Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study).

BACKGROUND: There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status. PATIENTS AND METHODS: Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest. RESULTS: From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%). CONCLUSIONS: The PLD-olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m2 is better tolerated in the combination.

Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma

BACKGROUND: The results of CHOP-21 (cyclophosphamide, doxorubicin, vincristine and prednisone given every 21 days) for the treatment of aggressive B-cell lymphoma have recently been improved by the addition of rituximab and by increasing the dose density. R-CHOP-14 combines these two approaches. PATIENTS AND METHODS: We present our experience with R-CHOP-14 in a retrospective single-centre review of 50 patients consecutively treated for aggressive B-cell lymphoma. RESULTS: The median age was 59 years and 48% of patients were >60 years. Stage III-IV was present in 62% of the patients and international prognostic index was high-to-intermediate risk or high risk in 32% of the patients. Toxicity was mainly haematological, with grade 3-4 neutropenia observed in 32% and febrile neutropenia in 18%. Other relevant toxicities were peripheral neuropathy in 45% (grade 3 in 4%) and cardiac dysfunction grade 3 in 7.5%. After therapy, 82% of the patients achieved complete response or unproved complete response. With a median follow-up of 30 months, 3-year event-free survival and overall survival were 67% and 82% respectively. CONCLUSIONS: In our experience the combination of RCHOP- 14 is highly effective in patients with aggressive B-cell lymphoma. However special attention must be paid to the control of early and late toxicities (AU)

Primary duodenal follicular lymphoma successfully treated with rituximab.

Non-Hodgkin's lymphoma (NHL) of the gastrointestinal (GI) tract is the most common extranodal lymphoma, accounting for approximately 40% of all extranodal NHLs. Initial treatment of duodenal lymphoma includes surgery, chemotherapy and radiotherapy, alone or in combination. Here, we present a case of stage I primary duodenal follicular lymphoma (FL) showing a complete response after rituximab therapy. Rituximab alone can be an effective alternative treatment for duodenal FL.

Primary duodenal follicular lymphoma successfully treated with rituximab

Non-Hodgkin's lymphoma (NHL) of the gastrointestinal (GI) tract is the most common extranodal lymphoma, accounting for approximately 40% of all extranodal NHLs. Initial treatment of duodenal lymphoma includes surgery, chemotherapy and radiotherapy, alone or in combination. Here, we present a case of stage I primary duodenal follicular lymphoma (FL) showing a complete response after rituximab therapy. Rituximab alone can be an effective alternative treatment for duodenal FL (AU)

Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis.

BACKGROUND: Bisphosphonates (BP) decrease the incidence of skeletal related events among cancer patients with bone metastases from solid tumors and multiple myeloma. Renal safety and osteonecrosis of the jaws (ONJ) are two major concerns of toxicity. Information about safety of using BP beyond 2 years is scarce. MATERIALS AND METHODS: Patients receiving zoledronic acid (ZA) at the time of the study were reviewed. Serum creatinine levels (SCL) were collected at three different moments: before the start of BP (baseline), at the time of analysis (final), and the highest SCL during the treatment (highest). Oral examination was carried out in every patient. Separated analysis was made for patients on BP for >2 years. Concomitant risk factors for both renal toxicity and ONJ were evaluated. RESULTS: Sixty-seven patients were included. Median time of BP was 22 months, with 22 patients receiving BP for >2 years. Median baseline and final values of SCL were 0.71 mg/dl and 0.70 mg/dl, respectively (P = 0.121). Median highest SCL during treatment was 0.82 mg/dl (P <0.0001). A notable increase in the SCL was observed in six of the 67 patients (9%), four of them receiving BP for >2 years (P = 0.085). ONJ was also diagnosed in six patients, four of them in the group of prolonged BP treatment. CONCLUSION: ZA showed to be safe with a low rate of reversible renal toxicity. Patients receiving BP should be monitored carefully for renal toxicity and ONJ, especially those with exposure to BP beyond 2 years.

Osteonecrosis of the jaws in patients with bone metastasis receiving intravenous bisphosphonates. A rising concern.

Osteonecrosis of the jaws (ONJ) is a recognized complication of bisphosphonates (BP) therapy in cancer patients with bone metastasis. We report 2 additional cases of ONJ in women with breast cancer after long-term exposure to BP, discussing some considerations about the presentation and management of this rare and new complication.

