Antonio Giordano Resti

Regression of Ocular Adnexal Lymphoma After Chlamydia Psittaci–Eradicating Antibiotic Therapy

PURPOSE Some infectious agents contributing to lymphomagenesis have been considered targets for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of ocular adnexal lymphomas. The present pilot study was carried out to assess whether C psittaci-eradicating antibiotic therapy is associated with tumor regression in ocular adnexal lymphomas. PATIENTS AND METHODS Nine patients with C psittaci-positive marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up. RESULTS All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four positive patients. Objective response was complete in two patients, partial response (> 50%) was observed in two patients, and minimal response (< 50%) was observed in three patients. Duration of response in the seven responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively. CONCLUSION C psittaci-eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas.

Chlamydophila Psittaci Eradication With Doxycycline As First-Line Targeted Therapy for Ocular Adnexae Lymphoma: Final Results of an International Phase II Trial

PURPOSE The pathogenic association between Chlamydophila psittaci (Cp) and ocular adnexal marginal zone lymphoma (OAMZL) and the efficacy of doxycycline monotherapy have been investigated in retrospective series with variations in stage, management, and follow-up duration. To our knowledge, this is the first international phase II trial aimed at clarifying Cp prevalence and activity of first-line doxycycline in a homogeneous series of consecutive patients with newly diagnosed stage I OAMZL. PATIENTS AND METHODS Forty-seven patients were registered. Tumor tissue, conjunctival swabs, and peripheral blood from 44 patients were assessed for seven Chlamydiaceae infections by three polymerase chain reaction protocols. Thirty-four patients with measurable or parametrable disease were treated with doxycycline and assessed for chlamydial eradication and lymphoma response (primary end point). RESULTS Cp DNA was detected in biopsies of 39 patients (89%); no other Chlamydiaceae were detected. Twenty-nine patients had Cp DNA in baseline swabs and/or blood samples and were evaluable for chlamydial eradication, which was achieved in 14 patients (48%). Lymphoma regression was complete in six patients and partial in 16 (overall response rate, 65%; 95% CI, 49% to 81%); 11 had stable disease, and one had progressive disease. At a median follow-up of 37 months (range, 15 to 62 months), 20 patients remained relapse free (5-year progression-free survival [PFS] ± standard deviation, 55% ± 9%). Cp eradication was associated with improved response rate (86% v 47%; P = .02) and 5-year PFS (68% v 47%; P = .11). CONCLUSION Upfront doxycycline is a rational and active treatment for patients with stage I Cp-positive OAMZL. Lymphoma regression is consequent to Cp eradication, which can easily be monitored on conjunctival and blood samples. Prospective trials aimed at identifying more effective administration schedules for doxycycline are warranted.

Ocular Adnexal Lymphoma: Diffusion-weighted MR Imaging for Differential Diagnosis and Therapeutic Monitoring

PURPOSE To describe the magnetic resonance (MR) imaging and diffusion-weighted (DW) imaging features of ocular adnexal lymphomas (OALs), to determine the diagnostic accuracy of apparent diffusion coefficient (ADC) for discriminating OALs from other orbital mass lesions, and to assess whether variations in ADC constitute a reliable biomarker of OAL response to therapy. MATERIALS AND METHODS Institutional ethical committee approval and informed consent were obtained. In this prospective study, 114 white subjects (65 females and 49 males) were enrolled. Thirty-eight patients with histopathologically proved OAL underwent serial MR and DW imaging examination of the orbits. ADCs of OALs were compared with those of normal orbital structures, obtained in 18 healthy volunteers, and other orbital mass lesions, prospectively acquired in 58 patients (20 primary non-OAL neoplasms, 15 vascular benign lesions, 12 inflammatory lesions, 11 metastases). Interval change in ADC of OALs before and after treatment was analyzed in 29 patients. Analysis of covariance and a paired t test were used for statistical analysis. RESULTS Baseline ADCs in OALs were lower than those in normal structures and other orbital diseases (P < .001). An ADC threshold of 775 x 10(-6) mm(2)/sec resulted in 96% sensitivity, 93% specificity, 88% positive predictive value, 98.2% negative predictive value, and 94.4% accuracy in OAL diagnosis. Following appropriate treatment, 10 (34%) of 29 patients showed OAL volumetric reduction, accompanied (n = 7) or preceded (n = 3) by an increase in ADC (P = .005). Conversely, a further reduction of ADC was observed in the seven patients who experienced disease progression (P < .05). CONCLUSION ADC permits accurate diagnosis of OALs. Interval change in ADC after therapy represents a helpful tool for predicting therapeutic response.

Six-month oral clarithromycin regimen is safe and active in extranodal marginal zone B-cell lymphomas: final results of a single-centre phase II trial.

