Identification and survival outcomes of a cohort of patients with cancer of unknown primary in Ontario, Canada.

BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS). MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. We cross-validated CUP diagnosis and obtained additional information about metastasis through data linkage with the SDS/DAD database. OS was assessed using Cox regression models adjusting for histology and sites of metastases. RESULTS: We identified 3564 patients diagnosed with CUP. Patients without histologically confirmed disease (n = 1821) had a one-year OS of 10.9%, whereas patients with confirmed histology (n = 1743) had a one-year OS of 15.6%. The most common metastatic sites were in the respiratory or digestive systems (n = 1603), and the most common histology was adenocarcinoma (n = 939). Three-year survival rates were 3.5%, 5.3%, 41.6% and 3.6% among adenocarcinoma, unspecified carcinoma, squamous cell carcinoma and undifferentiated histology, respectively. Three-year survival rates were 40%, 2.4%, 8.0% and 4.6% among patients with metastases localised to lymph nodes, the respiratory or digestive systems, other specified sites, and unspecified sites, respectively. CONCLUSION: CUP patients in Ontario have a poor prognosis. Some subgroups may have better survival rates, such as patients with metastases localised to lymph nodes and patients with squamous cell histology.

Risk and outcomes of second malignant neoplasms in chronic myeloid leukemia survivors.

The risk of second malignant neoplasms (SMN) in chronic myeloid leukemia (CML) survivors remains unclear. We utilized the Surveillance, Epidemiology and End Results 18 (SEER 18) registries to evaluate the risk and subsequent outcomes of SMN in CML survivors. There were 3407 patients included. Of these, 170 (4.99%) developed a SMN with SIR of 1.40 (95% C.I. 1.19-1.62). An increased risk was noted for cancers of the respiratory tract, genitourinary (GU) tract and skin excluding basal cell and squamous cell carcinoma. Using 3:1 matching (3 de novo malignancies to 1 post-CML SMN case), we compared survival data for cancers of the respiratory, GU and gastrointestinal (GI) tract. Patients with GU malignancies developing after CML had worse overall survival than patients without prior CML diagnosis (P = 0.018). There was no difference in survival between post-CML and non-post-CML patients with respiratory or GI malignancies.

Combination docetaxel and trastuzumab treatment for patients with HER-2-overexpressing metastatic breast cancer: a multicenter, phase-II study.

BACKGROUND: Pre-clinical and clinical studies indicate that a combination of docetaxel and trastuzumab may effectively treat patients with human epidermal growth factor receptor-2 (HER-2) overexpressing metastatic breast cancer. We evaluated the efficacy and safety of this combination in a multicenter, open-label phase II study in Japan. METHODS: Women with metastatic breast cancer whose tumors overexpressed HER-2, as assessed by immunohistochemistry and by fluorescence in situ hybridisation, received 2 to 6 cycles of docetaxel (70 mg/m2, every 3 weeks) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). The primary endpoint was tumor response. Secondary endpoints were time to disease progression and adverse events. RESULTS: Of the 40 women enrolled in the study, 27 (68%) completed 6 cycles of treatment. Three patients discontinued the study before the second cycle. Median follow-up was 20.8 months (range, 0.6 to 30.9 months). The overall response rate was 65% (26/40; 95% CI, 48% to 79%). The median time to progression was 6.8 months (range, 0.6 to 21.2 months). Of the 40 patients, 35 (88%) had grade 3 or 4 leukopenia, and 33 (83%) had grade 3 or 4 neutropenia. Most instances of leukopenia and neutropenia were manageable by reducing the dose of docetaxel or by treatment with granulocyte colony-stimulating factor. In 4 patients, left ventricular ejection fraction decreased by more than 10% from baseline. CONCLUSIONS: The combination of docetaxel and trastuzumab was as effective as reported in other similar studies and was well tolerated in these patients.

Squamous cell carcinoma of the esophagus infiltrating the respiratory tract is less sensitive to preoperative concurrent radiation and chemotherapy.

