Impact of breast cancer molecular subtypes on the incidence, kinetics and prognosis of central nervous system metastases in a large multicentre real-life cohort.

BACKGROUND: Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses. METHODS: The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient's prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan-Meier method). RESULTS: CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2-/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR- (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8-92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5-17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18-3.75, triple-negative and HER2-/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2-8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50-0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65-0.81) for HER2+/HR-, 4.4 months (HR = 1.55, 95% CI: 1.42-1.69) for triple-negative and 7.1 months for HER2-/HR+ patients (p <0.0001). CONCLUSIONS: Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients. CLINICAL TRIAL REGISTRATION: NCT03275311.

Medullary thyroid carcinoma with nodular goiter carries an excellent prognosis.

BACKGROUND: In our institution, patients with medullary thyroid carcinoma (MTC) concurrent with nodular goiter (NG) have a nearly 100% survival rate, but the reasons and characteristics are unclear. METHODS: Eighty patients with MTC who underwent surgery in our center between 1971 and 2011 were reviewed. RESULTS: A total of 21 MTC/NG and 59 MTC only patients were identified. The stage of the two groups had no significant difference (P = 0.13). The MTC/NG group had lower preoperative serum calcitonin (CT) levels (914.7 ng/L vs. 1162.6 ng/L, P = 0.003), lower postoperative serum CT levels (371.4 ng/L vs. 582.5 ng/L, P < 0.001), lower carcinoembryonic antigen levels (18.3 ng/ml vs. 130.5 ng/ml, P < 0.001), a lower propensity toward lymph node metastasis (40.0% vs. 66.7%, P = 0.07), and a lower proportion of multifocality (19.1% vs. 42.4%, P = 0.06), capsular invasion (9.5% vs. 25.4%, P = 0.21), and vascular invasion (4.8% vs. 10.1%, P = 0.67). The mean tumor diameter of the two groups was similar (20.3 mm vs. 22.1 mm, P = 0.6). Overall 15-year survival in MTC/NG versus MTC only groups was 100% versus 57.0% (P = 0.03). CONCLUSIONS: MTC with NG is an indolent disease and has an excellent prognosis. The only independent predictor of survival was the TNM stage of disease.

[Clinical manifestation and radiological features of small cell lung cancer (SCLC)]. / Obraz kliniczny i radiologiczny drobnokomórkowego raka pluca.

INTRODUCTION: Small cell lung cancer (SCLC) includes 10-15% of primary lung tumors and it is very aggressive neoplasm. The aim of this study was to evaluate radiological and clinical features of SCLC and its spread. MATERIAL AND METHODS: The retrospective analysis included 31 patients (18 women, 13 men, mean age: 68.2 +/- 8.34 years).The extensive disease (ED) in most patients was present. 25 patients (80,6%) reported habitual cigarette smoking. Localization of primary tumor, metastases, clinical symptoms and main blood abnormalities were assessed. RESULTS: The most common locations of the primary tumor were: the lung hilus--15 (48.4%), the upper lobe of lung--6 (19.3%) and mediastinum--3 (9.7%). In most cases, mediastinal, subcarinal--both (41.9%) and hilus--(32.2%) lymph nodes were involved. Distant metastases were present in 20 patients (64.5%) at the moment of diagnosis. The most common locations of metastases were: liver--12 (60%), lungs--7 (35%), suprarenal glands--6 (30%), bones--3 (15%) and CNS--3 (15%). The most common symptoms were: cough (77.4%), weakness (51.6%), dyspnea (45.2%), chest pain (41.9%) and the weight loss (30%). Superior vena cava syndrome occurred in 4 patients (13%). The symptoms lasted an average 115 days, but the most persistent were: cough (216 days) and dyspnea (150 days). The main blood tests abnormalities were increased activities of: CRP (mean 63.4 mg/L), AspAT (65U), LDH (1852.7 U/l) and D-dimer (1892.5 microg/l). CONCLUSIONS: SCLC was mainly manifested in CT as central mass lung involving hilus or mediastinum. In most cases, distant metastases were present at the moment of diagnosis.

