Richard L. Bakst

How I treat extramedullary acute myeloid leukemia

Extramedullary (EM) manifestations of acute leukemia include a wide variety of clinically significant phenomena that often pose therapeutic dilemmas. Myeloid sarcoma (MS) and leukemia cutis (LC) represent 2 well-known EM manifestations with a range of clinical presentations. MS (also known as granulocytic sarcoma or chloroma) is a rare EM tumor of immature myeloid cells. LC specifically refers to the infiltration of the epidermis, dermis, or subcutis by neoplastic leukocytes (leukemia cells), resulting in clinically identifiable cutaneous lesions. The molecular mechanisms underlying EM involvement are not well defined, but recent immunophenotyping, cytogenetic, and molecular analysis are beginning to provide some understanding. Certain cytogenetic abnormalities are associated with increased risk of EM involvement, potentially through altering tissue-homing pathways. The prognostic significance of EM involvement is not fully understood. Therefore, it has been difficult to define the optimal treatment of patients with MS or LC. The timing of EM development at presentation versus relapse, involvement of the marrow, and AML risk classification help to determine our approach to treatment of EM disease.

Hypofractionated Dose-Painting Intensity Modulated Radiation Therapy with Chemotherapy for Nasopharyngeal Carcinoma, a Prospective Trial

PURPOSEnTo evaluate the feasibility of dose-painting intensity-modulated radiation therapy (DP-IMRT) with a hypofractionated regimen to treat nasopharyngeal carcinoma (NPC) with concomitant toxicity reduction.nnnMETHODS AND MATERIALSnFrom October 2002 through April 2007, 25 newly diagnosed NPC patients were enrolled in a prospective trial. DP-IMRT was prescribed to deliver 70.2 Gy using 2.34-Gy fractions to the gross tumor volume for the primary and nodal sites while simultaneously delivering 54 Gy in 1.8-Gy fractions to regions at risk of microscopic disease. Patients received concurrent and adjuvant platin-based chemotherapy similar to the Intergroup 0099 trial.nnnRESULTSnPatient and disease characteristics are as follows: median age, 46; 44% Asian; 68% male; 76% World Health Organization III; 20% T1, 52% T2, 16% T3, 12% T4; 20% N0, 36% N1, 36% N2, 8% N3. With median follow-up of 33 months, 3-year local control was 91%, regional control was 91%, freedom from distant metastases was 91%, and overall survival was 89%. The average mean dose to each cochlea was 43 Gy. With median audiogram follow-up of 14 months, only one patient had clinically significant (Grade 3) hearing loss. Twelve percent of patients developed temporal lobe necrosis; one patient required surgical resection.nnnCONCLUSIONSnPreliminary findings using a hypofractionated DP-IMRT regimen demonstrated that local control, freedom from distant metastases, and overall survival compared favorably with other series of IMRT and chemotherapy. The highly conformal boost to the tumor bed resulted low rates of severe ototoxicity (Grade 3-4). However, the incidence of in-field brain radiation necrosis indicates that 2.34 Gy per fraction is not safe in this setting.

RADIATION THERAPY FOR CHLOROMA (GRANULOCYTIC SARCOMA)

OBJECTIVESnChloroma (granulocytic sarcoma) is a rare, extramedullary tumor of immature myeloid cells related to acute nonlymphocytic leukemia or myelodysplastic syndrome. Radiation therapy (RT) is often used in the treatment of chloromas; however, modern studies of RT are lacking. We reviewed our experience to analyze treatment response, disease control, and toxicity associated with RT to develop treatment algorithm recommendations for patients with chloroma.nnnPATIENTS AND METHODSnThirty-eight patients who underwent treatment for chloromas at our institution between February 1990 and June 2010 were identified and their medical records were reviewed and analyzed.nnnRESULTSnThe majority of patients that presented with chloroma at the time of initial leukemia diagnosis (78%) have not received RT because it regressed after initial chemotherapy. Yet most patients that relapsed or remained with chloroma after chemotherapy are in the RT cohort (90%). Thirty-three courses of RT were administered to 22 patients. Radiation subsite breakdown was: 39% head and neck, 24% extremity, 9% spine, 9% brain, 6% genitourinary, 6% breast, 3% pelvis, and 3% genitourinary. Median dose was 20 (6-36) Gy. Kaplan-Meier estimates of progression-free survival and overall survival in the RT cohort were 39% and 43%, respectively, at 5 years. At a median follow-up of 11 months since RT, only 1 patient developed progressive disease at the irradiated site and 4 patients developed chloromas at other sites. RT was well tolerated without significant acute or late effects and provided symptom relief in 95% of cases.nnnCONCLUSIONSnThe majority of patients with chloromas were referred for RT when there was extramedullary progression, marrow relapse, or rapid symptom relief required. RT resulted in excellent local disease control and palliation of symptoms without significant toxicity. We recommend irradiating chloromas to at least 20 Gy, and propose 24 Gy in 12 fractions as an appropriate regimen.

