Treatment and Outcome of Patients with Stage IS Testicular Cancer: A Retrospective Study from the Spanish Germ Cell Cancer Group.

PURPOSE: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including α-fetoprotein and/or ß-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. MATERIALS AND METHODS: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. RESULTS: The elevated prechemotherapy tumor markers were α-fetoprotein in 48% of cases, ß-human chorionic gonadotropin in 14%, and α-fetoprotein and ß-human chorionic gonadotropin in 38%. Median α-fetoprotein and ß-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. CONCLUSIONS: Stage IS testicular cancer is more commonly associated with elevated α-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

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.

Incidence and clinical pattern of contralateral synchronous and metachronous germ cell testicular cancer.

BACKGROUND: Incidence of a second testicular tumor is higher in patients diagnosed with testicular cancer than in the general population. As incidence of unilateral germ cell cancer is increasing worldwide and most of these patients are cured, a growing number of patients at risk of developing a contralateral testis cancer is expected. OBJECTIVE: To analyze clinical and histological characteristics, as well as the absolute and cumulative incidence of a second testicular cancer in a cohort of 3,834 patients diagnosed with germ cell testicular cancer between I/1994 and I/2018 in 18 referral hospitals of the Spanish Germ Cell Cancer Group. METHODS: Patients were treated according to stage and year of diagnoses. Contralateral testis biopsy was not routinely performed, according to European Association of Urology rules. Follow-up of the contra lateral testis consists of a physical exam only and an annual optional testicular ultrasound for 10 years. RESULTS: Median age of the patients included was 32 years (18-82). With a median follow-up of 61 months (0-240), 67/3,834 patients (1.74%) were diagnosed with a second testicular tumor. The second testicular tumor was synchronic (diagnosed within 6 months of the first orchiectomy) in 19 patients, and metachronous in 48. Pathology of the second tumor was reported as a seminomatous testis tumor in 47 patients and a nonseminomatous cancer in 20. Cumulative incidence of contralateral testicular cancer was 2% at 5 years, and 4% (IC 95% 3%-5%) at 14 years. Younger age was a risk factor for developing a second testicular tumor (P = 0.006), whereas chemotherapy reduced the risk for a metachronous testicular cancer (P = 0.046). Within our cohort, 6 families with testicular cancer aggregation (more than 2 tumors in the same family) were identified. CONCLUSIONS: Incidence of second testicular neoplasm in this cohort of 3,834 patients was similar to that which has been reported in other countries. Metachronous tumors and seminomas are more common. Follow-up of the contralateral testis is mandatory, as well as adequate information for patients to prevent a second neoplasm if feasible, and to detect and treat it as soon as possible.

Population-based risk assessment of second primary cancers following a first head and neck cancer: patterns of association and difficulties of its analysis.

PURPOSE: The diagnosis of a second primary cancer (SPC) is a major concern in the follow-up of survivors of a primary head and neck cancer (HNC), but the anatomic subsites in the head and neck area are close, making it difficult to distinguish a SPC of a recurrence and therefore register it correctly. METHODS: We performed a retrospective cohort study using data from two population-based cancer registries in Catalonia, Spain: the Tarragona Cancer Registry and the Girona Cancer Registry. All patients diagnosed with HNC during the period 1994-2013 were registered and followed-up to collect cases of SPC. We analysed the standardized incidence ratio (SIR) and the excess absolute risk (EAR) to determine the risk of second malignancies following a prior HNC. RESULTS: 923 SPC were found in a cohort of 5646 patients diagnosed of a first head and neck cancer. Men had an increased risk of a SPC with a SIR of 2.22 and an EAR of 216.76. Women also had an increased risk with a SIR of 2.02 and an EAR of 95.70. We show the risk for different tumour sites and discuss the difficulties of the analysis. CONCLUSION: The risks of a SPC following a prior HNC in Tarragona and Girona are similar to those previously found in other similar cohorts. It would appear to be advisable to make a revision of the international rules of classification of multiple tumours, grouping the sites of head and neck area with new aetiological criteria to better determine and interpret the risks of SPC obtained in these studies.

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.

Attenuation of the epidemic increase in non-Hodgkin's lymphomas in Spain.