Attenuated multimutated herpes simplex virus-1 effectively treats prostate carcinomas with neural invasion while preserving nerve function.

Many cancers can cause disability and pain by invading nerves. In particular, prostate carcinoma has a high propensity for neural invasion (NI) at an early stage. Attempted surgical treatment of tumors with NI often leads to erectile dysfunction and deteriorated quality of life. Therefore, there is a need for novel modalities that will selectively target cancer cells while preserving neural function. Herpes simplex viruses (HSVs) have a natural trophism for peripheral nerves. We hypothesized that oncolytic therapy using HSV engineered to minimize neurotoxicity would be appropriate for this clinical setting. Attenuated HSV (NV1023) injected to sciatic nerves of nude mice had no toxic effect on nerve function (n=30). NV1023 had significant oncolytic effect on prostate carcinoma cells (PC3, DU145, and LNCap) in vitro. An in vivo model of NI was established by implanting prostate carcinoma cells in the sciatic nerves of nude mice. Mice were treated with NV1023 or saline 7 days after establishment of tumors. Significant reduction in tumor size and inhibition of NI was found 6-8 wk after treatment (P<0.005). All animals treated with saline developed complete paralysis <5 wk post-treatment, whereas most NV1023-treated animals had preserved nerve function >12 wk after treatment (P<0.0001). We conclude that oncolytic therapy effectively treats prostate carcinomas with NI in an in vivo murine model while preserving neural function. These findings may hold significant clinical implications for patients with prostate cancer or other neurotrophic tumors.

Cerebrospinal fluid markers in African Burkitt's lymphoma with central nervous system involvement.

Several cerebrospinal fluid markers were found to be elevated in Burkitt's lymphoma patients with central nervous system (CNS) involvement. Antibody levels to the virus capsid antigen of the Epstein-Barr virus and to the brain cell antigens myelin and cerebroside were elevated during active CNS disease. Immune complexes were present in levels above 100 micrograms/ml in most patients with CNS involvement but tended to be low or negative in patients without CNS disease. Oligoclonal IgG bands were present in 12 of 13 patients with CNS disease and in only 3 of 26 patients with no clinical evidence of disease. None of these markers were present in 6 other tumor patients without CNS disease. The presence of these markers in 12 of 13 patients in whom CNS disease was involved suggests that these markers may be useful in determining the status of the tumor with regard to involvement of the CNS.

[Medulloblastoma with extracentral nervous system metastases: clinical presentation and risk factors]. / Medulloblastoma with extracentral nervous system metastases: clinical presentation and risk factors.

PURPOSE: Extra-central nervous system (extra-CNS) metastases are relatively unknown failure patterns in medulloblastoma. The aim of this study was to analyse epidemiological, clinical and aetiopathological aspects of these extra-CNS localisations. PATIENTS AND METHODS: Extra-CNS metastases were retrospectively identified in patients treated in the department of radiation therapy at Salah-Azaïz institute (ISA) for medulloblastoma. These metastases were diagnosed as extra-CNS for all secondary localisations not related to other tumour aetiology. Aetiopathological aspects are discussed with a literature review. RESULTS: Among 103 patients treated and followed-up in the department of radiation therapy of ISA from 1970 to 1992, 8 developed extra-CNS metastases (7.7%). Age at diagnosis of primitive tumour varied from 3 to 23 years. Sex ratio was 1. Primitive tumour treatment was: complete surgical resection in 4 patients with preoperative cerebrospinal fluid shunting in two, cerebrospinal axis irradiation in 7 patients and a cerebral-limited irradiation in 1. Two patients received chemotherapy for their initial treatment (systemic in one case and intrathecal in the other). The mean free-interval from diagnosis of primitive tumour to extra-CNS metastases was 23 months, varying from 8 to 53 months. These metastases were located in the liver (1 case), cervical lymph nodes (2 cases), bone marrow (1 case) and bone (2 cases). Two patients had multiple metastases: bone and bone marrow (in one), lung, pleura, cervical lymph node and bone localisations (in one). Treatment of these metastases was: chemotherapy in 5 cases, chemotherapy and radiation in one, radiation therapy in one and 2 patients were given only supportive care treatment. All patients died or are in progressive disease in less than one year from the diagnosis of extra-CNS metastases. CONCLUSION: Extra-CNS metastases are not rare and have a poor prognosis. The most commonly involved sites are bone, cervical lymph nodes and bone marrow. A complete work-up at initial diagnosis is recommended to screen early metastases. Literature review showed that histopathologic grading might help to identify groups at risk.