BACKGROUND: The prognosis of upper thoracic esophageal cancer is poor when compared with middle and lower thoracic esophageal cancer because the tumor easily infiltrates the respiratory tract and surgical en-bloc resection is difficult. Recently, preoperative chemoradiation therapy has been shown to lead to down-staging of the disease and improve prognosis. But the benefit of this therapy for tumors infiltrating the respiratory tract remains unknown. STUDY DESIGN: Fifty-six patients with thoracic esophageal cancer infiltrating neighboring organs, but with no hematogeneous metastasis, were given preoperative concurrent chemotherapy (5-fluorouracil and cisplatin) and radiation (40 Gy) therapy. When a clinical response was observed, making a curative resection potentially possible, patients were scheduled for esophagectomy with extended lymphadenectomy. Patient prognosis with respect to the organs infiltrated by the tumors was estimated by calculating survival curves using the Kaplan-Meier method and comparing the curves by the log-rank test. RESULTS: The prognosis was significantly poorer for patients with tumors infiltrating the respiratory tract (T) or aorta plus respiratory tract (A + T) than for patients with tumors infiltrating the aorta alone (A) or other organs (Oth) (p < 0.05 for Oth versus T; p < 0.05 for Oth versus A + T; p < 0.0001 for A versus T; p < 0.0001 for A versus A + T by log-rank test). Patients positive for respiratory tract invasion (T, T + A), compared with those negative for respiratory tract invasion (A, Oth), showed a poorer clinical response to chemoradiation (3.0%, 45.5%, 39.4%, and 9.1% versus 4.3%, 82.6%, 4.3%, and 8.7% in complete response (CR), partial response (PR), nonresponse (NC) and progressive disease (PD), respectively, p = 0.0156) and surgical resectability (36.4% vs. 87.0%, p = 0.0003). Histologic effectiveness (8.3%, 50.0%, and 41.7% versus 25.0%, 70.0%, and 5.0% in grade 3, grade 2, and grade 1, respectively, for patients with respiratory tract invasion versus those without it, p = 0.0189) and histologic stages (8.3%, 8.3%, 8.3%, 8.3%, 25.0%, and 41.7% versus 20.0%, 0%, 15.0%, 25.0%, 40.0%, and 0% in pathologic CR, stage I, stage IIA, stage IIB, stage III, and stage IV, respectively, for patients with respiratory tract invasion versus those without it, p = 0.0496) were significantly better in patients negative for respiratory tract invasion; the percentages of patients with lymph node metastasis did not differ significantly between the two groups. Comparison of the recurrence patterns showed that local failure was most common in patients with respiratory tract invasion, and distant failure was the leading cause of recurrence in patients without it. CONCLUSIONS: Because the prognosis of patients with thoracic esophageal cancer infiltrating the respiratory tract is extremely poor, partially because of the low local effectiveness of preoperative concurrent chemotherapy and radiation therapy, caution is needed when deciding on salvage surgery.

Radiotherapy of early glottic cancer.

Patients (383) with stage Tis, Tla and Tlb NoMo glottic cancer are reviewed. Radiotherapy cured 93% of Tis patients and 86% of Tla and Tlb cases. Of all recurrences, 63% were cured. No patient with stage Tis died as a result of tumor and only 5% of stage Tla and Tlb died from tumor. Involvement of the anterior commissure or both vocal cords did not influence control rates by radiotherapy. Mobility of the vocal cord and size of radiotherapy field were significant factors influencing control by radiotherapy. Late recurrences and/or second primaries in the larynx following radiotherapy are rare. Second primaries in the respiratory tract (especially lung) are common and are as important a cause of death as laryngeal cancer in T1 cases. It is concluded that moderate dose radiotherapy with surgery for salvage is a highly effective method of management for early glottic cancer.

Upper aerodigestive tract metastases in disseminated malignant melanoma.

Cutaneous malignant melanoma sometimes metastasizes to the upper respiratory and digestive tracts. It may cause significant local symptoms such as airway obstruction and dysphagia, and, in some cases, may represent the initial manifestation of disseminated disease. Of the 8,823 patients with cutaneous malignant melanoma seen at The University of Texas-M.D. Anderson Hospital and Tumor Institute at Houston between 1944 and 1983, metastases to this region developed in 54 patients. The most common sites involved were the tonsil, tongue, nasopharynx, larynx, and lip. Five of ten cases in which an autopsy was performed were noted to have previously undiagnosed metastatic mucosal lesions. We conclude that metastases to the upper aerodigestive tract in patients with cutaneous malignant melanoma is a distinct possibility. Melanoma patients who manifest symptoms localized to this region should be carefully examined to exclude the possibility of metastatic tumor, since alternative treatment may be required. Local endoscopic treatment may be necessary to relieve airway or digestive tract obstruction.

Upper respiratory tract involvement in adult T-cell leukemia.

Adult T-cell leukemia (ATL) is characterized by peripheral lymph node enlargement, hepatosplenomegaly and skin lesions. The association of local mass lesions of other organs with ATL is extremely rare. This report describes a 57-year-old woman with chronic type ATL with associated local tumor masses in the nasal cavity, paranasal sinuses and larynx as well as skin infiltration. Histologic investigation of the skin lesion and nasal mucosa revealed non-Hodgkin lymphoma, diffuse, mixed type. Her chief complaints were progressive dyspnea and hoarseness. Leukemic cell masses in her upper respiratory tract caused narrowing of the airway, which was responsible for her complaints.

