Prognostic factors for relapse in stage I seminoma: a new nomogram derived from three consecutive, risk-adapted studies from the Spanish Germ Cell Cancer Group (SGCCG).

BACKGROUND: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. PATIENTS AND METHODS: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). RESULTS: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). CONCLUSION: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.

ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.

In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.

Clinicopathological risk factors of Stage II colon cancer: results of a prospective study.

AIM: Adjuvant 5-fluorouracil based chemotherapy has demonstrated benefit in Stage III colon cancer but still remains controversial in Stage II. The aim of this study was to analyse the prognostic impact of clinicopathological factors that may help guide treatment decisions in Stage II colon cancer. METHOD: Between 1996 and 2006 data from patients diagnosed with colorectal cancer at Hospital Universitari Bellvitge and its referral comprehensive cancer centre Institut Català d'Oncologia/L'Hospitalet were prospectively included in a database. We identified 432 patients with Stage II colon cancer operated on at Hospital Universitari Bellvitge. The 5-year relapse-free survival (RFS) and colon-cancer-specific survival (CCSS) were determined. RESULTS: The 5-year RFS and CCSS were 83% and 88%, respectively. Lymphovascular or perineural invasion was associated with RFS [hazard ratio (HR) 1.84; 95% CI 1.01-3.35]. Gender (women, HR 0.48; 95% CI 0.23-1) and lymphovascular or perineural invasion (HR 3.51; 95% CI 1.86-6.64) together with pT4 (HR 2.79; 95% CI 1.44-5.41) influenced CCSS. In multivariate analysis pT4 and lymphovascular or perineural invasion remained significantly associated with CCSS. We performed a risk index with these factors with prognostic impact. Patients with pT4 tumours and lymphovascular or perineural invasion had a 5-year CCSS of 61%vs the 93% (HR 5.87; 95 CI 2.46-13.97) of those without any of these factors. CONCLUSION: pT4 and lymphatic, venous or perineural invasion are confirmed as significant prognostic factors in Stage II colon cancer and should be taken into account in the clinical validation process of new molecular prognostic factors.

Patterns of relapse and treatment outcome after active surveillance or adjuvant carboplatin for stage I seminoma: a retrospective study of the Spanish Germ Cell Cancer Group.

PURPOSE: Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences. METHODS: We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups. RESULTS: No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free. CONCLUSION: In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome.

Metronomic chemotherapy: an antiangiogenic scheduling.

Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule.

The oncology acute toxicity unit (OATU): an outpatient facility for improving the management of chemotherapy toxicity.

OBJECTIVE: To provide an outpatient facility to improve the management of chemotherapy toxicity in cancer patients. PATIENTS AND METHODS: We set up an oncology acute toxicity unit (OATU) to improve toxicity management. A telephone helpline was the initial contact which filters out inappropriate non-toxicity-related events. Patients were provided an information booklet describing the possible side effects of the chemotherapy and the helpline telephone number. A specialist nurse received the calls and consulted the doctor if necessary. Depending on requirements, the patient's problem was resolved by telephone, or a consultation visit at the OATU was arranged. RESULTS: Between February 1999 and August 2001, 1126 patients made 2007 contacts with the OATU. The most common tumours were breast (26%), colorectal (20%) and lung (20%). The telephone helpline was used in 87% of contacts and 37% were considered inappropriate. Of the 1263 appropriate contacts, the most frequent chemotherapy schedules that had been administered were 5FU-leucovorin (11.2%) and CMF (10.4%). The most frequent side effects were fever (35.5%), diarrhoea (18.5%), mucositis (16.2%) and emesis (13%). The problem was resolved by telephone in 48% of cases and 52% required attendance in the OATU, of which 40% required hospital admission, i.e., 21.1% of the initial appropriate helpline contacts. The most frequent reason was Grade 3-4 neutropenic fever (56.5%). CONCLUSIONS: The OATU enables prompt and efficient access of patients to medical oncology facilities in the event of toxicity due to chemotherapy. Unnecessary emergency room use is avoided while oncology outpatient and hospitalisation facilities are optimised.

