Malignant mesothelioma (MM) is a rare, highly aggressive tumor, accounting for less than 1% of all cancer deaths in the world 1. This neoplasm arises from the surface serosal cells of the pleural (> 90% of cases), peritoneal, and pericardial cavities and from the tunica vaginalis of the testis 2. Several epidemiological and clinicopathological studies have shown a correlation between exposure to asbestos and development of pleural mesothelioma 3; nevertheless, the exact mechanism whereby asbestos induces the mesothelioma is still unknown 45. Interestingly, recent studies have proposed a role for Simian Virus 40 large T antigen (SV40-Tag) in the pathogenesis of human mesothelioma, but there are discordant opinions in the scientific literature 678 Due to the low incidence of the disease, only few randomized studies have been performed [reviewed in 9]. The prognosis is generally poor with a reported median survival of 4 to 12 months in either untreated or treated (surgery, radiotherapy, or chemotherapy) patients 10. Moreover, mesothelioma has proven resistant to classical chemotherapeutic and radiation regimes and the natural history has not been influenced by standard therapy 11. Various drugs have been tested in different combinations so far; among the most commonly employed are doxorubicin, cyclophosphamide, cisplatin (CDDP), carboplatin, gemcitabine, and pemetrexed 1112131415. Of interest, the combination of these drugs, with the exception of pemetrexed, does not appear to provide any clear advantage over mono-therapy 9. Therefore, there is need of more effective therapies, possibly based on the most recent discoveries on the molecular events involved in mesothelioma pathogenesis and progression. Our research group has recently demonstrated that piroxicam, a commonly used NSAID and COX-inhibitor, has the capability to potentiate the chemotherapic effects of cisplatin on mesothelioma cells, both in vitro and in vivo 16. This tumor has been infrequently reported in dogs 17 and even more rarely described in cats 18192021222324. Moreover, treatment has been limited to palliation with corticosteroids or repeated drainage of malignant effusion, or intracavitary platinum coumpounds 2425.

A recent study in a mouse model has suggested a potential synergic action between piroxicam and platinum compounds for the treatment of orthotopic mesothelioma xenografts 16.

Privately owned companion animals (two dogs and one cat) with MM were enrolled to receive the combination of platinum compounds and piroxicam.

MM was diagnosed by means of ultrasonographic examination confirmed by histopathologically examination of biopsy specimens.

All the enrolled patients well tolerated the treatment protocol without significant side effects that were limited to 1 episode of hematochezia in a dog and in the cat, requiring one week discontinuation of the piroxicam therapy. All the patients had cavitary effusion at the time of presentation: abdominal centesis lead to the removal of 180 ml of fluid as an average. Grossly, the fluid had a yellowish appearance with pink streaks and with occasional filaments of fibrin, microscopically the sample resulted highly cellular showed mesothelial cells isolated or gathered to form clusters, with coarse cromatin, presence of binucleate cells and nuclei of variable size with prominent and large nucleoli (not shown). Abdominal ultrasonography showed thickening of the abdominal serosal surfaces (not shown). Explorative surgery was performed to perform a tumor debulking in a dog and to collect biopsies in the other patients. Histological examination revealed for the two dogs a mixed mesothelioma while the cat had an epithelioid mesothelioma. In figure 1 the histoligical aspect of the epitheliod mesothelioma of the cat is depicted. One of the two dogs is still disease free after debulking and systemic therapy at 2 years, the other dog and the cat had a reduction of the fluid production by 90% as confirmed by sequential centesis, but developed progressive disease that let to organ strangulation after 8 and 6 months, respectively. Table 1 summarizes the patients' characteristics and follow-up.

As with humans, pets cannot be cured of MM 17. As with humans with down-staged MM at the time of diagnosis, surgical excision can only be rarely performed in pets 17. The only exception to this rule may be pericardial MM, where successful palliation can sometimes be achieved by total or partial pericardiectomy, relieving the hemodynamic problems caused by tamponade 2728. Systemic chemotherapy using mitoxantrone or doxorubicin has been limited to case reports or to small series. Its effectiveness has been limited when used as single modality, while its use as an adjunct to cytoreduction (especially pericardiectomy) has led to reports of prolonged tumour control 293031. Probably the best use of chemotherapy for canine mesothelioma is still confined to palliation for advanced disease by means of intracavitary instillation. This approach is well tolerated and is capable of significantly decrease the amount of fluid released by the mesothelioma, furthermore it seems to induce tumor shrinking for a limited amount of time. A review of the literature showed that, in a small cohort of 6 dogs, treatment with intracavitary cisplatin resulted in survival times approaching one year in 5 patients 25. Unfortunately the low penetration of the drug within the mesothelial layers (2–3 mm in depth) limits its usefulness in case of bulky disease. The use of other drugs such as tetracycline, talk, or bleomycin (Spugnini EP, personal observation) to induce pleurodesis has been unrewarding 3233. Our protocol showed to be highly tolerable by our patients and proved to successfully palliate the malignant effusion secondary to MM in two pets and was capable to induce a long term control in the third. Interestingly, none of the dogs had haematological or gastrointestinal toxicities, in particular vomiting that is one of the limiting factors to the use of cisplatin in dogs. Also the cat tolerated the therapy without side effects.

In conclusion, considering that there are not established chemotherapy protocols for pets with MM, the combination of intracavitary platinum compounds coupled with piroxicam should be further evaluated, also in view of the many similarities shared by canine and feline MM with that of humans. In fact, it has been shown in several research articles that veterinary cancer patients should be considered valuable models for the study of novel approaches such as chemosensitizers, immune modulators, imaging studies and new delivery systems for loco-regional therapy 34. However, results should be evaluated with caution since it's likely that MM has a more benign biological course in dogs than it does in people and this has to be considered in evaluating uncontrolled case reports of 1 year survival in the dog.

EPS performed the experiments and wrote the paper together with AB. SC, AS and GC participated in the design of the study and performed the histological staining. GC conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.