BACKGROUND: Attenuation of the epidemic increase in non-Hodgkin's lymphoma (NHL) incidence has recently been reported in the USA and Nordic European countries. After two decades of steadily increasing NHL, this study sought to ascertain whether a similar stabilisation might have taken place in Spain in recent years. PATIENTS AND METHODS: NHL cases were drawn from 13 population-based Spanish cancer registries with a record of at least 10 years of uninterrupted registration during the period 1975-2004. Overall and age-specific changes in incidence rates were evaluated using change-point Poisson models, which allow for accurate detection and estimation of trend changes. RESULTS: A total of 21 335 NHL cases (11 531 male and 9804 female) were identified. Although overall age- and registry-adjusted incidence rates rose by 5.74% annually among men and 6.58% among women across the period 1975-95, a statistically significant change-point was nevertheless detected in both sexes in 1996, followed by stabilisation. CONCLUSIONS: In Spain, NHL incidence levelled off in 1996 after a sharp increase during the 1970s and 1980s. This stabilisation is, partially at least, linked to the decrease in incidence of AIDS-related lymphomas among young adults.

ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations.

Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC.

The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5.

The adipose tissue microenvironment plays a key role in tumour initiation and progression because it provides fatty acids and adipokines to tumour cells. The fatty acid-binding protein (FABP) family is a group of small proteins that act as intracellular fatty acid transporters. Adipose-derived FABPs include FABP4 and FABP5. Both have an important role in lipid-related metabolic processes and overexpressed in many cancers, such as breast, prostate, colorectal and ovarian. Moreover, their expression in peritumoural adipose tissue is deregulated, and their circulating levels are upregulated in some tumours. In this review, we discuss the role of the peritumoural adipose tissue and the related adipokines FABP4 and FABP5 in cancer initiation and progression and the possible pathways implicated in these processes.

Germline promoter hypermethylation in BRCA1 and BRCA2 genes is not present in hereditary breast cancer patients.

PURPOSE: Germline promoter hypermethylation of BRCA1 and BRCA2 genes is an alternative event of gene silencing that has not been widely investigated in hereditary breast and ovarian cancer (HBOC) syndrome. METHODS: We analyzed germline BRCA promoter hypermethylation in HBOC patients with and without BRCA mutations and control subjects, using a recently developed BRCA methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay. RESULTS: Neither the patients tested nor the control subjects showed germline hypermethylation of the BRCA1 and BRCA2 promoter regions analyzed. CONCLUSIONS: Despite the results achieved at somatic levels by other researchers, these were not confirmed in our study at the germline level. Our results show the need to establish more predictive CpG sites in the BRCA promoter regions to optimize the MS-MLPA assay for the detection of germline hypermethylation as an effective pre-screening tool for whole-BRCA genetic analysis in HBOC, because we can not rule out the existence of germline promoter hypermethylation in BRCA.

HDL-c levels predict the presence of pleural effusion and the clinical outcome of community-acquired pneumonia.

OBJECTIVES: To investigate if HDL cholesterol (HDL-c) could be a biomarker of the degree of severity according to prognostic prediction scores in community-acquired pneumonia (CAP) or the development of clinical complications such as pleural effusion. METHODS: We included in a retrospective study 107 patients admitted to the hospital that fulfilled diagnostic criteria for CAP between the 30th October 2011 and 1st September 2012. HDL-c levels at admission, CAP prognosis scores (PSI and CURB65) and clinical outcomes were recorded for the study. RESULTS: Basal HDL-c levels were not statistically different according to prognostics scores neither PSI nor CURB-65. Significantly lower levels of HDL-c were also associated to the development of septic shock and admission to the intensive care unit. HDL-c were inversely correlated with acute phase reactants CRP (r = -0.585, P < 0.001), ESR (r = -0.477, P < 0.001), and leukocytes cell count (r = -0.254, P < 0.009). Patients with pleural effusion showed significant lower levels of HDL-c [28.9 (15.5) mg/dl vs. 44.6 (21.1) mg/dl]; P = 0.007. HDL-c is a good predictor of the presence of pleural effusion in multivariate analyses and using ROC analyses [AUC = 0.712 (0.591-0.834), P = 0.006]. HDL-c levels of 10 mg/dl showed a sensitivity of 97.6 % and a specificity of 82.4 % for the presence of pleural effusion. CONCLUSION: Monitoring HDL-c in CAP is an useful serum marker of acute phase response, clinical outcome and the presence of pleural effusion.

SEOM clinical guidelines for the management of germ cell testicular cancer (2016).

Testicular cancer represents the most common malignancy in males aged 15-34 years and is considered a model of curable neoplasm. Maintaining success, reducing treatment burden, and focusing on survivorship are then key objectives. Inguinal orchiectomy is the first recommended maneuver that has both diagnostic and therapeutic aims. Most patients are diagnosed with stage I disease (confined to the testicle). Close surveillance and selective, short-course adjuvant chemotherapy are accepted alternatives for these cases. In patients with more advanced disease (stages II and III), 3-4 courses of cisplatin-based chemotherapy (according to IGCCCG risk classification) followed by the judicious surgical removal of residual masses represent the cornerstone of therapy. Poor-risk patients and those failing a first-line therapy should be referred to specialized tertiary centers. Paclitaxel-based conventional chemotherapy and high-dose chemotherapy plus autologous hematopoietic support can cure a proportion of patients with relapsing or refractory disease.