Control of E1A under an E2F-1 promoter insulated with the myotonic dystrophy locus insulator reduces the toxicity of oncolytic adenovirus Ad-Delta24RGD.

We previously described Ad-Delta24RGD as an enhanced-infectivity oncolytic adenovirus that targets tumors with an impaired RB pathway. The common alteration of this pathway in cancer eliminates the interaction of pRB with E2F and releases free E2F to activate E2F-responsive promoters, including the E2F-1 promoter. To improve the selectivity towards RB pathway-defective tumors and reduce the toxicity of Ad-Delta24RGD we aimed to control E1A-Delta24 expression under the E2F-1 promoter. A polyA signal was inserted upstream of the E2F-1 promoter to stop transcription initiated at the adenovirus ITR and packaging signal. The human myotonic dystropy locus insulator (DM-1) was also located between the E1a enhancers and the E2F-1 promoter to further insulate the promoter. The Ad-Delta24RGD derivative containing these insulation sequences expressed less E1a-Delta24 in normal cells and resulted less toxic while maintaining the potent oncolytic activity of the parental virus. These results demonstrate that the human DM-1 inslulator can function in an adenovirus context to maintain heterologous promoter selectivity. The new oncolytic adenovirus presented here may represent a valuable therapeutic option for a broad range of tumors with a deregulated E2F/pRB pathway.

K-ras and p16 aberrations confer poor prognosis in human colorectal cancer.

PURPOSE: Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways. PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated. RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered. CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.

Giant parallel tube arrays (PTAs), a new type of lymphocyte inclusion.

In a 56-year-old male patient, receiving chemotherapy after radical surgery for bladder carcinoma, an unusual type of cytoplasmic inclusion was discovered in about 30% of peripheral blood lymphocytes. This was a single, large (about 2 microns in diameter), round or ovoid body, darker than the nucleus and reddish-violet in May-Grünwald-Giemsa stain. The examination with transmission electron microscope demonstrated that such inclusions were made up of giant parallel tube arrays (PTAs). The absolute lymphocyte count was normal, but there was an expansion of CD3+, CD4-, CD8+, CD11b, TCR alpha beta lymphocytes. The lymphocytes bearing the inclusion were CD3+ and CD8+. DNA studies suggested an expansion of T-cell population with clonal rearrangement of TCR beta and TCR gamma. This case can be classified as an asymptomatic disorder of large granular lymphocytes, with unusual morphology. Giant PTAs should be taken into account in the differential diagnosis of lymphocyte cytoplasmic inclusions.

Alpha-fetoprotein-concanavalin A binding as a marker to discriminate between germ cell tumours and liver diseases.

In order to differentiate whether slight alpha-fetoprotein (AFP) increases observed in any patient are due to germ cell tumours (GCT) or to liver diseases (including hepatotoxicity of chemotherapy), we measured the binding ratio of the AFP to concanavalin A (ConA). A total of 218 serum samples were studied: 102 samples from 72 GCT patients and 116 from patients with liver diseases. Considering a cut-off value to be a ConA binding ratio of 15%, we distinguished AFP produced by GCT (> 15%) from AFP produced by tumoral and non-tumoral liver diseases (< or = 15%) with a sensitivity of 98% and specificity of 100%. The difference between mean ConA binding ratios was statistically significant (P < 0.0001). We did not distinguish AFP produced by tumoral and non-tumoral liver diseases. ConA binding ratio may be a sensitive index to distinguish whether an increase of AFP concentration as low as 15 U/ml in a GCT patient during the follow-up is produced by the tumour or by liver dysfunction (including hepatotoxicity of chemotherapy).

Prognostic value of the expression of E-cadherin and beta-catenin in bladder cancer.