Carcinoid syndrome: a statistical evaluation of 748 reported cases.

No statistical evaluation of patients with carcinoid syndrome in a reliable number of cases has been available in the past 35 years. To update our knowledge about the syndrome, we have evaluated from various clinicopathologic viewpoints a large series of patients with the syndrome reported up to date. The data of 748 patients with the syndrome were collected from 8876 carcinoid patients reported in the literature and analyzed by the Gut-Pancreatic Endocrinoma Analyzing System (the Niigata Registry). The results are summarized as follows. 1) The patients with the syndrome had a tendency to be older than those without it. 2) The incidence of the syndrome was 8.4% of 8876 carcinoid patients. 3) Serotonin activities were extremely high in patients with the syndrome as compared to those without it (91.7% versus 26.6%). 4) The rate of metastases was higher in patients with the syndrome than in those without it (84.8% versus 29.2%), and higher in the liver than in lymph nodes among patients with the syndrome (73.4% versus 37.4%). 5) Flushing and carcinoid heart as most specific clinical manifestations of the syndrome were recorded at 78.3% and 17.4%, respectively. 6) The 5-year survival rate after resection of primary lesions was 76.0% of 304 patients with the syndrome, lower in patients with digestive carcinoids than in those with extradigestive lesions (67.2% versus 88.7%). It is expected that the results obtained in the present evaluation on patients with carcinoid syndrome will provide investigators active in this specialized field with useful and extensive information for their future activities.

Field change and oral cancer: new evidence for widespread carcinogenesis?

Patients with oral squamous cell carcinoma (OSCC) are at risk of developing second or multiple primary cancers as a result of field cancerization in the upper aerodigestive tract. In order to quantify the incidence of field change observable in oral mucosa, 26 consecutive new (untreated) patients presenting with a unilateral OSCC (18) or a premaligant lesion (eight) underwent 'mirror image' biopsies from clinically normal-looking mucosa at corresponding anatomical sites. A total of 15 patients (58%) demonstrated histologically abnormal tissue upon microscopic examination: six showed reactive change/cellular atypia associated with chronic irritation, seven exhibited frank dysplasia, whilst two displayed carcinoma-in-situ (CIS) or microinvasive SCC. Although not statistically significant, there was an observable trend for the lateral/ventral tongue and floor of mouth to display increased vulnerability to dysplastic change.

[The role of endoscopic surgery in respiratory tract neoplasia]. / Il ruolo della chirurgia endoscopica nelle neoplasie dell'apparato respiratorio.

Laser therapy--either by contact or non-contact method--can be considered the best palliative option for patients affected by airway obstruction due to malignant tumors considered inoperable and/or in emergency because of inadequate ventilation. The Nd-YAG laser is widely used in endoscopy. From 1988 to September 2002 at the Department of Surgery "P Valdoni" of the University of Rome "La Sapienza" 251 clinical cases affected by airway obstruction caused by primary or metastatic malignant tumors are treated; moreover 76 stents were used. The symptomatological improvement and beneficial changes in functional breathing tests, haemogasanalysis and X-ray findings were registered 48-72 hours after each treatment. The results showed an improvement in functional breathing values especially after treatment of the main airways such as trachea and main bronchi. The therapy offered an acceptable quality of life. A fairly good number of patients may also return to radio and/or chemotherapy (if previously interrupted) and sometimes to radical surgery. In terms of costs-effectiveness, the endoscopic treatment is widely competitive.

Cytopathology, including transmission and scanning electron microscopy, of pleomorphic liposarcomas in pleural fluids.

Liposarcoma cells in pleural fluid from two patients with metastatic pleomorphic liposarcoma are described. The major diagnostic feature of such specimens, perceivable by light microscopy, is the presence of solitary, pleomorphic giant cells with cytoplasmic vacuoles. In some cells, transmission electron microscopy revealed numerous cytoplasmic lipidic droplets. With scanning electron microscopy, the cellular surfaces were markedly pleomorphic, with ruffles, blebs and long, thin processes.

[Secondary neoplasms in upper respiratory and digestive tracts]. / Segundas neoplasias en tumores de vías aerodigestivas altas.

Patients enduring cancer of the upper respiratory tract present greater risk of developing a second neoplasm, either synchronous or metasynchronously. Possible causes of this major risk are studied, giving a special attention to the role released for the treatment done in the primary neoplasm, in the later appearance of the second one.

