Dennis L. Cooper

Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma.

This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 microg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 x 10(6) CD34(+) cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 x 10(6) CD34(+) cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34(+) cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.

Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases.

PURPOSE To determine the clinicopathologic features of lymphoproliferative disorders (LPD) that occur in the setting of methotrexate (MTX) therapy for rheumatic diseases (RD) and to define the relationship between the presence of Epstein-Barr virus (EBV) in tumor cells and the response of LPD to MTX withdrawal. PATIENTS AND METHODS In addition to nine new cases, we analyzed 28 cases previously reported in the literature of LPD in patients receiving MTX for RD. In addition to MTX, immunosuppressive therapy included corticosteroids in 19 patients, azathioprine in three, and cyclosporine in one. Extranodal disease was identified in 16 patients, but none had CNS involvement. Pathologic findings included five cases of Hodgkins disease and seven low-grade lymphomas. The remaining patients had intermediate or aggressive lymphomas. In situ hybridization studies (ISHS) for EBV-RNA transcripts were positive in 12 of 27 patients (44%). RESULTS Among 37 patients, 16 were initially observed after MTX withdrawal without additional antitumor therapy. Six achieved a spontaneous complete remission (CR), three had a partial response (PR), one had a minimal response, and six had no response to MTX withdrawal. Of 10 responding patients, EBV was detected by ISHS (n = 6) or polymerase chain reaction (PCR) (n = 2); one patient had a CR despite the absence of EBV by PCR and one had a CR but did not have viral assays performed. Only one of six patients with negative EBV by ISHS or PCR responded to MTX withdrawal. CONCLUSION MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Responses were consistently observed, but not limited to patients in whom EBV was detected by ISHS or PCR. Further studies are required to confirm these findings and to evaluate the role for EBV in LPD that occur in patients receiving MTX.

Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study

Phase II study of Herceptin (Trastuzumab) in patients with advanced salivary gland tumors overexpressing Her2/neu. Patients with advanced, incurable salivary gland tumors and 2(+) or 3(+) Her2/neu expression in their tumors were enrolled in the study. After an initial dose of 4 mg/kg, patients received 2 mg/kg weekly. Patients were treated until they experienced progression of disease or unacceptable toxicity. The study was closed early when it has become clear that the majority of tumors screened did not overexpress Her2/neu. Fourteen patients were enrolled in the study. A total of 86 cycles of Herceptin were delivered with a median of three cycles per patient (range 1-40). Median time to progression was 4.2 months. One patient with metastatic mucoepidermoid carcinoma has received 40 cycles of Herceptin to date with a documented partial response. Herceptin given as a single agent has a low activity in salivary gland tumors overexpressing Her2/neu. New agents are still needed.

Bazex Syndrome (Acrokeratosis paraneoplastica) An analytic review

Bazex syndrome (acrokeratosis paraneoplastica) is characterized by a psoriasiform eruption that favors acral sites and has been associated with an underlying malignancy in all reported cases. Of the 93 patients in this series, 89 were male with a mean age of 60 +/- 8.5 years. Squamous cell carcinomas of the head and neck and squamous cell tumors of unknown primary with cervical lymph node metastases were the most commonly associated neoplasms, suggesting that the factor(s) responsible for the development of the syndrome are relatively specific for tumors of the upper aerodigestive tract. The cutaneous lesions were erythematous to violaceous in color and had associated scale; the most frequently observed sites of involvement were the ears, nose, hands, and feet, including the nails. In 63% of the cases, the cutaneous lesions preceded the initial symptoms or diagnosis of the tumor by an average of 11 months (range, 1-72) and, in general, the eruption was resistant to a variety of topical treatments. Occasionally, a reappearance of the papulosquamous lesions signaled the recurrence of the tumor (6 cases) or the appearance of skin lesions coincided with the development of metastatic disease (3 cases). In 91% (64/70) of the patients, the skin eruption either improved significantly following treatment of the underlying malignancy or did not improve in the setting of persistent tumor. However, even when all of the skin lesions cleared, the nail dystrophy often persisted. Fifteen of the patients developed vesicles, bullae, and crusts in addition to papulosquamous lesions. Possible explanations include the formation of an epidermal-dermal split via a bullous lichen planus-like mechanism, or the coexistence of two diseases; i.e., acrokeratosis paraneoplastica plus either porphyria cutanea tarda, bullous pemphigoid, or epidermolysis bullosa acquisita. One possible explanation for the development of the characteristic cutaneous eruption is an immune reaction, humoral or cellular, directed against a common antigen present on the tumor and the normal skin. Alternatively, tumor production of a keratinocyte growth factor such as TGF-alpha may be involved in the induction of the psoriasiform skin lesions.

Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy

Pain from oral mucositis afflicts from 40% to 70% of patients receiving chemotherapy or radiation therapy. Current methods of clinical pain management (for example, topical anesthetics, systemic analgesics) have limited success. In a pilot study, we examined the ability of oral capsaicin to provide temporary relief of oral mucositis pain. Capsaicin, the active ingredient in chili peppers, desensitizes some neurons and has provided moderate pain relief when applied to the skin surface. Oral capsaicin in a candy (taffy) vehicle produced substantial pain reduction in 11 patients with oral mucositis pain from cancer therapy. However, this pain relief was not complete for most patients and was only temporary. Additional research is needed to fully utilize the properties of capsaicin desensitization and thus optimize analgesia.

Second solid tumors in patients with Hodgkin's disease cured after radiation or chemotherapy plus adjuvant low-dose radiation.

PURPOSE Late solid tumors (STs) are a significant cause of morbidity and mortality in long-term survivors of Hodgkins disease. To investigate the carcinogenic potential of two different therapeutic approaches, we measured the relative risk (RR) of STs in patients with early-stage disease cured after primary full-dose (approximately 40 Gy) radiation therapy (RT) and in patients with advanced disease who were treated with chemotherapy followed by low-dose (15 to 30 Gy) involved-field radiation (CMT). PATIENTS AND METHODS Because therapy-induced STs generally begin after a latency period of 5 to 10 years, we restricted our analysis to patients treated before 1986 who achieved durable remissions. Patients who required salvage chemotherapy or who died of Hodgkins disease were excluded from analysis. The RR of STs was calculated by dividing the observed number of cases by the expected number in a matched population from the Connecticut Tumor Registry. The actuarial incidence of STs was also measured. RESULTS A total of 197 patients formed the RT group and 116 the CMT group. The median follow-up period in the RT group was 12.8 years, versus 13.5 years in the CMT group. The overall RR of STs in the CMT group was 1.5 (95% confidence interval [CI], 0.6 to 3.5; P = .122). There were no cases of lung or breast cancer. In the RT group, the overall RR of STs was 3.3 (95% CI, 2.0 to 5.3; P < .001). There were seven cases of lung cancer (RR = 10.8; 95% CI, 5.3 to 22.2; P < .001) and two cases of breast cancer (RR = 2; 95% CI, 0.6 to 7.4; P = .07). All six benign tumors occurred in the RT group. CONCLUSION In patients cured by initial treatment for Hodgkins disease, RT was associated with a statistically significant increase in STs, particularly lung cancer. CMT was not associated with a significant increase in STs. These data may have important implications for the design of newer therapies for early-stage Hodgkins disease.

Cisplatin, Fluorouracil, and Leucovorin Induction Chemotherapy Followed by Concurrent Cisplatin Chemoradiotherapy for Organ Preservation and Cure in Patients With Advanced Head and Neck Cancer: Long-Term Follow-Up

PURPOSE The poor functional outcome in patients with advanced head and neck squamous cell carcinoma (HNSCC) with surgery and radiation has led to alternative approaches to advanced disease. We conducted a phase II study of induction chemotherapy followed by concurrent chemoradiotherapy for organ preservation in patients with advanced resectable and unresectable (nasopharyngeal) tumors. PATIENTS AND METHODS Forty-two patients with stage III to IV resectable HNSCC and nasopharyngeal tumors received induction chemotherapy with two courses of cisplatin (20 mg/m2/d continuous infusion [CI]), fluorouracil (800 mg/m2/d CI), and leucovorin (500 mg/m2/d CI; PFL) for 4 days followed by concurrent therapy with cisplatin (100 mg/m2/d on days 1 and 22) and approximately 70 Gy of external-beam radiotherapy. RESULTS Response to induction chemotherapy included partial response rate of 52% and complete response rate of 24%. The most common grade 3 or 4 toxicity was neutropenia (59%). After cisplatin chemoradiotherapy the complete response rate was 67%. Toxicities of cisplatin chemoradiotherapy consisted of grade 3 or 4 mucositis (79%) and neutropenia (51%). At a median follow-up of 71.5 months, 43% of the patients are still alive and disease-free. The 5-year progression-free survival (PFS) rate was 60%, and the 2- and 5-year overall survival (OS) rates were 67% and 52%, respectively. Three patients died of second primaries. Late complications of treatment included xerostomia and hoarseness. One patient had persistent dysphagia and required laser epiglotectomy 108 months after treatment. CONCLUSION Induction chemotherapy with PFL followed by concurrent cisplatin chemoradiotherapy is well tolerated and results in a good likelihood of organ preservation and excellent PFS and OS.