The purpose of this study was to assess the prognostic effect of the expression of E-cadherin, beta-catenin and CD44 adhesion molecules in bladder carcinoma. 22 superficial and 18 invasive bladder tumour samples were studied by immunohistochemistry. The median follow-up was 24 months (range: 1-50 months). Loss of E-cadherin and beta-catenin immunoreactivity was found in 14 (35%) and 17 (43%) tumours, respectively, and was significantly associated with invasiveness, high grade and p53 overexpression. There was no correlation between CD44 variant expression and clinicopathological findings. Loss of E-cadherin expression was an independent predictor of poor survival in a multivariate analysis, when assessed with age, grade, stage and p53 status (hazards ratio adjusted (HRa)=4.45 [95% confidence interval (CI), 1.06-18.63]). This effect was particularly augmented in patients with invasive bladder cancer. When expression of E-cadherin and beta-catenin were evaluated simultaneously, loss of immunoreactivity of both proteins was a strong predictor of poor survival (HRa=13.06 [95% CI, 0.95-178.55]). The same pattern was found when progression-free survival in relation to these variables was assessed. In conclusion, assessment of E-cadherin and beta-catenin immunoreactivity may be a useful prognostic marker in bladder cancer complementary to established prognostic factors.

Randomised double-blind study comparing tropisetron alone and in combination with dexamethasone in the prevention of acute and delayed cisplatin-induced emesis.

In a randomised, double-blind and parallel-design multicentre study, 282 chemotherapy-naive cancer patients received tropisetron 5 mg intravenously (i.v.) before high-dose cisplatin on day 1, and oral tropisetron 5 mg daily on days 2-6, in combination with either placebo (n = 143) or dexamethasone (n = 135), given i.v. on day 1 and orally on days 2-6. Complete protection from acute vomiting/nausea was achieved in 76.3%/79.3% of patients receiving the combination and in 55.2%/61.5% of those receiving tropisetron alone. Complete protection on days 2-6 from delayed vomiting/nausea was obtained in 60%/60% and 39.2%/40.6%, respectively. Tropisetron in combination with dexamethasone is safe and more effective than tropisetron alone in the prevention of both acute and delayed cisplatin-induced emesis.

Indium-111-antimyosin scintigraphy after doxorubicin therapy in patients with advanced breast cancer.

Indium-111-antimyosin (111In-antimyosin) scans were performed in 20 women with advanced breast cancer after 10 cycles of chemotherapy consisting of cyclophosphamide, 5-fluorouracil and doxorubicin (total cumulative dose of doxorubicin of 500 mg/m2). Antimyosin uptake in the myocardium was quantified by means of a heart-to-lung ratio (HLR). Antimyosin uptake in the myocardium was observed in 17/20 (85%) patients, and HLR after chemotherapy was 1.86 +/- 0.25. Left ventricular ejection fraction (EF) was determined before and after chemotherapy. Patients with decreased EF (8/20, 40%) presented with more intense antimyosin uptake (HLR of 2.11 +/- 0.10 versus 1.70 +/- 0.16 (p = 0.01]. HLR values correlated with EF values after chemotherapy (r = -0.47, p less than 0.05). Positive antimyosin studies after chemotherapy including doxorubicin, indicate the presence of myocardial damage in these patients. Antimyosin studies are a sensitive method to detect myocyte damage in patients after doxorubicin therapy.

Bone marrow regeneration after hormonal therapy in patients with bone metastases from prostate carcinoma.

Two patients with prostate carcinoma and bone metastases were treated with hormonal therapy. Radioimmune imaging of bone marrow performed with 99mTc-labeled antigranulocyte antibody BW 250/183 before treatment demonstrated absence of granulopoietic bone marrow in extensive regions of the central and proximal peripheral skeleton, indicating diffuse bone marrow invasion. Bone marrow scans performed after treatment demonstrated presence of granulopoietic bone marrow in these regions, indicating bone marrow regeneration. This finding was consistent with favorable response to treatment.

Radioimmune imaging of bone marrow in patients with suspected bone metastases from primary breast cancer.