Patterned distribution of metastases from malignant melanoma in humans.

Malignant melanoma has an unpredictable clinical course in terms of metastatic behavior, and further understanding might lead to improved therapeutic intervention with immune agents or antagonists. To determine whether metastases show patterns or are randomly distributed, we analyzed the distributions of metastases in the 56 patients with metastatic malignant melanoma, subjected to complete autopsy at The Johns Hopkins Hospital, using parametric statistics and cluster analysis. Variables examined included age, race, sex, location of primary tumor, length of survival, mode of therapy, histology of tumor, location of metastases, and extent of tumor infiltration at each metastatic site. The results indicate that the distributions of metastases from malignant melanoma are patterned such that significant positive correlations (p less than 0.05 or better) were observed among various tissues and organs. We identified several aggregations with respect to the distributions of metastases: (a) central nervous system; (b) mesodermal; (c) endocrine; (d) reticuloendothelial; and (e) foregut. Organs and tissues comprising each aggregation were interrelated by their similar developmental origins or functions. A very highly significant negative correlation between central nervous system and hepatic metastases (p less than 0.001) was also demonstrated by cluster analysis. We concluded that the distributions of metastases from malignant melanoma are not random; the patterns of metastases may be related to the embryological derivation of tissues involved.

Sanctuary therapy: a randomized trial of 724 children with previously untreated acute lymphoblastic leukemia: A Report from Children's Cancer Study Group.

Between 1972 and 1974, Childrens Cancer Study Group enrolled 724 children with newly diagnosed acute lymphoblastic leukemia on a single randomized clinical trial. Study CCG-101 was designed to test four types of presymptomatic central nervous system and sanctuary therapies consisting of (a) 2400-rad craniospinal radiation therapy (RT) plus 1200-rad extended-field RT, which included the liver, spleen, kidneys, lower abdomen, and gonads; (b) 2400-rad craniospinal RT; (c) 2400-rad cranial RT plus intrathecal methotrexate (i.t. MTX); and (d) i.t. MTX alone. Patients all received a 28-day induction course of vincristine, prednisone, and L-asparaginase and were maintained subsequently on a regimen consisting of daily 6-mercaptopurine, weekly MTX, and monthly pulses of vincristine and prednisone. Patients treated with six doses of i.t. MTX alone had a significantly higher incidence of central nervous system relapse than did patients treated with 2400-rad craniospinal RT plus 1200-rad abdominal RT, 2400-rad craniospinal RT, or 2400-rad cranial RT plus i.t. MTX. There was no significant differences in marrow remission duration or survival of the treatment groups. There appears to be a benefit with regard to length of bone marrow remission and survival for patients with initial white blood counts greater than or equal to 20,000/cu mm treated with cranial RT plus i.t. MTX. The majority of the patients remaining on study have now discontinued maintenance therapy. The 8-year overall estimated survival rate on this study is 56%, and the disease-free survival rate is 52%.

[Efficacy and Security of Intrathecal with Methotrexate in the Treatment of Meningeal Carcinomatosis].

