A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer.

BACKGROUND: We hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC) or urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally two times daily. The primary endpoint was objective response rate (ORR). Immunohistochemistry was used to assess programmed death-ligand 1 (PD-L1) expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was assessed by whole-exome sequencing. RESULTS: A total of 61 patients were enrolled and treated (NSCLC, n = 41; UC, n = 20); 5 remained on treatment at data cut-off (26 February 2021). The confirmed ORR was 31.7% in the NSCLC cohort and 10.0% in the UC cohort (all partial responses). Antitumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (≥median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (

Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma.

BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort. RESULTS: Of 27 patients treated, 20 patients had received ≥ 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade ≤ 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus. CONCLUSIONS: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC.

Chronic bacterial inflammation induces prostatic intraepithelial neoplasia in mouse prostate.

BACKGROUND: Although the aetiology of prostate cancer remains unknown, we hypothesised that chronic bacterial insult has a major role in prostate carcinogenesis. METHODS: Male C3H/HeOuJ mice, infected with phosphate-buffered saline or Escherichia coli bacteria, were killed at 5 days, or at 12 or 26 weeks. Harvested prostate tissues were evaluated for inflammatory responses and immunostained for neoplastic transformation markers. RESULTS: All infected mice developed bacterial prostatitis. Control mice had no prostate infections or inflammation. Mice infected for 5 days showed foci of acute inflammation with infiltrating neutrophils and epithelial necrotic debris in the prostatic glandular lumen. All mice infected for 12 weeks had evidence of chronic inflammation with dense inflammatory infiltrates in the stroma. The prostatic epithelium showed varying degrees of atypical hyperplasia with increased epithelial cell layers and cytological atypia. At 26 weeks, the dysplastic changes were more pronounced and mimicked a prostatic intraepithelial neoplasia and high-grade dysplasia. Prostatic glands exhibiting reactive dysplasia had a stronger staining for oxidative DNA damage, increased epithelial cell proliferation, and a decrease in androgen receptor, GSTP1, p27(Kip1), and PTEN expression, when compared with control prostate glands. CONCLUSION: These data demonstrate that chronic inflammation induces focal prostatic glandular atypia and suggest a potential linkage between inflammation and prostatic neoplasia.

New onset of heterophilic antibody interference in prostate-specific antigen measurement occurring during the period of post-prostatectomy prostate-specific antigen monitoring.

Laboratories evaluated whether an interference was causing a false-positive PSA for the Immulite 2000 immunoassay after a time course of increasing prostate-specific antigen (PSA) in a post-prostatectomy patient led to salvage therapy, which had no effect on the elevated PSA. Serial dilutions of PSA for the patient sample (6.1 ng/mL; post-prostatectomy reference range: <0.1 ng/mL [undetectable]) were linear (r > 0.99). However, the PSA measurement was reduced to 0.1 ng/mL after pretreatment of the sample with heterophilic antibody blocking reagent. PSA was undetectable (<0.1 ng/mL) when measured using two alternative immunoassays. These results were consistent with the presence of heterophilic antibody interference for the Immulite 2000 assay. In this case, heterophilic antibody interference with PSA measurement must have originated during the period of post-prostatectomy monitoring, and the apparent progressive increases in PSA may have been due solely to the progressive increase of this heterophilic antibody assay interference. In the absence of clinical correlation, positive PSA monitoring results should always be assessed for heterophilic antibody interference for at least one time point.

Treatment of non-Hodgkin lymphoma.

Preliminary results of new therapies in the areas of cytotoxic agents and immunotherapy for advanced indolent lymphomas have been encouraging. Long-term follow-up on high-dose therapy suggests a potential role for this modality in this group of lymphomas. In aggressive lymphomas, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) continues to hold ground as first-line therapy when compared against other regimens. Several studies reinforce past findings that patients with chemosensitive relapse are better candidates for high-dose therapy. In relapsed or refractory disease, selected compounds appear to have activity as single agents and others have shown activity in combination therapy. Despite high treatment-related mortality rates, allogeneic transplantation in relapsed aggressive lymphoma warrants further investigation. Last, as patients are surviving longer, complications of therapy are having to be addressed.

A new approach to non-Hodgkin's lymphoma.

The incidence of non-Hodgkin's lymphomas continues to rise and the number of deaths attributable to these malignancies currently rank in the top five causes of cancer-related deaths in the United States. Recent insights into the pathogenesis and molecular characterization of these disorders have led to improvements in a clinicopathologically relevant classification system, as well as in the ability to accurately diagnose specific entities. Several new treatment modalities have been developed which may improve the outcome for selected patients. A better understanding of the biology of non-Hodgkin's lymphomas will hopefully translate into different therapies with improved outcomes. This article describes a new system for classifying the non-Hodgkin's lymphomas, highlights key aspects of the pathogenesis of non-Hodgkin's lymphomas and briefly reviews clinical and therapeutic approaches to the most common of these lymphomas.