Osteonecrosis of the jaws in patients with bone metastasis receiving intravenous bisphosphonates. A rising concern

Osteonecrosis of the jaws (ONJ) is a recognized complication of bisphosphonates (BP) therapy in cancer patients with bone metastasis. We report 2 additional cases of ONJ in women with breast cancer after long-term exposure to BP, discussing some considerations about the presentation and management of this rare and new complication (AU)

Bronquiolitis obliterante con neumonía organizada secundaria a quimioterapia / Bronchiolitis obliterans organizing pneumonia induced by chemotherapy

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Estudio sobre factores pronósticos comparando 5-FU-Levamisol vs 5-FU-Levamisol-Leucovorin en pacientes con carcinoma colorrectal en estadios II-III / Study of prognostic factors comparing 5-FU-Levamisol with 5-FU-Levamisol-Leucovorin treatments in patients with stages II-III colorectal carcinoma

Propósito: Presentar los resultados de un estudio sobre factores pronósticos comparando la administración de 5-Fluorouracilo (5-FU) más Levamisol (Lev) versus 5-FU más Lev y Leucovorín (LV) en una serie pacientes con cáncer de cólon y recto en estadios II-III de la UICC (B2-C de Dukes). Material y métodos: Entre 1991 y 1997 doscientos pacientes fueron distribuidos en dos grupos, tras la cirugía, para recibir tratamiento con quimioterapia adyuvante. Grupo A: 5-FU 370 mg/m2 iv. día 1 cada cuatro semanas durante un año y Levamisol vo. 50mg/8 horas por tres días, cada 15 días durante un año. Grupo B: 5-FU y Lev a las mismas dosis más Leucovorín 200mg/m2 iv. una hora antes del 5-FU. Todos los pacientes con cáncer de recto recibieron tratamiento con radioterapia luego de la cirugía. Resultados: Ciento ochenta y cuatro pacientes fueron evaluables para el análisis estadístico. Los dos grupos, A y B, presentaron una distribución homogénea en cuanto a edad, sexo, localización tumoral, tipo de cirugía, estadio y modalidad de tratamiento. Con una media de seguimiento de 85 meses (rango 2-120meses), en el grupo A se produjeron 30/91 recaídas y 28/91 muertes, y en el grupo B 32/93 recaídas y 34/93 muertes. La supervivencia libre de enfermedad (SLE) y supervivencia global (SG) a los 10 años para el grupo A fueron de 67 por ciento y 69 por ciento y para el grupo B de 64 por ciento y 63 por ciento, con una p no significativa. Los análisis de supervivencia multivariante, realizados en base a la localización del tumor (colon o recto) para el estadio en relación con la SLE, mostró una estimación de riesgo RR=2,75 (IC 95 por ciento 1,59-4,77), para la afectación ganglionar >4 vs 0 un RR=6,46 (IC 95 por ciento 3,38-12,3) y para 1-3 vs 0 un RR=2,37(IC 95 por ciento 1,29-4,35).Para el estadio en relación con la SG se estimó un riesgo RR=2,46 (IC 95 por ciento 1,42-4,28), para la afectación ganglionar >4 vs 0 un RR=5,1 (IC 95 por ciento 2,68-9,88) y para 1-3 vs 0 un RR=2,03(IC 95 por ciento 1,11-3,69). En ninguno de los estudios de supervivencia realizados se observó que la modalidad de tratamiento complementario afectase al comportamiento clínico de los pacientes. Los tratamientos fueron bien tolerados y las toxicidades más relevantes fueron leucopenia, mucositis y diarrea grado I/II. Conclusiones: En nuestro estudio el estadio y el número de ganglios afectos, independientemente de la localización tumoral, demostraron ser los factores pronóstico más importantes con un RR progresivamente ascendente para la SLE y para la SG. La asociación de Leucovorín a la combinación 5FU-Levamisol, no supuso ningún beneficio en la Supervivencia Libre de Enfermedad ni en la Supervivencia Global de los pacientes. (AU)

Cellular, serological, and molecular polymorphism of the class I and class II loci of the canine Major Histocompatibility Complex.

This study was undertaken to determine the relationships between canine cellular and serological determinants and more recently described genes. Such relationships might reveal information about immunological reactivity or function of various proteins. To do this we studied the haplotypic associations of dog leukocyte antigen (DLA) class I and class II alleles determined from a panel of 14 DLA-D homozygous dogs. This panel of dogs was typed for the serological determinants DLA-A, DLA-B and DLA-C. Polymorphisms for DLA-DQA1, DLA-DQB1, DLA-DRB1 and DLA-88 were also determined. The number of alleles (one or two) for two microsatellite markers in the DLA region were also determined. Analyses of the nucleotide sequences and of the serological and cellular typing data revealed that phenotypic homozygosity, as defined by the DLA-D type in mixed leukocyte culture (MLC), tended to correlate with homozygosity at the DLA-DRB1 locus but not necessarily at the DLA-DQB1 locus. Furthermore, MLC specificity was determined by other loci besides DLA-DRB1 and DLA-DQB1. The amino acid at position 63 of the DR beta chain could contribute to the DLA-B serological specificity. DLA-88, the most polymorphic class I gene characterized to date, did not have an easily identifiable association with either the DLA-A or DLA-C class I serological specificities. Homozygosity or heterozygosity of each of two microsatellite markers, FH 2200 and FH 2202, located in the class I or class II region, respectively, did not correlate with homozygosity or heterozygosity of the most polymorphic known class I (DLA-88) or class II (DLA-DRB1) genes.

A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer.

