Aromatase Inhibitor-Associated Tendinopathy and Muscle Tendon Rupture: Report of Three Cases of This Exceedingly Rare Adverse Event.

Aromatase inhibitors (AIs) are a commonly used antihormonal therapy in the treatment of breast cancer in postmenopausal women, specifically in the treatment of hormone receptor-positive breast cancer. AI-associated tendinopathy and muscle tendon rupture is exceedingly rare. Until now, only one case with AI-associated severe tendinopathy has been reported in the medical literature, and there are no recorded cases of AI-associated muscle tendon rapture. We report three cases of postmenopausal women with hormone receptor-positive breast cancer, who experienced tendinopathy or muscle tendon rupture under antihormonal treatment with letrozole. All of the three women were in the adjuvant setting, and the treatment of tendinopathy or tendon rupture consisted of AI discontinuation, initiation of corticosteroids, or surgical treatment. Diagnosis was made via MRI. Furthermore, in our cases, there were no signs of underlying systemic disease, there was no abnormal physical activity preceding the complaints, and there was no use of other drugs beside letrozole. AIs are one of the most commonly used drugs in antihormonal therapy for hormone receptor-positive breast cancer. In every case of a female patient with hormone receptor-positive breast cancer under treatment with AIs and arthralgia, an MRI should be performed in order to exclude the presence of tendinopathy or muscle tendon rupture.

Proliferating fibroblasts and HeLa cells co-cultured in vitro reciprocally influence growth patterns, protein expression, chromatin features and cell survival.

AIM: to identify biological interactions between proliferating fibroblasts and HeLa cells in vitro. MATERIALS AND METHODS: Fibroblasts were isolated from both normal and tumour human tissues. Coverslip co-cultures of HeLa and fibroblasts in various ratios with medium replacement every 48 h were studied using fixed cell staining with dyes such as Giemsa and silver staining, with immunochemistry for Ki-67 and E-cadherin, with dihydrofolate reductase (DHFR) enzyme reaction, as well as live cell staining for non-specific esterases and lipids. Other techniques included carmine cell labeling, autoradiography and apoptosis assessment. RESULTS: Under conditions of feeding and cell: cell ratios allowing parallel growth of human fibroblasts and HeLa cells, co-cultured for up to 20 days, a series of phenomena occur consecutively: profound affinity between the two cell types and exchange of small molecules; encircling of the HeLa colonies by the fibroblasts and enhanced growth of both cell types at their contact areas; expression of carbonic anhydrase in both cell types and high expression of non-specific esterases and cytoplasmic argyrophilia in the surrounding fibroblasts; intense production and secretion of lipid droplets by the surrounding fibroblasts; development of a complex net of argyrophilic projections of the fibroblasts; E-cadherin expression in the HeLa cells; from the 10th day onwards, an increasing detachment of batches of HeLa cells at the peripheries of colonies and appearance of areas with many multi-nucleated and apoptotic HeLa cells, and small HeLa fragments; from the 17th day, appearance of fibroblasts blocked at the G2-M phase. Co-cultures at approximately 17-20 days display a cell-cell fight with foci of (a) sparse growth of both cell types, (b) overgrowth of the fibroblasts and (c) regrowth of HeLa in small colonies. These results indicate that during their interaction with HeLa cells in vitro, proliferating fibroblasts can be activated against HeLa. This type of activation is not observed if fibroblast proliferation is blocked by contact inhibition of growth at confluency, or by omitting replacement of the nutrient medium. CONCLUSION: The present observations show that: (a) interaction between proliferating fibroblasts and HeLa cells in vitro drastically influences each other's protein expression, growth pattern, chromatin features and survival; (b) these functions depend on the fibroblast/HeLa ratio, cell topology (cell-cell contact and the architectural pattern developed during co-culture) and frequent medium change, as prerequisites for fibroblast proliferation; (c) this co-culture model is useful in the study of the complex processes within the tumour microenvironment, as well as the in vitro reproduction and display of several phenomena conventionally seen in tumour cytological sections, such as desmoplasia, apoptosis, nuclear abnormalities; and (d) overgrown fibroblasts adhering to the boundaries of HeLa colonies produce and secrete lipid droplets.

A case of paraneoplastic autoimmune pancreatitis: mini-review of paraneoplastic syndromes in breast cancer.

Breast cancer (BC), the most common type of cancer in women of the Western world, is often associated with paraneoplastic syndromes (PNS). Autoimmune pancreatitis is a recently recognized entity belonging to the spectrum of IgG4-related systemic diseases, which are characterized by target-organ plasmacytic infiltration and fibrosis. In this report we review PNS associated with BC and we present the first case of BC-associated autoimmune pancreatitis as well as its successful management with steroids and immunosuppressive BC-tailored chemotherapy.