Lymphocytes with cerebriform nuclei in chronic B-cell lymphoproliferative diseases.

Two patients with chronic lymphoproliferative diseases, a splenic marginal zone lymphoma and hairy cell leukaemia variant, were reported. In both diseases a B-immunophenotype was demonstrated but a variable percentage of lymphoid cells (30 and 52%) showed a highly irregular nuclear outline, sometimes mimicking the nuclei of Sézary cells.

Secondary prophylactic G-CSF (filgrastim) administration in chemotherapy of stage I and II Hodgkin's lymphoma with ABVD.

UNLABELLED: The purpose of this study was to determine the effect of granulocyte colony-stimulating factor (filgrastim, G-CSF) for maintenance of chemotherapy dose-intensity in patients with stage I or II Hodgkin's lymphoma treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Fifty-six patients with stage I or II Hodgkin's lymphoma treated with ABVD were eligible for secondary prophylactic G-CSF administration because of neutropenia (absolute neutrophil count < 1 x 10(9) /L) causing treatment delay or febrile neutropenia. Patients received 300 microg (total dose) of G-CSF (filgrastim) subcutaneously on days 3 to 7 and 17 to 21 of each cycle in order to prevent dose reduction or delay in subsequent cycles of treatment continuing the G-CSF until completion of chemotherapy. Results showed that 30 (54%) of the patients required the use of G-CSF, 26 (47%) during the first or second cycle. After G-CSF administration delay in chemotherapy did not occur in 25 patients, whereas delays in the fifth or sixth cycle occurred in four patients. Despite treatment with G-CSF, one patient had febrile neutropenia. Dose intensity greater than 90% of that planned was delivered to more the 85% of patients. IN CONCLUSION: Secondary prophylactic G-CSF administration was necessary in more than half of patients with stage I or II Hodgkin's lymphoma during chemotherapy with ABVD. The use of G-CSF allowed maintenance of chemotherapy schedule and dose intensity in the majority of patients.

Pain suppression by peripheral nerve stimulation. Part I. Observations with transcutaneous stimuli.

A systematic, strict appraisal was made of 100 patients, after preliminary clinical trials suggested that some patients with pain could be helped by peripheral nerve stimulation. Transcutaneous stimulation of different nerve trunks was done with a special electrical stimulation device with various selected electrical parameters. More than half of the patients experienced some relief; in many, this effect was obtained by stimulating nerves distant from the area of referred pain. Pain relief lasted for varying periods after stimulation. The maximum benefit was noticed after certain specific parameters were reached for each patient. A few patients had response decay, gain or worsening. Results differ to some degree from previous reports. The results seem encouraging for the treatment of certain forms of intractable pain.

Pain suppression by peripheral nerve stimulation. Part II. Observations with implanted devices.

Twenty-three patients underwent implantation of a stimulator system and were followed for 6-20 months. Twenty patients estimated between 50% and 100% pain relief. The effect was largely consistent and reproducible. Reduced drug intake and improved social performance were associated with subjective improvement. The surgical technique is given, complications are analyzed and parameters are discussed.

[Ambulatory transesophageal echocardiography: 2 years of experience]. / Ecocardiografía transesofágica ambulatoria: dos años de experiencia.

In this report we study the value of ambulatory transesophageal echocardiography (TEE) in the clinical setting after a 2-year experience at our department. Since December 1988 until February 1991, 470 TEE examinations were indicated in 430 patients. Excluded were 8 cases, two out of them due to a formal contraindication and six who did not tolerate the procedure. The clinical indications for the examination, in the 462 studies performed, were as follows: possible cardiac source of emboli in 165 (35%); native mitral valve disease in 91 (20%); prosthetic valve dysfunction in 54 (12%); diseases of the aorta in 44 (10%); suspected infective endocarditis in 41 (9%); study of left ventricular function in 26 (6%); congenital heart disease in 18 (4%); tumor or intracardiac mass in 11 (2%); miscellaneous in 12 (2%). Based on this experience, we can conclude that TEE is a clinically useful technique for: 1) the study of mitral regurgitation, either native or prosthetic; 2) the detection of vegetations and abscesses in infective endocarditis; 3) the evaluation of a possible cardiac source of emboli; 4) the examination of the aorta in cases of suspected dissection; 5) the completion of the anatomic study in some congenital heart diseases, particularly after a surgical correction; 6) the study of patients with a technically inadequate transthoracic approach.

[The single coronary artery. Presentation of a case]. / Arteria coronaria única. Presentación de un caso.