Notch receptors mediate cell-fate decisions through interaction with specific ligands during development. The biological role of a novel Notch ligand, Dll4, in mice was explored by reconstituting lethally irradiated mice with bone marrow (BM) cells transduced with Dll4 retroviral vector. White blood cell and lymphocyte counts in Dll4-overexpressing mice were reduced at the early stage of reconstitution but increased significantly at approximately 10 weeks after BM transplantation. BM, spleen, lymph nodes, and peripheral blood of Dll4-overexpressing mice contained predominantly CD4(+)CD8(+) T cells and virtually lacked B cells. The Dll4-overexpressing mice eventually developed a lethal phenotype that was characterized by the progression of a T-cell lymphoproliferative disease (restricted to BM and lymphoid tissues) to transplantable monoclonal T-cell leukemia/lymphoma scattered to multiple organs. Results suggest that the interaction of Dll4 with Notch1 may provide key signals for T-cell development.

Análisis de algunos aspectos epidemiológicos del cáncer de mama en Gran Canaria / Analysis of some epidemiological aspects of breast cancer in Gran Canaria

Propósito: La incidencia y mortalidad por cáncer de mama en Gran Canaria es una de las más altas de España. En este estudio analizamos las características epidemiológicas y clínico-patológicas de un grupo de pacientes con diagnóstico de cáncer de mama. Material y métodos: Se estudiaron 474 pacientes con cáncer de mama, diagnosticadas y tratadas entre diciembre de 1990 y marzo de 1996, en los dos Hospitales Generales de nuestra Provincia. Se confeccionó una base de datos y los análisis estadísticos realizados fueron, fundamentalmente, medidas de tendencia central y medidas de dispersión. Resultados: La edad media y mediana fue de 60 años. El grupo entre 56 y 60 años representó el 17,7 por ciento. El 83,8 por ciento de las neoplasias se detectaron por autopalpación y el 9,3 por ciento por mamografía. El 8,9 por ciento tenían antecedentes familiares de carcinoma de mama en primer grado. Se practicó mastectomía radical modificada en el 78,1 por ciento y cirugía conservadora en el 19,4 por ciento de los casos. Conclusiones: En nuestra serie, un alto porcentaje de tumores 83,8 por ciento fueron palpables precisando en el 78,1 por ciento la realización de mastectomía radical modificada (AU)

Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family.

We have identified a cytokine of the IL-6 family and named it novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3). NNT-1/BSF-3 cDNA was cloned from activated Jurkat human T cell lymphoma cells. Its sequence predicts a 225-aa protein with a 27-aa signal peptide, a molecular mass of 22 kDa in mature form, and the highest homology to cardiotrophin-1 and ciliary neurotrophic factor. The gene for NNT-1/BSF-3 is on chromosome 11q13. A murine equivalent to NNT-1/BSF-3 also was identified, which shows 96% homology to human NNT-1/BSF-3. NNT-1/BSF-3 mRNA is found mainly in lymph nodes and spleen. NNT-1/BSF-3 induces tyrosine phosphorylation of glycoprotein 130 (gp130), leukemia inhibitory factor receptor beta, and signal transducer and activator of transcription 3 in the SK-N-MC human neuroblastoma cells. NNT-1/BSF-3 shows activities typical of IL-6 family members. In vitro, it supports the survival of chicken embryo motor and sympathetic neurons. In mice, it induces serum amyloid A, potentiates the induction by IL-1 of corticosterone and IL-6, and causes body weight loss and B cell hyperplasia with serum IgG and IgM increase. NNT-1/BSF-3 is a gp130 activator with B-cell stimulating capability.

Passage of leptin across the blood-testis barrier.

Leptin is a 17-kDa protein, secreted by fat, that controls adiposity and has been proposed to have numerous effects on reproduction in the mouse. To assess whether the effects of leptin on testicular function are direct, we determined whether leptin can cross the murine blood-testis barrier. Multiple time regression analysis showed that a small amount of blood-borne leptin is able to enter the testis but does so by a nonsaturable process. In addition, no significant expression of leptin receptors was found at the Leydig cells or Sertoli cells of the testis. This compares with the presence of a saturable transport system for leptin at the blood-brain barrier and abundant receptors for leptin at the leptomeninges, neurons, and choroid plexus of the central nervous system (CNS). These results support the hypothesis that the effects of leptin on reproductive function are not mediated at the level of the testis but indirectly, probably through the CNS.

T-cell co-stimulation through B7RP-1 and ICOS.

T-cell activation requires co-stimulation through receptors such as CD28 and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine costimulatory receptor-ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS, is expressed on activated T cells and resting memory T cells. The ligand, which has homology to B7 molecules and is called B7-related protein-1 (B7RP-1), is expressed on B cells and macrophages. ICOS and B7RP-I do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells in vitro independently of CD28. Transgenic mice expressing a B7RP-1-Fc fusion protein show lymphoid hyperplasia in the spleen, lymph nodes and Peyer's patches. Presensitized mice treated with B7RP-1-Fc during antigen challenge show enhanced hypersensitivity. Therefore, B7RP-1 exhibits co-stimulatory activities in vitro and in vivo. ICOS and B7RP-1 define a new and distinct receptor-ligand pair that is structurally related to CD28-B7 and is involved in the adaptive immune response.