Salvage chemotherapy with cisplatin and 5-fluorouracil in metastatic breast cancer. Particular activity against liver metastases.

BACKGROUND: The prognosis of patients with metastatic breast cancer who have failed to respond to at least two different chemotherapy regimens is poor. Such patients with metastatic disease to the liver have even worse prognosis. Cisplatin and 5-fluorouracil (5-FU) can be given in patients with impaired hepatic function but their combination has not been extensively studied in this setting. PATIENTS AND METHODS: We retrospectively collected data from our registry on patients with advanced metastatic breast cancer who received combination of cisplatin/5-FU. We sought to determine the toxicity, the response rate, the disease control rate and the survival of this combination. RESULTS: We identified 25 heavily pre-treated patients, out of which 19 (76%) had liver metastases. They had been treated before with a median of three lines of cytotoxic chemotherapy. The majority of patients had also received hormonal manipulation or trastuzumab. The median number of cisplatin/5-FU administered cycles, without toxic deaths or unexpected toxicities was four. The partial response (PR) rate was 32% and the disease control rate (DCR) was 68%. The time to progression was five months and the median survival after starting on cisplatin/5-FU was six months. CONCLUSION: The combination of cisplatin/5-FU is active and safe in heavily pre-treated patients with metastatic breast cancer even in the presence of liver metastases and jaundice.

Role of stromal fibroblasts in cancer: promoting or impeding?

The basement membrane, immune cells, capillaries, fibroblasts and extracellular matrix (ECM) constitute the tumour stroma, commonly referred to as the 'reactive stroma'. The fibroblasts from the initial stages of a tumour, as the main constituents of the reactive stroma, present a different phenotype from the normal fibroblasts and play a crucial role in tumour progression. This review presents the differences between normal and tumour stromal fibroblasts and analyzes the molecular mechanisms (which involve growth factors, ECM components, matrix metalloproteinases, integrins and cell adhesion molecules) in the complex interactions between stromal fibroblasts and tumour cells. To date, several examples of heterotypic interactions between tumour stromal fibroblasts and tumour cells have supported the hypothesis that the tumour stroma promotes the growth of the tumour mass, as well as invasion and metastasis. However, it remains possible that the stroma acts essentially as a local modulator to impede tumorigenesis at an early stage and that the desmoplastic response is a host defence reaction designed to confine the developing tumour. The latter hypothesis has largely been neglected. The review aims to give a broader view on the role of stromal fibroblasts in tumour growth, invasion and metastasis.

Pneumocystis carinii pneumonia in patients with solid tumors and lymphomas: predisposing factors and outcome.

AIM: The incidence of Pneumonocystis carinii pneumonia (PCP) is increasing in patients with cancer. The possible routes of transmission in this population, as well as the epidemiological data of PCP, are not very well understood. The collection and analysis of data concerning the predisposing factors for PCP will elucidate this subject. PATIENTS AND METHODS: We studied 26 patients suffering from cancer who developed PCP during the five-year period 1997--2002. RESULTS: Twenty-one patients had a solid tumor diagnosis while the remaining five had a lymphoma. All of them received intensive combination chemotherapy, while eight of them also received high-dose therapy and bone marrow transplantation. Nineteen of our patients had long hospitalization before the onset of PCP. All of them had received corticosteroids for various reasons. Among them, many patients had been exposed to radiotherapy and, in particular, in fields which encompass the major thoracic duct. Eighteen patients survived after the initiation of appropriate treatment, while eight others succumbed. CONCLUSION: In this series, protracted deep lymphopenia, long hospitalization, radiotherapy and intensive chemotherapy were considered serious risk factors for developing PCP.

Is weekly paclitaxel superior to paclitaxel given every 3 weeks? Results of a phase II trial.

Twenty-four patients previously treated with platinum containing regimens with stage IIIB-IV non-small-cell lung cancer (NSCLC) participated in the study. Sequential cohorts of patients were treated with 60 and 90 mg/m(2) of Paclitaxel per week. Paclitaxel was administered weekly over 1 h infusion for 6 consecutive weeks followed by 2 weeks without treatment (8-week cycle). A total of 252 treatments were administered to the 24 patients. In 29 (12%) of 252 treatments grade 2 granulocytopenia was observed while four patients (17%) developed grade 2 neuropathy. Seven patients (29%) achieved a partial response and five (21%) had stable disease. Paclitaxel 90 mg/m(2) per week as salvage treatment is well tolerated and has shown promising activity in patients with NSCLC who progress after platinum treatment.