Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial

BACKGROUND: In the previously reported ALSYMPCA trial in patients with castration-resistant prostate cancer and symptomatic bone metastases, overall survival was significantly longer in patients treated with radium-223 dichloride (radium-223) than in patients treated with placebo. In this study, we investigated safety and overall survival in radium-223 treated patients in an early access programme done after the ALSYMPCA study and before regulatory approval of radium-223.

METHODS: We did an international, prospective, interventional, open-label, single-arm, phase 3b study. Enrolled patients were aged 18 years or older with histologically or cytologically confirmed progressive bone-predominant metastatic castration-resistant prostate cancer with two or more skeletal metastases on imaging (with no restriction as to whether they were symptomatic or asymptomatic; without visceral disease but lymph node metastases were allowed). Patients received intravenous injections of radium-223, 50 kBq/kg (current recommendation 55 kBq/kg after implementation of National Institute of Standards and Technology update on April 18, 2016) every 4 weeks for up to six injections. Other concomitant anticancer therapies were allowed. Primary endpoints were safety and overall survival. The safety and efficacy analyses were done on all patients who received at least one dose of the study drug. The study has been completed, and we report the final analysis here. This study is registered with ClinicalTrials.gov, number NCT01618370, and the European Union Clinical Trials Register, EudraCT number 2012-000075-16.

FINDINGS: Between July 22, 2012, and Dec 19, 2013, 839 patients were enrolled from 113 sites in 14 countries. 696 patients received one or more doses of radium-223; 403 (58%) of these patients had all six planned injections. Any-grade treatment-emergent adverse events occurred in 523 (75%) of 696 patients; any-grade treatment-emergent adverse events deemed to be related to treatment were reported in 281 (40%) patients. The most common grade 3 or worse treatment-related treatment-emergent adverse events were anaemia in 32 (5%) patients, thrombocytopenia in 15 (2%) patients, neutropenia in ten (1%) patients, and leucopenia in nine (1%) patients. Any grade of serious adverse events were reported in 243 (35%) patients. Median follow-up was 7·5 months (IQR 5-11) and 210 deaths were reported; median overall survival was 16 months (95% CI 13-not available [NA]). In an exploratory analysis of overall survival with predefined factors, median overall survival was longer for: patients with baseline alkaline phosphatase concentration less than the upper limit of normal (ULN; median NA, 95% CI 16 months-NA) than for patients with an alkaline phosphatase concentration equal to or greater than the ULN (median 12 months, 11-15); patients with baseline haemoglobin levels 10 g/dL or greater (median 17 months, 14-NA) than for patients with haemoglobin levels less than 10 g/dL (median 10 months, 8-14); patients with a baseline Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (median NA, 17 months-NA) than for patients with an ECOG PS of 1 (median 13 months, 11-NA) or an ECOG PS of 2 or more (median 7 months, 5-11); and for patients with no reported baseline pain (median NA, 16 months-NA) than for those with mild pain (median 14 months, 13-NA) or moderate-severe pain (median 11 months, 9-13). Median overall survival was also longer in patients who received radium-223 plus abiraterone, enzalutamide, or both (median NA, 95% CI 16 months-NA) than in those who did not receive these agents (median 13 months, 12-16), and in patients who received radium-223 plus denosumab (median NA, 15 months-NA) than in patients who received radium-223 without denosumab (median 13 months, 12-NA).

INTERPRETATION: Our findings show that radium-223 can be safely combined with abiraterone or enzalutamide, which are now both part of the standard of care for patients with metastatic castration-resistant prostate cancer. Furthermore, our findings extend to patients who were asymptomatic at baseline, unlike those enrolled in the pivotal ALSYMPCA study. The findings of prolonged survival in patients treated with concomitant abiraterone, enzalutamide, or denosumab require confirmation in prospective randomised trials.

FUNDING: Pharmaceutical Division of Bayer.

Special Issues in the Young and Pregnant Patient with Breast Cancer

This chapter presents a series of multiple choice questions and answers on the special issues in the young and pregnant patient with breast cancer. It also presents a series of case studies with questions and answers on the special issues in the young and pregnant patient with breast cancer. The chapter examines whether the genomic testing by Oncotype DX or MammaPrint be helpful in managing the patient. It also examines the factors that are the most important in determining the risk of chemotherapyinduced amenorrhea (CIA) in the patient, and a role for sentinel lymph node biopsy (SLNB) in patients diagnosed with breast cancer during pregnancy. The chapter discusses counselling of a patient who became accidentally pregnant on maintenance therapy with trastuzumab or tamoxifen. In addition, It examines the options that could be offered to preserve fertility.

iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice.

