-cause mortality differences were not statistically significant between EK and EU.

Malignancy and myositis: novel autoantibodies and new insights.

PURPOSE OF REVIEW: Currently available data support the idea that inflammatory myopathies, particularly dermatomyositis, are paraneoplastic diseases. Cancer screening is usually recommended in patients with these conditions, but there is no consensus regarding how and how often screening should be performed. This review will address recent advances in our understanding of the relationship between cancer and myositis and describe new data regarding the best approach for cancer screening in myositis patients. RECENT FINDINGS: A newly described autoantibody to a 155-kDa nuclear protein, identified as transcription intermediary factor 1-gamma (TIF1-γ), has proven useful for cancer screening in patients with dermatomyositis. Occult tumor detection by PET/computed tomography (PET/CT) seems to be a good alternative to broad conventional screening. A combination of both methods, detection of autoantibodies against p155 and PET/CT study, may be the best approach to ascertain the presence of occult malignancy in patients with dermatomyositis. SUMMARY: Advances in immunology and imaging techniques are increasing the accuracy of occult malignant cancer detection in dermatomyositis patients. Nevertheless, the diagnosis of cancer in this population remains elusive in some cases. Further investigation is needed to improve our knowledge of the link between myositis and cancer.

Thrombotic thrombocytopenic purpura as the first manifestation of metastatic adenocarcinoma in a young woman.

Thrombotic microangiopathy occurs in 5-10% of patients with mucin-producing disseminated adenocarcinoma. A 28-year-old woman complained of fatigue, bone pain, and weight loss. There were pallor, icterus, and tenderness in the bones on physical examination. Microangiopathic hemolytic anemia, leukoerythroblastic picture, thrombocytopenia, and normal coagulation tests were detected. Thrombotic thrombocytopenic purpura (TTP) was diagnosed and therapeutic plasma exchange was performed on the patient. On day 5 a laparotomy had to be performed because of acute abdomen due to the rupture of a corpus hemorrhagicum follicle of an ovary. Signet ring cell adenocarcinoma stained with cytokeratin 7 and mucicarmine was seen on ovaries and bone marrow, after the pathological examination. The primary site of tumor could not be investigated, because of the patient's refusal. Although chemotherapy including cis-platinum, infusional 5-fluorouracil, and calcium leucovorin were administered in two courses, she died from respiratory failure. In conclusion, malignancy and bone marrow involvement should be considered when associated with leukoerythroblastic picture and TTP.

Prognostic factors in cancer of unknown primary site.

AIMS AND BACKGROUND: Patients with cancer of an unknown primary site (CUP) usually have a poor outcome. The identification of prognostic factors that affect survival can help clinicians find a better approach to such cases in terms of diagnostic and therapeutic management. METHODS: We conducted a retrospective study including the cases of CUP recorded at the University Hospital 12 de Octubre Tumor Registry between 1999 and 2003. RESULTS: CUP was diagnosed in 265 patients during the analyzed period. One hundred and seventy-one were men (64.5%) and the mean age of the patients was 66.9 years (range 32-98 years). The median survival was 2.5 months, and the survival rate was 35.1% 6 months from diagnosis (95% CI: 28.9-41.3) and 24.5% 1 year from diagnosis (95% CI: 18.7-30.3). Univariate analysis revealed as significant predictive variables of a better outcome age under 70 years; involvement of a single organ; normal serum levels of alkaline phosphatase and albumin; normal erythrocyte sedimentation rate; normal levels of the serum tumor markers CEA, CA 19.9 and CA 15.3; squamous carcinoma histology; clinical presentation as lymph node enlargement; and the administration of treatment. Multivariate analysis showed that albumin and alkaline phosphatase levels, squamous carcinoma histology, age and treatment were the most important prognostic factors. Other variables analyzed (liver, bone or lung involvement, lactate dehydrogenase levels, gender) did not affect survival. CONCLUSIONS: CUP has a poor prognosis. Some prognostic factors that affect survival in these patients, however, may be identified.

Screening may not be accurate word to represent the cases submitted to PET/CT evaluation for primary tumor in a patient who has abnormal serum tumor marker.

OBJECTIVE: Determine the value of PET/CT in unknown primary cancer patient with high tumor marker and negative study for clinical and conventional imaging. MATERIAL AND METHOD: A retrospective database review of 417 patients who received PET/CT between July 2006 and August 2007 in National cyclotron and PET center at Chulabhorn cancer center was done. Patients were included in this study if the diagnosis were unknown primary cancer and rising tumor marker. Twelve patients were included in this study. Data included age, gender, tumor marker rising, anatomical imaging finding (CT and MRI), PET finding and clinical follow-up. RESULTS: Nine cases had normal PET/CT. This showed that PET/CT does not get more information than conventional imaging. The PET scan showed positive in three cases, #5, #6 and #10. Two cases were false positive, #5 and #6. Case #5 had clinical follow-up for one year and revealed to be normal. Case #6 PET showed markedly glucose avid lesion at tumor thrombus but contrast CT confirm blood clot and the patient was treat with wafarin and claxane. The follow-up clinical showed improvement. The high serum CA 125 explained by lung infarction caused the false positive. In case #10, the PET/CT suggested lung cancer at basal segment of LLL. CONCLUSION: Screening 18F FDG PET/CT is not appropriate in unknown primary with rising tumor marker and normal conventional imaging is required.