BACKGROUND: Leptomeningeal carcinomatosis is a rare type of metastatic tumors of the central nervous system. In recent years, with the improvement of neoplasms therapies and longer survival of patients by better systemic control, incidence of leptomeningeal metastases has increased every year. However, there is still lack of effective therapies. The aim of this study is to investigate the efficacy, security and prognosis of intrathecal chemotherapy with methotrexate (MTX) in the treatment of neoplastic meningitis. METHODS: A total of 27 patients were enrolled. We investigated clinical features and cerebrospinal fluid (CSF) examination results retrospectively, and analyzed the adverse reactions as well as prognosis after intrathecal chemotherapy. RESULTS: All 27 patients were treated by intrathecal MTX, 70.4% had clinical remission, however, there was no significant difference in CSF pressure and CSF biochemical changes. We observed that 55.6% patients were all appropriate, 25.9% appeared lower limb numbness and mild pain, no serious irreversible adverse reactions occurred. Median overall survival was 4 months. CONCLUSIONS: We suggest that intrathecal administration of MTX is associated with improvement of symptoms of leptomeningeal metastasis patients and no severe adverse events observed.

Facial Paralysis Secondary to Extensive Perineural Spread of Adenocarcinoma of the Parotid Gland Identified by PET/CT.

Brain MRI in an 82-year-old man with presumed Bell's palsy revealed a clinically unsuspected right parotid gland mass but no other acute findings. Biopsy revealed poorly differentiated adenocarcinoma. Staging F-FDG PET/CT revealed an FDG-avid parotid mass, abnormal FDG uptake along the course of the facial nerve from mass to skull base, and multiple FDG-avid right level II neck lymph nodes and hepatic metastases. The PET/CT findings and prolonged clinical course suggest that diffuse perineural spread of tumor from a smoldering parotid neoplasm, and not idiopathic Bell's palsy, was responsible for the patient's facial paralysis.

Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group.

PURPOSE: To determine the analgesic effect of the addition of gabapentin to opioids in the management of neuropathic cancer pain. PATIENTS AND METHODS: One hundred twenty-one consecutive patients with neuropathic pain due to cancer, partially controlled with systemic opioids, participated in a multicenter, randomized, double-blind, placebo-controlled, parallel-design, 10-day trial from August 1999 to May 2002. Gabapentin was titrated from 600 mg/d to 1,800 mg/d in addition to stable opioid dose. Extra opioid doses were available as needed. Zero to 10 numerical scale was used to rate average daily pain. The average pain score over the whole follow-up period was used as main outcome measure. Secondary outcome measures were: intensity of burning pain, shooting/lancinating pain, dysesthesias (also scored on 0 to 10 numerical scale), number of daily episodes of lancinating pain, presence of allodynia, and daily extra doses of opioid analgesics. RESULTS: Overall, 79 patients received gabapentin and 58 (73%) completed the study; 41 patients received placebo and 31 (76%) completed the study. Analysis of covariance (ANCOVA) on the intent-to-treat population showed a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4; P =.0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P =.0077; ANCOVA on modified intent-to-treat population = 115 patients with at least 3 days of pain assessments). Reasons for withdrawing patients from the trial were adverse events in six patients (7.6%) receiving gabapentin and in three patients receiving placebo (7.3%). CONCLUSION: Gabapentin is effective in improving analgesia in patients with neuropathic cancer pain already treated with opioids.

Intraocular retinoblastoma group V: an analysis of prognostic factors.

A retrospective analysis of the University of Minnesota (Minneapolis) experience with retinoblastoma is presented. Seventy-five patients were diagnosed with retinoblastoma between 1958 and 1983, of which 53 (71%) had at least one Reese-Ellsworth group V eye. Nineteen group V patients and one group II patient developed extraocular disease recurrence. The cumulative actuarial rate of recurrence at 12 years was 36% for patients with group V disease. The median time from diagnosis to recurrence for unilateral patients was seven months and for bilateral patients 28 months (P = .001). Patients developing extraocular disease had a 10-year actuarial survival rate postrecurrence of 34%. The four long-term survivors of extraocular recurrences had had isolated orbital or local soft tissue recurrences only. Features of group V patients associated with extraocular recurrences were identified by univariate life table analyses. Clinical poor-risk factors included the nongenetic form of the disease (P = .03) and male sex (P = .02). Pathologic poor risk factors included rubeosis (P = .01), undifferentiated histology (P = .03), large tumor size (P = .05), and intraocular extension to the anterior segment (P = .02), retinal pigment epithelium (P = .03), choroid (P less than .001), and optic nerve beyond the lamina cribrosa (P = .02). Treatment-associated poor-risk factors included an optic nerve length of less than 5 mm removed at enucleation (P = .003). Multivariate life table analyses demonstrated the following parameters to be independent poor-prognostic factors: optic nerve length of less than 5 mm removed at enucleation (P = .001), optic nerve involvement (P = .004), and large tumor size (P = .01). These results will help to identify patients with retinoblastoma who are at greatest risk for extraocular recurrence.