Leishmania major parasites reside and multiply in late endosomal compartments of host phagocytic cells. Immune control of Leishmania growth absolutely requires expression of inducible Nitric Oxide Synthase (iNOS/NOS2) and subsequent production of NO. Here, we show that CD11b+ CD11c+ Ly-6C+ MHC-II+ cells are the main iNOS-producing cells in the footpad lesion and in the draining lymph node of Leishmania major-infected C57BL/6 mice. These cells are phenotypically similar to iNOS-producing inflammatory DC (iNOS-DC) observed in the mouse models of Listeria monocytogenes and Brucella melitensis infection. The use of DsRed-expressing parasites demonstrated that these iNOS-producing cells are the major infected population in the lesions and the draining lymph nodes. Analysis of various genetically deficient mouse strains revealed the requirement of CCR2 expression for the recruitment of iNOS-DC in the draining lymph nodes, whereas their activation is strongly dependent on CD40, IL-12, IFN-gamma and MyD88 molecules with a partial contribution of TNF-alpha and TLR9. In contrast, STAT-6 deficiency enhanced iNOS-DC recruitment and activation in susceptible BALB/c mice, demonstrating a key role for IL-4 and IL-13 as negative regulators. Taken together, our results suggest that iNOS-DC represent a major class of Th1-regulated effector cell population and constitute the most frequent infected cell type during chronic Leishmania major infection phase of C57BL/6 resistant mice.

The role of laparoscopy and intraoperative ultrasound in the diagnosis and staging of lymphomas

aparoscopic surgery plays today an important role in the diagnosis and staging of abdominal lymphomas; in fact it provides adequate lymph node sampling for histological typing and immunophenotyping. The mini-invasive procedure is safe and effective. Intra-operative ultrasound permits to study the parenchimal organs in addition to intra-abdominal lymph node and/or masses.

Lipofilling in skin affected by radiodermatitis: clinical and ultrasound aspects. Case report

In recent years, lipofilling has established itself as one of the most effective and least invasive techniques to treat connective dystrophy subsequent to radiotherapy. We report the case of a patient diagnosed with intraductal carcinoma of the right breast in 1996, at the age of 41. The patient underwent quadrantectomy with ipsilateral axillary lymph node dissection and adjuvant chemotherapy and radiotherapy. Four years later, a recurrence led the patient to undergo a subcutaneous mastectomy and immediate reconstruction, involving the submuscular insertion of a permanent implant. In 2007 the patient suffered both radiodermatitis and capsular contracture around the implant, causing constant pain and significant functional limitation. She first took a leukotriene inhibitor (Zafirlukast, 20 mg daily for 8 months) to reduce the capsular contracture. She then underwent lipofilling (Coleman’s technique) of the area affected by radiodermatitis, in which the skin was considerably thinned and visibly ischemic. A second session followed four months later. Clinical, photographic and ultrasound examination revealed clear and lasting thickening of the superficial tissues, increased coverage of the implant, and reduced skin discoloration and tension.

Cirurgia endoscópica em tumores nasosinusais: experiência do IPOLFG

Introdução: Os tumores nasais são, classicamente, abordados pela via externa mas recentemente tem-se optado, também, pela via endoscópica. No entanto, em tumores localmente avançados, poderá não ser possível a remoção completa. Material e métodos: Foram analisados os processos clínicos dos 14 doentes com tumor das fossas nasais removido por via endoscópica no IPOLFG entre 2005 e 2012. Resultados: Dos 14 doentes, 8 apresentavam tumor maligno e 5 tumor benigno. Não houve preponderância de nenhum tipo histológico. 7 doentes realizaram RT adjuvante e 1 foi submetido a esvaziamento ganglionar cervical ipsilateral. Foram registadas 2 complicações cirúrgicas: 1 fístula de LCR e 1 complicação minor. Apenas 2 doentes recidivaram, recorrendo-se à via externa em 1. Conclusões: A abordagem de tumores nasais por via endoscópica é uma opção eficaz mas é necessária uma correta avaliação da extensão tumoral para decisão da via cirúrgica a utilizar, para remoção completa e obtenção de margens livres.

