A phase II study of pazopanib as front-line therapy in patients with non-resectable or metastatic soft-tissue sarcomas who are not candidates for chemotherapy

Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA-approved for metastatic soft-tissue sarcomas (STSs) after the first line. We proposed a phase II study evaluating pazopanib as a first-line agent in patients with advanced disease who are deemed not to be candidates for chemotherapy. Eligible patients were at least 18 years old, not candidates for chemotherapy and were treatment naive. Pazopanib was titrated from 200 mg twice daily to a goal of 800 mg daily. The primary end point was the clinical benefit rate (CBR) (CBR = completed response + partial response + stable disease per Response Evaluation Criteria in Solid Tumours [RECIST 1.1]) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesised CBR of ò35% against an unfavourable CBR of ó20%. If ò 17 patients achieved benefit, the null CBR of 20% would be rejected at a nominal 5% alpha level. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life and serum biomarkers. Fifty-six patients were enrolled from May 2015 to February 2019 and are included in the intention-to-treat analysis. Median PFS was 3.67 (2.62-7.25) months. Median OS was 14.16 (95% confidence interval [CI]: 8.4-NR) months, CBR = 39.29% (22/56) (CI = 0.265-0.533, p = 0.0007). No new or unexpected adverse events were seen. The most common grade I-II events were diarrhea, nausea and fatigue. The most common grade III-IV events were hypertension and liver function test abnormalities. These data suggest that there is a benefit to front-line pazopanib in patients with STSs who are not candidates for cytotoxic chemotherapy.

The guideline committee for clinical care of extra-abdominal desmoid-type fibromatosis in Japan conducted a systematic review of treatment with doxorubicin-based chemotherapy for desmoid-type fibromatosis. We searched the pertinent literature. Two reviewers evaluated and screened it independently for eligibility and extracted data. They rated each report according to the grading of recommendations development and evaluation methodology. Based on the ‘body of evidence’, which the reviewers created, the clinical guideline committee decided a recommendation for the clinical question, ‘Is doxorubicin-based chemotherapy effective for patients with extra-abdominal desmoid-type fibromatosis? Fifty-three articles were extracted by the literature search, and one from hand search. After the first and second screenings, five articles were subjected to the final evaluation. There were no randomized controlled trials. According to response evaluation criteria in solid tumors criteria, the response rates of doxorubicin-based regimens and liposomal doxorubicin were 44% (28.6-54) and 33.3% (0-75) on average, respectively. In two reports, the response rates of doxorubicin-based regimens were higher than those of non-doxorubicin-based ones; 54% vs 12%, 40% vs 11%, respectively. The rates of G3 or G4 complications according to common terminology criteria for adverse events were 28% and 13% with doxorubicin-based and liposomal doxorubicin chemotherapy, respectively, including neutropenia or cardiac dysfunction. None of the reports addressed the issue of QOL. Although the evidence level was low in the evaluated studies, doxorubicin-based and liposomal doxorubicin chemotherapy was observed to be effective. However, doxorubicin-based chemotherapy is associated with non-ignorable adverse events, and is not covered by insurance in Japan. We weakly recommend doxorubicin-based chemotherapy for patients with extra-abdominal desmoid-type fibromatosis in cases resistant to other treatments.

Implant-based breast reconstruction forms the main modality of breast reconstruction in patients with breast cancer. Implant-related anaplastic large cell lymphoma has been reported over the last decade and is a well-recognised entity now. An understanding of the diagnosis and management of implant-related fibromatosis is consequentially imperative for early management. In the present report, we describe an unusual case of implant-related fibromatosis in a 52-year-old woman.

The aim of our study was to assess the clinicoepidemiological profile, prognostic factors, and treatment outcome of desmoid tumors. A monocentric retrospective study was conducted over a period of 19 years between February 2000 and November 2019 at the oncology department of Salah Azaiz Institute. Our study concerns 30 patients with desmoid tumor. All data regarding patients were obtained from the medical record. Thirty patients were included. The median age was 35 years with a female predominance (sex ratio = 0.07). A palpable mass was the most common complaint (n = 27). Median tumor size was 5 cm. The principal site of involvement was the abdominal wall (n = 14). Surgery was performed in 27 patients. The histopathology reports listed 14 (52%) cases with negative margins and 13 (48%) cases with positive margins. Radiation therapy was performed in 2 patients. One patient received tamoxifen. Local recurrence occurred in 11 patients. Two patients died of their desmoid tumor. Abdominal wall tumors have less risk of recurrence compared with other sites (p=0.047). Macroscopic margin involvement (R2) was the only prognostic factor influencing disease-free-survival (p=0.034). Desmoid tumors are aggressive tumors with a tendency for local recurrence. Abdominal wall tumors have less risk of recurrence. Macroscopic margin involvement was the only prognostic factor that affects disease-free-survival.

Our case study is a 40-year-old male with a concomitant diagnosis of non-Hodgkin lymphoma and mesenteric fibromatosis, not associated with any of the risk factors mentioned above. We performed CT and PET scans and observed a vascularised and well-defined mesenteric centre-abdominal hypermetabolic solid mass in contact with the gastric body, duodenum, body and tail of the pancreas, transverse colon, and spleen. An ultrasound-guided tru-cut biopsy revealed features suggestive of mesenteric fibromatosis. An elective laparotomy was carried out and a giant mass, arising from mesentery, was excised, including a partial gastrectomy and segmental resection of the transverse colon. Distal pancreatectomy, small bowel resection and successive splenectomy were performed due to a large hypertensive component. The postoperative period was uneventful. The histopathology of the surgical pieces was compatible with intra-abdominal desmoid fibromatosis. As far as we know from the literature, this is the largest mesenteric fibromatosis tumour ever to be excised. We also noticed that this is the first reported case of the concomitant presence of mesenteric fibromatosis and non-Hodgkin lymphoma that is not related to any of the described risk factors.

Wnt/beta-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with beta-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of beta-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in beta-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the beta-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in beta-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/beta-catenin signaling induced by this mutation.