Rheumatic syndromes and occult tumor: 10-year experience in a teaching hospital. / Síndromes reumáticos y tumor oculto, experiencia de 10 años en un hospital universitario.

OBJECTIVE: To describe the different clinical characteristics of patients admitted to the Rheumatology Department due to rheumatic manifestations as the first expression of an unknown malignant process. PATIENTS AND METHODS: Retrospective and descriptive observational study involving the review of the medical records of those admitted to rheumatology in the University Hospital of Ciudad Real between January 2007 and August 2017 for initial rheumatic manifestations with a suspicion at discharge of an unknown tumor. RESULTS: In all, 64 patients were identified from more than 500 admissions. The most common rheumatic manifestations were inflammatory low back pain, polyarthralgia, hip pain, thoracic spine pain, cervical pain, polyarthritis and polymyalgia rheumatica. Forty-four percent had low hemoglobin, 70% had elevation of acute-phase reactants, 62% had abnormal tumor markers, 76% had metastatic lesions. In 20% the primary tumor was of pulmonary origin and only 26.56% received palliative treatment; 64% died. DISCUSSION: It is important to consider the possibility of an underlying malignant process in the differential diagnosis since its early identification can be determinant for prognosis.

Artificial Intelligence Estimates the Importance of Baseline Factors in Predicting Response to Anti-PD1 in Metastatic Melanoma.

OBJECTIVE: Prognosis of patients with metastatic melanoma has dramatically improved over recent years because of the advent of antibodies targeting programmed cell death protein-1 (PD1). However, the response rate is ~40% and baseline biomarkers for the outcome are yet to be identified. Here, we aimed to determine whether artificial intelligence might be useful in weighting the importance of baseline variables in predicting response to anti-PD1. METHODS: This is a retrospective study evaluating 173 patients receiving anti-PD1 for melanoma. Using an artificial neuronal network analysis, the importance of different variables was estimated and used in predicting response rate and overall survival. RESULTS: After a mean follow-up of 12.8 (±11.9) months, disease control rate was 51%. Using artificial neuronal network, we observed that 3 factors predicted response to anti-PD1: neutrophil-to-lymphocyte ratio (NLR) (importance: 0.195), presence of ≥3 metastatic sites (importance: 0.156), and baseline lactate dehydrogenase (LDH) > upper limit of normal (importance: 0.154). Looking at connections between different covariates and overall survival, the most important variables influencing survival were: presence of ≥3 metastatic sites (importance: 0.202), age (importance: 0.189), NLR (importance: 0.164), site of primary melanoma (cutaneous vs. noncutaneous) (importance: 0.112), and LDH > upper limit of normal (importance: 0.108). CONCLUSIONS: NLR, presence of ≥3 metastatic sites, LDH levels, age, and site of primary melanoma are important baseline factors influencing response and survival. Further studies are warranted to estimate a model to drive the choice to administered anti-PD1 treatments in patients with melanoma.

Blood coagulation and cancer: thrombosis and survival, clinical relevance and impact. An introduction.

There is a strong association between deep venous thrombosis and cancer. In this review, we will discuss the increased incidence of cancer following an idiopathic venous thrombotic event (VTE) and the increased incidence of VTE and its recurrence in cancer patients. Furthermore, we will review the adverse impact VTE has on cancer patients' morbidity and mortality. Finally, the potential influence of anticoagulation on survival of cancer patients is discussed. Although the data are encouraging, anticoagulation is still of limited value for routine clinical practice in anticancer treatment.

Microparticles and cancer.

Cancer is a prothrombotic state, with an increased prevalence of arterial and venous thromboemboli. Microparticles (MPs) are sub-micron-sized vesicles derived from activated or apoptotic cancer cells and/or host cells that may causally contribute to these clinical events, although the strength of the evidence thus far is inconclusive. We review the state-of-the-art understanding of the origin of circulating MPs, their role as a potentially important procoagulant entity in cancer, and their clinically documented association with malignancies. It is anticipated that if the functional importance of circulating MPs in clinically meaningful endpoints in cancer can be proven by appropriately designed and powered prospective studies, future investigation will focus on whether MPs can be targeted for therapeutic purposes.