Primary gastric choriocarcinoma: A rare case

Introduction Primary gastric choriocarcinoma accounts for 0.08% of all gastric cancers. It is a rapidly growing, widely metastatic and β-HCG-producing tumour of trophoblastic cells. Presentation of case A 69-year-old white man presented to the hospital with symptomatic anaemia. An upper gastrointestinal endoscopy showed an ulcer of the cardia and lesser curvature, whose biopsy specimens proved to be malignant (carcinoma cells, non-specified). The patient underwent total gastrectomy with D2 lymphadenectomy. A histologic evaluation revealed a choriocarcinoma admixed with adenocarcinoma cells without lymph node metastases. The patient died from haemorrhagic shock, due to rupture of liver metastases and a massive haemoperitoneum, within 2 months of the initial presentation. Discussion Primary gastric choriocarcinoma characteristics resemble those of gastric primary adenocarcinoma. The dedifferentiation theory is the most widely accepted theory to explain the pathogenesis of PGC. It is essential to rule out other possible primary lesions such as testicular tumour. The optimal treatment is not yet well established due to very few reported cases. Conclusion Primary gastric choriocarcinoma is a rare tumour with an aggressive behaviour and very poor prognosis.

Lymphadenopathy after Initiating HAART in an HIV-positive Patient with Kaposi's Sarcoma: a Case of Multicentric Castleman's Disease

We present the case of a 33-year-old lady who was diagnosed with disseminated Kaposi’s sarcoma and HIV infection. The patient improved on highly active antiretroviral therapy (HAART), however, nine days into treatment, she became febrile and dyspnoeic and developed tender cervical and axillary lymphadenopathy. Despite treatment for suspected sepsis and immune reconstitution, she died in intensive care. Lymph node biopsies revealed coexistent Castleman’s disease and Kaposi’s sarcoma. Initiation of HAART can be rarely associated with unmasking and rapid progression of Castleman’s disease, a phenomenon called immune reconstitution. Urgent investigation and treatment with agents such as steroids and cytotoxic drugs can be life-saving.

Estudo sobre a participação de roedores na cadeia de transmissão de Leishmania infantum (Protozoa: Trypanosomatidae) no Rio Grande do Norte

American visceral leishmaniasis is a zoonosis caused by Leishmania infantum and transmitted by the bite of the sand flies Lutzomia longipalpis.The main domestic reservoir is the dog, while foxes and opposums are the known wild reservoirs. However, identification of natural infections with L. infantum in rodents appears for need of investigating the participation of these rodents how source of infection of the parasite. In the present work the Leishmania infantum infection was investigated in rodents captured in Rio Grande do Norte, aiming at to offer subsidies to the understanding of the epidemic chains of LVA in the State. Thirteen Galea spixii were distributed in four groups, being G1 the group control with four animals and the others, G2, G3 and G4, with three animals each. Those animals were intraperitoneally inoculated with 107 promastigotas of L. infantum and accompanied for, respectively, 30, 90 and 180 days. Weekly the animals were monitored as for the corporal weight and rectal temperature. At the end of each stipulated period the animals were killed. Blood were used for determination of the parameters biochemical and haematological, PCR, ELISA, microscopic examination and cultivation in NNN medium. Liver, spleen and lymph node were used in Giemsa-stained impression and cultivation in NNN medium. Liver and spleen fragments were still used in PCR and histopathological, respectively. At the same time 79 rodents of the species Rattus rattus, Bolomys lasiurus, Oligoryzomys nigripis, Oryzomys subflavus and Trichomys apereoides were captured in the Municipal districts of Brejinho, Campo Grande, Coronel Ezequiel, Passa e Fica and Vázea for identification of natural infection with L. infantum. Evidence of infection was checked by direct examination of Giemsa-stained impression of liver, spleen and blood and culture of these tissues in NNN medium. Antibodies were researched by ELISA. They were not found differences among the weigh corporal final, rectal temperature and biochemical and haematological parameters of the Galea spixii controls and infected. The rectal temperature of the animals varied from 36OC to 40OC. For the first time values of the haematocrit (33,6% to 42,8%), hemoglobin (10,2 to 14,5g/dl), erythrocyts number (4,67x106 to 6,90x106/mm3), total leukocytes (0,9x103 to 9,2x103/mm3), platelets (49x103 to 509x103/mm3) total proteins (1,56 to 6,06 g/dl), albumin (1,34 to 3,05 g/dl) and globulins (0,20 to 3,01 g/dl) of the Galea spixii were determined. The lymphocytes were the most abundant leucocytes. Infection for L. infantum was diagnosed in two animals euthanasied 180 days after the infection. In one of the animals was also identified antibodies anti-Leishmania. The parasite was not found in none of the five other species of rodents captured. Galea spixii are resistant to the infection for L. infantum and they are not good models for the study for visceral leishmaniose, although they can act as infection sources. More studies are necessary to determine the paper of the rodents in the epidemic chain of transmission of the visceral leishmaniose in the State of Rio Grande do Norte