Primary Cutaneous B-Cell Lymphoma Treated With Radiotherapy: A Comparison of the European Organization for Research and Treatment of Cancer and the WHO Classification Systems

PURPOSE To determine the relationship between the WHO and European Organization for Research and Treatment of Cancer (EORTC) pathologic classifications for primary cutaneous B-cell lymphoma (CBCL) and the implication of this relationship on initial treatment. PATIENTS AND METHODS Patients with primary CBCL treated with radiotherapy were identified retrospectively. Initial biopsy specimens were reviewed by two dermatopathologists and classified according to the EORTC and WHO systems. Primary outcomes were recurrence-free and overall survival. RESULTS Thirty-four patients were identified; initial biopsy specimens were adequate for classification in 32 patients. Four different composite histopathologic subtypes of lymphoma were identified: 53% (17 of 32) follicle center cell by EORTC and diffuse large B-cell by WHO (FCC/DLB), 25% (eight of 32) follicle center cell by EORTC and follicular by WHO (FCC/Fol), 13% (four of 32) marginal zone by EORTC and WHO (MZ/MZ), and 9% (three of 32) large B-cell of the leg by EORTC and diffuse large B-cell by WHO (Leg/DLB). Five-year relapse-free survival ranged from 62% to 73% for FCC/DLB, FCC/Fol, and MZ/MZ but was 33% for Leg/DLB (P =.6). Five-year overall survival was 100% for FCC/DLB, FCC/Fol, and MZ/MZ but was 67% for Leg/DLB (P =.07). At 5 years, 21% of all patients had developed extracutaneous disease. CONCLUSION Two-thirds of primary cutaneous FCC lymphomas by EORTC criteria satisfy WHO criteria for DLB lymphoma. Unlike DLB lymphoma presenting in nodal or noncutaneous sites, these lesions are associated with an indolent course and may be treated with local radiotherapy alone.

Gallium scans in the management of patients with Hodgkin's disease: a study of 101 patients.

PURPOSE To evaluate the utility of periodic gallium (67Ga) scans in the management of patients with Hodgkins disease. PATIENTS AND METHODS From 1990 to 1994, 101 patients treated for Hodgkins disease (stage I to II, n = 67; stage III to IV, n = 34) had a positive 67Ga scan at the time of diagnosis. Treatment included chemotherapy in 27 patients, radiation therapy in 28, and combined modality therapy in 46. All patients underwent 67Ga scans at the time of diagnosis, near the end or just after treatment, and at periodic follow-up evaluation. RESULTS After treatment, the 67Ga scan remained positive in four patients and was interpreted as negative in 97. Among the four patients with positive scans, two died of progressive disease and two relapsed. Among the remaining 97 patients with negative 67Ga scans, 16 patients relapsed, including five with stage I to II (7.5%) and 11 with stage III to IV (34.4%) disease. The negative predictive value of posttherapy 67Ga scan was 83.5% for all patients; however, when calculated according to stage, it was 92.4% for patients with stage I to II disease and 64.5% for patients with stage III to IV disease (P < .01). CONCLUSION A positive 67Ga scan at the end of therapy is rarely seen in patients with Hodgkins disease and should be considered a manifestation of gross residual disease. However, a negative 67Ga scan after therapy had a significantly lower predictive value in patients with stage III to IV disease compared with stage I to II disease. The predictive value of 67Ga scans, as well as newer imaging studies, should be analyzed according to pretreatment stage.

Donor Y chromosome in renal carcinoma cells of a female BMT recipient: visualization of putative BMT-tumor hybrids by FISH.

Bone marrow-derived cells contribute to a wide variety of normal tissues such as liver, brain, and heart. This is due, at least in part, to cell fusion, in some cases with macrophages.1, 2, 3, 4, 5, 6 There are more than 25 reports of tumor hybridization in animals,7 and myeloid cell–tumor hybrids have been observed in melanoma,8 lymphoma,9 sarcoma,10, 11 and insulinoma models.12 In some cases, tumor hybridization was associated with metastasis.7 However, little is known of this in humans. Recently, the first genetic evidence for bone marrow–tumor cell hybridization in humans was reported.13 In that study, tumor DNA was analyzed from a child who developed metastatic renal cell carcinoma during a time when he had also received a BMT from his cancer-free, 6-year-old brother. Microdissected tumor cells of a nodal metastasis were shown through PCR to contain donor DNA, consistent with BMT–tumor hybridization.