Epstein-Barr virus-associated lymphoproliferative disorder after autologous bone marrow transplantation: report of two cases.

Epstein-Barr virus-associated lymphoproliferative disorders have been frequently reported as a complication of solid organ and allogeneic bone marrow transplantation. Their occurrence is rare after autologous bone marrow transplantation (BMT) with only five published reports in the literature. We report two cases of post-transplant lymphoproliferative disorder occurring after autologous BMT for Hodgkin's disease and non-Hodgkin's lymphoma. Post-transplant lymphoproliferative disorders can occur after autologous BMT and should be included in the differential diagnosis of patients with persistent fever, adenopathy or pulmonary infiltrates.

Molecular epidemiology of deletions and mutations of the latent membrane protein 1 oncogene of the Epstein-Barr virus in posttransplant lymphoproliferative disorders.

Latent membrane protein 1 (LMP1) is a protooncogene of the Epstein-Barr virus (EBV) that is expressed in most EBV-positive posttransplant lymphoproliferative disorders (PTLD). Small deletions in the carboxy-terminal domain of LMP1 have been recently described in Hodgkin's disease, nasopharyngeal carcinoma, and non-Hodgkin's lymphoma. We characterized the deletions and point mutations of LMP1 in 32 PTLD and 8 reactive lymphoid cases found to contain EBV by one or more methods, including LMP1 immunohistochemistry, EBV-encoded RNA in situ hybridization, LMP1 DNA amplification, or Southern blot analysis. Our goal was to study the relationship of LMP1 deletions and mutations with the PTLD morphology, clonality, EBV strain subtype, and survival of patients. We found a 30-bp deletion (Del-LMP1) in 13 of 32 (41%) PTLD cases and a similar incidence of Del-LMP1 and point mutations in 3 of 8 (38%) reactive EBV cases (rho = 0.87). The presence of the Del-LMP1 in the PTLD cases was not highly associated with a high-grade morphology or clonal immunoglobulin gene rearrangements compared with the wild-type LMP1. We found that 100% of B-strain isolates, compared with 30% of A-strain isolates, harbored the Del-LMP1. There was no significant difference in the survival of PTLD patients with or without Del-LMP1 (rho = 0.83). We conclude that the incidence of Del-LMP1 in PTLD may be reflective of the incidence of this EBV substrain in the regional population and that the Del-LMP1 sequence has no prognostic significance in PTLD.

Central nervous system Hodgkin's disease relapsing with eosinophilic pleocytosis.

Hodgkin's disease affecting the central nervous system is infrequent. Multiple lumbar punctures are sometimes required for cytological diagnosis. In this case fluoroscopy-guided cisternal puncture and routine lumbar punctures were used to obtain cerebrospinal fluid (CSF) samples for cytological analysis. Reed-Sternberg cells were observed on the CSF sample obtained through the cisternal puncture while none were seen in the samples obtained with routine lumbar punctures. Without cytology, the diagnosis of meningeal carcinomatosis remains elusive. In conclusion, cisternal punctures should be entertained early in the evaluation for meningeal carcinomatosis, particularly if lumbar punctures have been unsuccessful.

Hodgkin's disease following solid organ transplantation.

BACKGROUND: The incidence of second malignancies is markedly increased following transplantation of solid organs. However, the development of Hodgkin's disease has been described relatively infrequently in this setting, and there is little clinical information on these patients and few details on management. PATIENTS AND METHODS: We have reviewed the pathologic specimens and clinical history of four patients who developed Hodgkin's disease following transplantation of solid organs. RESULTS: Hodgkin's disease appeared 26-68 months following transplantation of the kidney (2 cases), liver, and heart. Three cases demonstrated evidence of Epstein-Barr virus (EBV) in Reed-Sternberg cells. One case appears to have arisen after a previous EBV-driven polymorphous lymphoproliferation. Hodgkin's disease was localized in three cases and disseminated in one. All patients achieved remission with standard therapy and continue in remission between 9 and 61 months after therapy. Graft function was preserved in all patients. CONCLUSION: Hodgkin's disease occurring in the post-transplantation period should probably be treated like Hodgkin's disease in non-immunosuppressed patients. Prolonged disease-free survival is possible and function of the transplanted organ can be preserved.