Antibiotics could be included in the long list of anticancer candidates by virtue of their good tolerability and direct proapoptotic effect on tumour cells. This effect is achieved by means of multiple antiproliferative mechanisms that deserve to be better explored. Among others, macrolides have been proposed as potential antineoplastic and immunomodulatory agents. They enhance the antitumour activity of macrophages, natural killerand CD8 cytotoxic T-cells, reduce neutrophil production of interleukin-8, and inhibit tumour necrosis factor-a and vascular endothelial growth factor activity (Aoki et al, 2005). Clarithromycin is a substrate of P-glycoprotein, induces apoptotic changes in tumour cells and exhibits antitumour activity in different murine cancer models (Wakasugi et al, 1998; Hamada et al, 2000). These preclinical data constitute the rationale for prospective clinical trials addressing the antineoplastic activity of macrolides. In particular, the combination of clarithromycin with other immunomodulatory agents has been associated with encouraging results in prospective trials on multiple myeloma and Waldenström macroglobulinemia (Niesvizky et al, 2008). Additionally, anecdotal case reports suggest an antineoplastic effect of clarithromycin in patients with marginal zone B-cell lymphoma (MZL) of the gastrointestinal tract (Arima & Tsudo, 2003; Matsumoto & Iida, 2005). Given its indolent behaviour, extranodal MZL (EMZL) is a suitable candidate to test the potential direct anticancer effect of macrolides. On this basis, we designed a pilot phase II trial to address the feasibility and activity of a 6-month oral clarithromycin regimen as exclusive treatment in patients with relapsed/refractory EMZL. The trial conformed to the tenets of the Declaration of Helsinki, and was approved by the Institutional Review Board of the San Raffaele Scientific Institute. From June 2006 to May 2008, 13 patients (median age 57 years, range 36–80 years; seven males) with relapsed/ refractory EMZL, Eastern Cooperative Oncology Group (ECOG) performance status (PS) £3 and at least one measurable or parametrable lesion were registered. Baseline assessment included physical examination, haemogram and biochemical profile, human immunodeficiency virus, hepatitis C virus (HCV) and hepatitis B virus serology, total body computed tomography scan, gastroscopy, and bone marrow biopsy. All patients were tested for Helicobacter pylori (Hp)

Chlamydophila psittaci is viable and infectious in the conjunctiva and peripheral blood of patients with ocular adnexal lymphoma: Results of a single‐center prospective case–control study

Ocular adnexal MALT lymphoma (OAML) is linked to Chlamydophila psittaci (Cp) infection. Viability and infectivity of Cp, demonstrated by growth in culture, has not been yet investigated in these patients. We conducted a single‐center prospective case–control study to assess the prevalence, viability and infectivity of Cp in 20 OAML patients and 42 blood donors registered in a 6‐month period. The presence of Cp in conjunctival swabs and peripheral blood mononuclear cells (PBMC) of patients and donors was assessed by TETR‐PCR and in vitro cultures. From an epidemiological point of view, OAML patients often resided in rural areas, and reported a history of chronic conjunctivitis and prolonged contact with household animals (85% vs. 38% of donors; p = 0.00001). Cp was detected in lymphoma tissue in 15 (75%) patients. Cp DNA was detected in conjunctival swabs and/or PBMC from 10 (50%) patients and in PBMC from 1 (2%) donor (p = 0.01). Viability and infectivity of Cp, demonstrated by growth in culture, were confirmed in conjunctival swabs and/or PBMC from 5 (25%) patients, but not in donors (p = 0.002). This prospective study demonstrates, for the first time, that Cp present in the conjunctiva and PBMC of OAML patients is capable to grow and be isolated in cell cultures. Cp infection is common in OAML patients and exceptional in blood donors. Epidemiological data of OAML patients (prolonged contact with household animals and chronic conjunctivitis) are consistent with Cp exposure risk.

A Reappraisal of the Diagnostic and Therapeutic Management of Uncommon Histologies of Primary Ocular Adnexal Lymphoma

Lymphoma is the most common malignancy arising in the ocular adnexa, which includes conjunctiva, lachrymal gland, lachrymal sac, eyelids, orbit soft tissue, and extraocular muscles. Ocular adnexal lymphoma (OAL) accounts for 1%-2% of non-Hodgkin lymphoma and 5%-15% of extranodal lymphoma. Histology, stage, and primary localizations are the most important variables influencing the natural history and therapeutic outcome of these malignancies. Among the various lymphoma variants that could arise in the ocular adnexa, marginal zone B-cell lymphoma (OA-MZL) is the most common one. Other types of lymphoma arise much more rarely in these anatomical sites; follicular lymphoma is the second most frequent histology, followed by diffuse large B-cell lymphoma and mantle cell lymphoma. Additional lymphoma entities, like T-cell/natural killer cell lymphomas and Burkitt lymphoma, only occasionally involve orbital structures. Because they are so rare, related literature mostly consists of anecdotal cases included within series focused on OA-MZL and sporadic case reports. This bias hampers a global approach to clinical and molecular properties of these types of lymphoma, with a low level of evidence supporting therapeutic options. This review covers the prevalence, clinical presentation, behavior, and histological and molecular features of uncommon forms of primary OAL and provides practical recommendations for therapeutic management.