A patient with a single coronary artery originating in the right coronary sinus is presented. The condition was diagnosed during aortic valve replacement surgery and later confirmed by coronary angiogram. The clinic significance in relation to the anomalous course of the coronary artery and the importance of correct diagnosis prior to cardiac surgery is discussed.

[Lipomatous hypertrophy of the interauricular septum as a cause of cerebral embolism in a patient with isolated Wernicke's aphasia]. / Hipertrofia lipomatosa del tabique interauricular como causa de embolismo cerebral en un paciente con afasia de Wernicke aislada.

The clinical observation of a 74 year old male presenting isolated Wernicke's aphasia due to a temporal left infarction of cardiac embolic origin secondary to paroxysmal auricular flutter is described. Transthoracic and transesophageal echocardiography, computerized tomography and magnetic resonance provided characteristic images which permitted the establishment of the diagnosis of lipomatous hypertrophy of the interauricular septum without requiring the use of invasive techniques. Lipomatous hypertrophy of the interauricular septum is a cardiac tumor of unusual presentation constituted of an abnormal accumulation of non-encapsulated fatty tissue which occupies a thickness greater than 15 mm of the interauricular septum. Wernicke's aphasia as a form of presentation of the lipomatous hypertrophy of the interauricular septum has not previously been described in the literature.

[Clinical pattern and therapeutic results obtained in Germ-Cell testicular cancer in Spain based on a consecutive series of 1250 patients]. / Patrón clínico y resultados terapéuticos obtenidos en el tumor germinal testicular en España a partir de una serie consecutiva de 1.250 pacientes.

BACKGROUND: Even its low incidence, germ-cell testicular cancer is very relevant due to its presentation at young ages and its potential curability over 90%. Spanish Germ Cell Cancer Group (GG) joins the efforts of 51 different Spanish centres to share their experience on the diagnosis and treatment of these special tumours. PATIENTS AND METHOD: We describe the clinical characteristics and the results of treatment in the first 1,250 patients registered throughout 6 years by the GG. RESULTS: 11% had previous criptorchidism. The most frequent initial local simptomatology was increased testis size (90%). 20% lasted more than six months in receiving the first treatment. Inguinal orquidectomy was done in 95% of patients. 435 cases (35%) were seminoma and 815 (65%)non-seminoma. 19% of seminoma and 78% of non-seminoma produced tumour markers. 75% of seminoma but only 56% of non-seminoma were clinical stage I. Following the IGCCCG prognosis classification,20% of non-seminoma fitted in the poor-prognosis group. Stage I seminoma treatment was surveillance, chemotherapy and complementary radiotherapy in 60, 32 and 6%, respectively. Those features were 65, 35% and none in non-seminoma cases. Chemotherapy schedules used in advanced cases were EP for seminoma and BEP or BOMP-EPIin non-seminoma, according to whether the patient was in the good or bad prognosis IGCCCG group. With a median of follow-up in all serie of 30 months, we have obtained a three years overall survival of 98% (CI 95%, 96,4-9,6), whereas non-seminoma patients had a three years overall survival of 94% (CI 95%, 92-96). CONCLUSION: The Spanish germ cell testicular cancer clinical pattern is similar to that registered in other occidental countries. Co-operative structures like GG,are able to gather an extensive experience in a short period of time that results in achieving a very high number of cured patients.

[Oncologic treatment of oto-neuro-ophthalmological metastases and their complications]. / Tratamiento oncológico de las metástasis otoneuroftalmológicas y sus complicaciones.

INTRODUCTION: Cerebral metastases and the sequelae of their treatment are the major cause of neurological symptoms in patients with cancer. OBJECTIVE: In this article we review the oto-neuro-ophthalmological complications of the treatment of metastases with radiotherapy and/or chemotherapy. DEVELOPMENT: When speaking of the iatrogenic diseases caused by radiotherapy treatment of metastases, it is important to emphasize that the major complications of this form of treatment are seen in the long term, in general, months or years later. When dealing with incurable diseases, such as most metastatic cancers, the benefit/risk balance of each therapeutic option has to be taken into account. Thus we have a population of patients with symptoms secondary to metastatic involvement, and with an overall life expectancy which may be measured in months. The oto-neuro-ophthalmological toxicity of the chemotherapy may present as an infrequent and unexpected complication or as a usual, expected secondary effect of the drug used. A large variety of drugs are used for the systemic control of cancer (cystostatic drugs, hormones and modifiers of the biological response) which, in one way or another, may cause neurological signs. CONCLUSION: The increasingly frequent use of high dose chemotherapy and of the combined use of chemotherapy and radiotherapy mean that these types of toxicity have become common clinical syndromes in current oncological practices.