Radioimmune imaging of bone marrow was performed by technetium-99m- (99mTc) labeled antigranulocyte monoclonal antibody BW 250/183 (AGMoAb) scans in 32 patients with suspected bone metastases from primary breast cancer. AGMoAb scans showed bone marrow defects in 25/32 (78%) patients; bone invasion was subsequently confirmed in 23 (72%) patients. Conventional bone scans performed within the same week detected bone metastases in 17/32 (53%) patients (p less than 0.001). AGMoAb scans detected more sites indicating metastatic disease than bone scans in 12 of these 17 patients (71%). All patients with bone metastases in the axial skeleton had bone marrow defects at least at the sites of bone metastases. Of 15 patients with normal, or indicative of, benign disease bone scans, 8 patients (53%) presented with bone marrow defects in the AGMoAb scans. Bone invasion was confirmed in six of them. AGMoAb bone marrow scans provide a method for the early detection of bone metastatic invasion in patients with breast cancer and suspected bone metastases.

Treatment of malignant superior vena cava syndrome by endovascular stent insertion. Experience on 52 patients with lung cancer.

BACKGROUND: Superior vena cava syndrome (SVCS) is a frequent presentation of malignancies involving the mediastinum and can seriously compromise treatment options and prognosis. Stenting of superior vena cava is a well-known but not so commonly used technique to alleviate this syndrome. PATIENTS AND METHODS: Between August 1993 and December 2000 we performed 52 stenting procedures in patients affected by non-small cell lung cancer (NSCLC). RESULTS: Phlebographic resolution of the obstruction was achieved in 100% of cases with symptomatic and subjective improvement in more than 80%. One major complication was observed due to bleeding during anticoagulation. Re-obstruction of the stent occurred in only 17% of the cases, the majority due to disease progression. Improvement of the syndrome allowed hydration necessary for full dose platinum treatment when indicated in patients affected by lung cancer. CONCLUSIONS: Stenting of the superior vena cava syndrome is a safe and effective procedure achieving a rapid alleviation of symptoms in almost all patients, and allowing for full dose treatment in lung cancer patients. This procedure could change the traditional poorer prognosis attributed to non-small cell lung cancer patients presenting with this syndrome.

CDC group IV c-2 infection in a stem cell transplant recipient.

Patients undergoing high-dose chemotherapy for cancer are at a high risk of infections caused by unusual microorganisms. Previous chemotherapy, use of indwelling catheters and prior antibiotic treatment are common predisposing factors. We present a case of septicaemia due to a rare non-fermentative bacillus, CDC group IV c-2, found in the blood and venous catheter from a patient with a testicular germ cell tumour undergoing high-dose consolidation chemotherapy.

Antigranulocyte antibody bone marrow scans in cancer patients with metastatic bone superscan appearance.

In clinical practice, it may be difficult to distinguish a metastatic bone superscan appearance from a normal bone scan. To determine if assessment of bone marrow is helpful in the diagnosis of bone invasion in patients with suspected bone superscans, the authors performed antigranulocyte antibody bone marrow scans in 10 consecutive cancer patients who had a conventional bone scan interpreted as metastatic superscan appearance. All patients presented with bone marrow scans showing marked absence of tracer uptake in the central skeleton suggesting tumour replacement. Laboratory tests showed decreased peripheral blood cells in 9 patients. Bone radiographs showed metastatic involvement with diffuse osteoblastic lesions in 9 patients. Antigranulocyte bone marrow scans show extensive bone marrow invasion in cancer patients with suspected bone superscans. This result reinforces the concept of these patients having extensive bone invasion despite mild abnormalities in the bone scan. Confirmation of extensive bone invasion on patients with suspected bone superscans may contribute to a proper staging of these patients.

[Clinical application of radioimmunolocalization in colorectal cancer]. / Aplicación clínica de la radioinmunolocalización en el cáncer colorrectal.

We present preliminary results of radioimmunolocalization (RIL) of colorectal cancer with 131I labelled F(ab')2 fragments from monoclonal anti CEA and anti CA 19.9 antibodies in 22 patients with colorectal cancer and in one patient with metastases of unknown origin and high CEA value. Positive images were obtained in 7 of 11 primary tumors from 10 patients evaluated preoperatively; in 2 of 3 recurrences; in 9 of 12 metastatic localizations and in the unknown primary tumor localized, finally in the cecum. One local recurrence was not detected by any diagnostic methods, but RIL. There was not false-positive images. Therefore, RIL appears as a promising method for the diagnosis and follow-up of colorectal cancer.