Update on imaging of ovarian cancer

This review will make familiar with new concepts in ovarian cancer and their impact on radiological practice. Disseminated peritoneal spread and ascites are typical of the most common (70–80 %) cancer type, highgrade serous ovarian cancer. Other cancer subtypes differ in origin, precursors, and imaging features. Expert sonography allows excellent risk assessment in adnexal masses. Owing to its high specificity, complementary MRI improves characterization of indeterminate lesions. Major changes in the new FIGO staging classification include fusion of fallopian tube and primary ovarian cancer and the subcategory stage IIIA1 for retroperitoneal lymph node metastases only. Inguinal lymph nodes, cardiophrenic lymph nodes, and umbilical metastases are classified as distant metastases (stage IVB). In multidisciplinary conferences (MDC), CT has been used to predict the success of cytoreductive surgery. Resectability criteria have to be specified and agreed on in MDC. Limitations in detection of metastases may be overcome using advanced MRI techniques.

Estratificação do carcinoma do colo do útero pré e pós-terapêutica - uma perspectiva global

O carcinoma do colo do útero é um dos tumores malignos mais frequentes a nível mundial. Para garantir a uniformização de critérios entre países com diferentes recursos, o estadiamento deste tumor permanece clínico, segundo as orientações da Federação Internacional de Ginecologia e Obstetrícia, e tem por principal objectivo a identificação das doentes que são candidatas à cirurgia. A avaliação radiológica é amplamente recomendada, quando disponível, com o objectivo de aumentar a acuidade do diagnóstico, assegurando a optimização terapêutica, sendo também recomendada no seguimento. Importa, assim, que o radiologista tenha presente não só o protocolo técnico adequado na suspeita de carcinoma do colo do útero e o respectivo espectro de apresentação radiológica, mas também algumas características da própria doença e possíveis abordagens terapêuticas, de forma a incluir no seu relatório toda a informação relevante. A ressonância magnética permanece o principal pilar na avaliação radiológica destas doentes, embora recentemente o papel da tomografia computorizada por emissão de positrões tenha vindo a ganhar relevo, sobretudo no que respeita à avaliação ganglionar e ao despiste de recidiva. Neste artigo as autoras dão uma perspectiva aprofundada da avaliação radiológica do carcinoma do colo do útero, deste o diagnóstico ao seguimento pós-terapêutico, à luz dos estudos mais recentes.

Estadiamento do carcinoma do colo do útero por ressonância magnética – comparação com os achados anátomo-patológicos

Objectivo: Avaliar a acuidade da Ressonância Magnética (RM) no estadiamento do carcinoma do colo do útero, comparando os achados em RM com os resultados Anátomo-Patológicos da peça operatória. Material e Métodos: Foi efectuado um estudo retrospectivo que incluiu 41 doentes operadas com o diagnóstico de carcinoma do colo do útero e previamente submetidas a RM para estadiamento, entre Janeiro de 2007 e Dezembro de 2009. Foram analisados os seguintes factores de estadiamento e prognóstico: dimensão do tumor, invasão dos paramétrios, invasão da vagina e metástases ganglionares. A dimensão do tumor determinada por RM foi comparada com a medição na peça operatória através da análise do declive e ordenada na origem de uma recta de regressão entre os dois métodos. Resultados: O tumor foi visualizado por RM na maioria dos casos (35 doentes, 85.4%). Nas restantes 6 doentes a avaliação anátomo-patológica revelou um tumor com menos de 6 mm de diâmetro. A dimensão do tumor foi adequadamente avaliada por RM, sem diferenças estatisticamente significativas entre a medição por RM e na peça operatória. Foi confirmado o elevado valor preditivo negativo da RM na exclusão de invasão dos paramétrios previamente reportado, com apenas 2 falsos negativos em que a anatomia patológica demonstrou apenas invasão microscópica focal. A invasão da vagina foi correctamente avaliada em 30 doentes (85.7%), tendo-se verificado nos restantes casos 2 falsos negativos e 3 falsos positivos. Em relação às metástases ganglionares verificaram-se 4 falsos negativos, no total das 41 doentes avaliadas. Conclusão: A dimensão do tumor, invasão dos paramétrios, invasão da vagina e metástases ganglionares foram adequadamente avaliadas por RM, confirmando a capacidade da RM no estadiamento do carcinoma do colo do útero.