Malignant transformation of well-differentiated papillary mesothelioma 13 years after the diagnosis: a case report.

Well-differentiated papillary mesothelioma (WDPM) is a rare mesothelial tumour affecting mostly the peritoneum of women in their reproductive age, but it may occur also at other sites, including the pleura. It is considered a specific pathological entity different from diffuse malignant mesothelioma as it displays a characteristic histological pattern and is associated with a slowly progressive clinical course. We report the case of a 79-year-old man with a history of right pleural WDPM at age 64, which was successfully treated with chemotherapy, radiotherapy and talc pleurodesis. Thirteen years after the first diagnosis, he presented with mediastinal lymph nodes metastasis and with an extremely rare pattern of tracheal and bronchial infiltration that was detected at bronchoscopy. Biopsy samples revealed loss of histological differentiation of the neoplastic cells. This case report highlights that WDPM is a tumour of uncertain malignant potential that may undergo transformation over many years. Finally, the role of immunohistochemistry in the diagnosis of WDPM and the possible mechanisms leading to this unique way of metastatisation are discussed.

Unusual thoracic CT manifestations of osteosarcoma: review of 16 cases.

Pulmonary metastases are common in osteosarcoma and the most common appearance is of multiple well-defined nodules in the lung parenchyma. However, a variety of atypical locations and presentations of osteosarcoma metastasis can occur in the thorax. We present a review of the thoracic CT findings in 16 patients with histopathologically confirmed osteosarcoma with unusual thoracic manifestations. The 16 patients were selected out of a total 136 patients who received a chest CT scan for osteosarcoma during a period of 3 years in a tertiary care hospital. Unusual imaging findings included a solitary large ossified lung mass, ossified mediastinal and hilar lymph nodes, an esophagomediastinal fistula, lymphangitic carcinomatosis, pulmonary artery tumor emboli, a solitary large pleural deposit along the major fissure, multiple pleural deposits, diffuse pleural calcification, pneumothorax, diaphragmatic deposits, an isolated chest wall deposit without lung involvement, and primary osteosarcoma of the rib. Our findings of lymphangitic carcinomatosis in a living patient as well as calcified mediastinal lymphadenopathy leading to esophageal fistula are unique in the literature, and there are only a few case reports of our other findings.

Second neoplasms after oesophageal cancer.

The authors considered the incidence of second neoplasms among 1,672 oesophageal cancers diagnosed between 1974 and 2004 in the Cancer Registries of the Swiss Cantons of Vaud and Neuchâtel, and followed-up to 2004. A total of 141 second neoplasms were observed versus 38.5 expected, corresponding to a standardized incidence ratio (SIR) of 3.7 (95% confidence interval: 3.1-4.3). The SIRs were statistically significant for cancers of the oral cavity and pharynx (57.3), larynx (24.3), lung (6.6) and intestines (2.6). The SIRs were higher in subjects diagnosed below age 50 and in the first year after diagnosis. The SIR of upper digestive and respiratory tract neoplasms was higher for oesophageal cancers diagnosed in the upper (87.5) and middle (68.1), as compared with the lower third (19.4). There was no rise of second oral, pharyngeal and laryngeal cancer with advancing age, and their incidence tended indeed to decline from 100/1,000 at age 40-49 to 25/1,000 at age 70-79. There was no tendency to rise with age in the incidence of first oesophageal cancer in subjects who subsequently developed another upper digestive or respiratory tract neoplasm. The excess risks of upper digestive and respiratory tract neoplasms are attributable to increased diagnosis and registration of second neoplasms following a diagnosis of oesophageal cancer, as well as to heavy tobacco and alcohol consumption in oesophageal cancer cases. The absence of rise in incidence with age is also compatible with the existence of a subset of the population of susceptible individuals.

Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer.

PURPOSE: The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer. PATIENTS AND METHODS: Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes. RESULTS: Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032) CONCLUSION: CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.

Interferons in the treatment of human papillomavirus diseases.

A variety of epithelioproliferative benign neoplasms, both trivial and life-threatening, are caused by subtypes of human papillomaviruses. Interferons objectively regress HPV-induced warty disease and affect the regrowth of the transformed epithelium. Interferons effectively control the most serious and potentially life-threatening papillomavirus associated diseases, respiratory papillomatosis and genital warts, but not without the anticipated side effects associated with this potent biological weapon. It is entirely possible and even likely that individual species of interferons act preferentially on certain cells, tissues or organs in response to particular viruses. Combined therapies, such as surgery in combination with interferon, or podophyllin in conjunction with interferon alfa-n1, may prove most efficacious.