A phase I trial of spirohydantoin mustard (NSC 172112) in patients with advanced cancer.

Spirohydantoin mustard (spiromustine, NSC 172112) is a classical bifunctional alkylating agent synthesized in an effort to develop antitumor agents effective against CNS tumors. The rationale was to combine the reactive moiety of an active antitumor agent with the hydantoin part of the molecule, which might serve as a carrier to cross the blood brain barrier. Thirty-eight patients with refractory solid tumors received spiromustine as part of a phase I trial at the Johns Hopkins Oncology Center. Three schedules were investigated: intravenously (IV) daily for three consecutive days, IV every other day for 3 days, and IV on a weekly basis for three doses, all cycled every 28 days. Hematologic toxicity was infrequently seen. Mild to moderate nausea and vomiting occurred on all schedules. The dose limiting toxicity was CNS toxicity characterized by mydriasis, xerostomia, lethargy, confusion, and hallucinations. This CNS toxicity was dose related, cumulative, and reversible. IV physostigmine appeared to diminish the neurotoxicity if administered before spiromustine and at frequent intervals following the drug. The maximum tolerated dose of spiromustine (without concomitant physostigmine) on the three times a week schedule is 6 mg/m2. With physostigmine pretreatment, 8 mg/m2 can be administered. The three times daily and every other day for three days schedules are not recommended for further study due to the severity of neurotoxicity. It is recommended that 6 mg/m2 be used as the starting dose for any phase II studies using the three times weekly schedule, and that physostigmine be used as needed to minimize neurotoxicity. Dose escalation above this level can be considered when individual tolerance has been established. Phase II trials to investigate the activity of this agent against primary and metastatic CNS malignancies appear indicated on the basis of three transient radiographic responses in refractory malignancies metastatic to the CNS.

Small cell carcinoma of the lung.

Small cell lung cancer is a common, usually fatal neoplasm. Although palliative therapy is available for the majority of patients, only a very small minority enjoy long-term survival. Ironically, this neoplasm is nearly entirely preventable and a successful antismoking program is desperately needed. Our efforts to understand the basic biology of this tumor should continue, and, hopefully, will eventually translate into improvements in therapy. In addition to following the leads provided by basic research, a concerted clinical research effort needs to continue to build upon the advances already achieved.

Effects of antimetastatic, antiinvasive and cytotoxic agents on the growth and spread of transplantable leukemias in mice.

The effects of cytotoxic (cyclophosphamide, CCNU, GANU), antiinvasive (vincristine, vinblastine) and antimetastatic (ICRF-159, DM-COOK) agents have been compared in mice-bearing P388 and L1210 leukemias, and TLX5 lymphoma. The drugs tested increase the survival time of the treated mice in a manner consistent with a cytotoxic action in the case of cyclophosphamide, CCNU, GANU, vincristine and vinblastine. Leukemic infiltration of the brain after i.p. tumor implantation has been determined by bioassay of this organ, and is reduced by treatment with all of the drugs tested, with the exception of ICRF-159. DM-COOK appears to increase the life-span of the treated animals by the inhibition of leukemic spread rather than by a cytotoxic action. The marked cytotoxicity of vincristine and vinblastine is sufficient to account for failure to detect any antimetastatic effects of these agents. The lack of antidisseminative effect observed for ICRF-159 under the experimental conditions employed might be connected with the observation that the antimetastatic action of this drug on solid tumors is due to its effects on tumor blood vessels.