Histologic response after neoadjuvant chemoradiotherapy in locally advanced rectal adenocarcinoma: experience from Sudan.

Background: Locally advanced rectal cancer can be down staged by neoadjuvant therapy and the resultant tumor response can be quantified histologically. This study aimed to assess pathological response of neoadjuvant chemoradiation in patients with locally advanced rectal cancers treated in Wad Medani Teaching Hospital (WMTH) and National Cancer Institute (NCI), Wad Medani, Sudan. Patients and Methods: A total of 36 consecutive patients with locally advanced rectal cancer that were managed in WMTH and NCI during the period from 2006-2011 were reviewed. Preoperative pelvic radiotherapy was delivered. Total of 46 Gray were delivered concurrently with 5- fluorouracil (5-FU) on the first and last week of radiation. Total mesorectal excision of the rectal tumour either by anterior or abdominoperineal resections was planned at 6-8 weeks from completion of preoperative treatment. The pathological response to therapy was assessed by histopathology examination of the surgical specimen. Results: Initial clinical staging of patients revealed 58.3% of them were stage T3/T4N2M0 and 41.7% were stage T3N0M0. Down-staging to stage T1/T2N0M0 was found in 36.1% and stage T3N0M0 in 30.6%. No response was seen in 8.3% of cases with stage T3/T4N2M0 while complete clinical response (no residual) was seen in 25.0%. Complete histological response was observed in 13.8%. Positive lymph-nodes metastasis was confirmed in 8.3% of cases. Conclusion: Neoadjuvant chemoradiation is a reasonable option for cases of rectal cancer and deserves further evaluation.

PPARα regulates endothelial progenitor cell maturation and myeloid lineage differentiation through a NADPH oxidase-dependent mechanism in mice

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Exogenous Administration of 15d-PGJ(2)-Loaded Nanocapsules Inhibits Bone Resorption in a Mouse Periodontitis Model

The 15-deoxy-(Delta 12,14)-PG J(2) (15d-PGJ(2)) has demonstrated excellent anti-inflammatory results in different experimental models. It can be used with a polymeric nanostructure system for modified drug release, which can change the therapeutic properties of the active principle, leading to increased stability and slower/prolonged release. The aim of the current study was to test a nano-technological formulation as a carrier for 15d-PGJ(2), and to investigate the immunomodulatory effects of this formulation in a mouse periodontitis model. Poly (D, L-lactide-coglycolide) nanocapsules (NC) were used to encapsulate 15d-PGJ(2). BALB/c mice were infected on days 0, 2, and 4 with Aggregatibacter actinomycetemcomitans and divided into groups (n = 5) that were treated daily during 15 d with 1, 3, or 10 mu g/kg 15d-PGJ(2)-NC. The animals were sacrificed, the submandibular lymph nodes were removed for FACS analysis, and the jaws were analyzed for bone resorption by morphometry. Immunoinflammatory markers in the gingival tissue were analyzed by reverse transcriptase-quantitative PCR, Western blotting, or ELISA. Infected animals treated with the 15d-PGJ(2)-NC presented lower bone resorption than infected animals without treatment (p < 0.05). Furthermore, infected animals treated with 10 mu g/kg 15d-PGJ(2)-NC had a reduction of CD4(+)CD25(+)FOXP3(+) cells and CD4/CD8 ratio in the submandibular lymph node (p < 0.05). Moreover, CD55 was upregulated, whereas RANKL was downregulated in the gingival tissue of the 10 mu g/kg treated group (p < 0.05). Several proinflammatory cytokines were decreased in the group treated with 10 mu g/kg 15d-PGJ(2)-NC, and high amounts of 15d-PGJ(2) were observed in the gingiva. In conclusion, the 15d-PGJ(2)-NC formulation presented immunomodulatory effects, decreasing bone resorption and inflammatory responses in a periodontitis mouse model. The Journal of Immunology, 2012, 189: 1043-1052.