Inflammatory myofibroblastic tumor of the conjunctiva: Response to chemotherapy with low-dose methotrexate and vinorelbine†

Inflammatory myofibroblastic tumor (IMT) is an unusual entity that mainly affects children and young adults, and for which standardized therapies for inoperable cases are still lacking. We report on a 12‐year‐old patient with an extremely rare and inoperable conjunctival location that was treated with chemotherapy using low‐dose methotrexate plus vinorelbine, achieving complete tumor remission. This regimen is usually well tolerated and may be considered as the treatment of choice for cases of unresectable advanced IMT. Pediatr Blood Cancer 2010;54:483–485.

Therapeutic management of ocular adnexal MALT lymphoma.

Non-Hodgkin lymphomas constitute 50% of all orbital malignancies. Mucosa-associated lymphoid tissue (MALT)-type lymphoma is the most common histology category in this anatomic region. Ocular adnexal lymphoma of MALT-type is an indolent and rarely lethal malignancy that can often be managed with observation alone. Occasionally, lymphomatous lesions determine the symptoms that condition a patient’s quality of life, and so require an immediate antineoplastic treatment. Several strategies are available, but reliable indications supported by prospective trials do not exist. Some therapeutic strategies are associated with substantial side effects and require a well-balanced therapeutic decision, which should take into account several variables related to the patient, the lymphoma, and the treatment itself. In this review, the authors analyze related literature and propose therapeutic guidelines for the management of ocular adnexal lymphoma of MALT-type.

Outcome of 110 Basal Cell Carcinomas of the Eyelid Treated with Frozen Section–Controlled Excision: Mean Follow-up over 5 Years:

Purpose To analyze the outcome and risk factors of recurrence in patients with basal cell carcinomas (BCCs) of the eyelid treated by en face frozen section–controlled (FSC) excision with a mean follow-up over 5 years. Methods This was a retrospective series of 108 patients with 110 biopsy-proven eyelid BCCs. All lesions were excised with 2 mm margins clinically free from neoplasia at clinical examination. For each tumor, en face frozen section examination of surgical margins was employed for the histologic confirmation before the reconstruction. Subsequently, all margins were submitted for permanent paraffin sections. Results Of 110 malignancies, 80.9% represented primary carcinomas and 19.1% secondary ones. The overall recurrence rate was 1.8%, with a mean follow-up of 72.4 months (range 30–167). The mean time between the excision of the lesion and the diagnosis of the recurrence was 24 months (range 20–28). No recurrences were observed in 62 tumors followed up for at least 5 years. Secondary BCCs were associated with a higher recurrence rate compared with primary BCCs (4.8% and 1.1%, respectively, p = 0.262). Conclusions The FSC excision of eyelid BCCs yields recurrence rates comparable to those of Mohs micrographic surgery at 5-year follow-up. Intraoperative microscopic margin control improves the cure rate of eyelid BCCs, and FSC excision with small margins (2 mm) clinically free from neoplasia is associated with easier reconstruction and better cosmetic and functional outcomes.

Marginal zone B-cell lymphoma of the conjunctiva

Lymphomas are the most common orbital malignancies, marginal zone B-cell lymphoma being the most common histotype. One quarter of these lymphomas exhibit conjunctival involvement, which is almost exclusively observed in indolent lymphomas (96% of conjunctival lymphomas). Primary conjunctival marginal zone B-cell lymphoma exhibits interesting and peculiar features, with some molecular, biological, clinical and prognostic differences from the rest of the ocular adnexal lymphomas. Recent studies demonstrate that chromosomal abnormalities, autoimmune disorders and infectious agents are variably associated with the development and behavior of this lymphoma. Conjunctival lymphomas are rarely lethal tumors and, in selected cases, may be managed without anti-tumor treatment. In other cases, conjunctival lymphomas cause symptoms that require immediate treatment. To date, no guidelines for the management of patients with conjunctival lymphoma exist. Surgical resection, radiotherapy and chemotherapy are the most common approaches to these malignancies, but the use of systemic immunotherapy, bacteria-eradicating antibiotic therapy and local treatments, such as intralesional injections of interferon or rituximab and eyedrops of cytostatics, is progressively growing.