Numb chin syndrome in cancer patients: etiology, response to treatment, and prognostic significance.

We retrospectively evaluated 42 consecutive cancer patients with numb chin syndrome (NCS). Breast cancer comprised 64% of the primary tumors, and lymphoproliferative neoplasms comprised 14%. A standard workup (including imaging of the brain, base of skull, and mandible, and CSF analysis) led to the diagnosis of a metastatic etiology in 89% of the patients. Fifty percent of the patients had mandibular metastases, 14% base-of-skull bone lesions, and 22% leptomeningeal seeding. NCS was a late manifestation of malignancy, associated with disease progression in 67% of the patients or heralding a relapse, which was often confined to the leptomeninges, in 31%. Although various therapeutic strategies led to resolution of NCS, median survival after its diagnosis was 5 months when due to bone metastases and 12 months if associated with leptomeningeal seeding.

Prognostic value of neural invasion in rectal carcinoma: a multivariate analysis on 339 patients with curative resection.

To determine whether neural invasion or other clinico-pathological factors are prognostic, we performed a retrospective study on 339 rectal carcinomas. The overall 5-year survival was 62%. In the multivariate analysis, age over 60 years, a distance from the anal verge of less than 6 cm, the number of positive lymph nodes, neural invasion and tumour penetration were found to be prognostic. A scoring system identified five prognostic groups of patients. Neural invasion is an independent prognostic factor in our scoring system and it is suggested that this parameter should be taken into consideration for postsurgical treatment.

Intracranial tumors with risk of dissemination in neuroaxis.

The experience of the Radiotherapy Service, Clínica Puerta de Hierro, Madrid (Spain), in the treatment of intracranial tumors with risk of neural axis dissemination is analyzed. In 15 years (1964-1979) 415 primary central nervous system tumors were studied and treated; 67 corresponded to tumors with risk of meningeal dissemination. Clinical dissemination in cerebrospinal fluid was proven in 14 patients. The actuarial survival of 10 years for patients with neural axis dissemination, without prophylactic treatment to the neuroaxis, is 14% with an average survival of 10.5 months. In approximately 20% of meduloblastomas, ependymal and pineal region tumors, meningeal metastases at some distance from the primary tumor can take place. Patients at risk wtih these types of neoplasia must be identified, and an adequate radical therapeutic focus devised, not only for the primary tumor, but also for the risk of dissemination.

Tumor markers in patients with lung cancer.

The most examined tumor markers in lung cancer patients are CEA, hormonal peptides, and some neurogenic enzymes in small cell carcinoma. Calcitonin, ACTH, ADH, CEA, neurophysin, oxytocin, beta-endorphin, neuron-specific enolase, and CK BB are elevated in serum specimens in 25-75% of cases of small cell carcinoma. The level of these markers is related to the stage of the disease in groups of patients; elevated pretreatment levels decrease with tumor regression. Marker levels are not valid in defining the tumor load and the presence of disease in the individual patient. It has not yet been documented that the markers can be used for clinical decisions on antineoplastic therapy. A recent development is the finding that measurement of CSF and plasma concentrations of ADH, calcitonin, CK BB, bombesin, and neuron-specific enolase may contribute in the diagnosis of CNS metastases including meningeal carcinomatosis.

Cytologic and immunohistochemical diagnosis of neuroendocrine (Merkel cell) carcinoma in cerebrospinal fluid.

Neuroendocrine (Merkel cell) carcinoma of the skin is a rare entity. Often locally aggressive, this lesion may also metastasize to organ systems, including bone, liver, and brain. The authors report a case of a 64-year-old male who presented with hoarseness and dysphagia 17 months after resection of a primary Merkel cell carcinoma of the nose. Additional studies revealed bilateral vocal cord paralysis secondary to central nervous system dysfunction. Cytologic evaluation of the cerebrospinal fluid revealed malignant tumor cells consistent with metastatic Merkel cell carcinoma. Presented are the cytologic and immunohistochemical findings in a case of metastatic Merkel cell carcinoma involving the central nervous system.