Reirradiation for recurrent medulloblastoma

Previously irradiated recurrent medulloblastoma (MB) is a highly lethal disease. Reirradiation is often not considered secondary to its potential toxicity and uncertain efficacy. Analysis of retreatment could help identify the feasibility and role of reirradiation for recurrent MB.

Radiation Impairs Perineural Invasion by Modulating the Nerve Microenvironment

Purpose Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined. Experimental Design An in vitro co-culture system of dorsal root ganglia (DRG) and pancreatic cancer cells was used as a model of PNI. An in vivo murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer. Results Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function. Conclusions Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI.

Schwann cells induce cancer cell dispersion and invasion

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion, which carries a poor prognosis. Furthermore, the innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Here, we demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associates with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion. The formation of these processes was dependent on Schwann cell expression of neural cell adhesion molecule 1 (NCAM1) and ultimately promoted perineural invasion. Moreover, NCAM1-deficient mice showed decreased neural invasion and less paralysis. Such Schwann cell behavior reflects normal Schwann cell programs that are typically activated in nerve repair but are instead exploited by cancer cells to promote perineural invasion and cancer progression.

Effective Oncolytic Vaccinia Therapy for Human Sarcomas

BACKGROUNDnApproximately one fourth of bone and soft-tissue sarcomas recur after prior treatment. GLV-1h68 is a recombinant, replication-competent vaccinia virus that has been shown to have oncolytic effects against many human cancer types. We sought to determine whether GLV-1h68 could selectively target and lyse a panel of human bone and soft-tissue sarcoma cell lines inxa0vitro and inxa0vivo.nnnMETHODSnGLV-1h68 was tested in a panel of four cell lines including: fibrosarcoma HT-1080, osteosarcoma U-2OS, fibrohistiocytoma M-805, and rhabdomyosarcoma HTB-82. Gene expression, infectivity, viral proliferation, and cytotoxicity were characterized inxa0vitro. HT-1080 xenograft flank tumors grown inxa0vivo were injected intratumorally with a single dose of GLV-1h68.nnnRESULTSnAll four cell lines supported robust viral transgene expression inxa0vitro. At a multiplicity of infection (MOI) of five, GLV-1h68 was cytotoxic to three cell lines, resulting in >80% cytotoxicity over 7 d. Inxa0vivo, a single injection of GLV-1h68 into HT-1080 xenografts exhibited localized intratumoral luciferase activity peaking at d 2-4, with gradual resolution over 8 d and no evidence of spread to normal tissues. Treated animals exhibited near-complete tumor regression over a 28-d period without observed toxicity.nnnCONCLUSIONnGLV-1h68 has potent direct oncolytic effects against human sarcoma inxa0vitro and inxa0vivo. Recombinant vaccinia oncolytic virotherapy could provide a new platform for the treatment of patients with bone and soft tissue sarcomas. Future clinical trials investigating oncolytic vaccinia as a therapy for sarcomas are warranted.

Recurrent Neurotropic Chloroma: Report of a Case and Review of the Literature

We are reporting a case of a young woman with acute myelogenous leukemia status postallogeneic transplantation who developed multiply recurrent chloromas occurring along peripheral nerves in the absence of bone marrow relapse, all treated with radiation therapy. The patient is currently free of disease nearly four years after her first posttransplant chloroma. The case presented is unique for its isolated peripheral nervous system involvement, rare posttransplant occurrence, and indolent course without marrow relapse despite multiple extramedullary recurrences.

Oncolytic vaccinia virus therapy of salivary gland carcinoma.

OBJECTIVEnTo examine the therapeutic effects of an attenuated, replication-competent vaccinia virus (GLV-1h68) against a panel of 5 human salivary gland carcinoma cell lines.nnnDESIGNnThe susceptibility of 5 salivary gland carcinoma cell lines to infection and oncolysis by GLV-1h68 was assessed in vitro and in vivo.nnnRESULTSnAll 5 cell lines were susceptible to viral infection, transgene expression, and cytotoxic reactions. Three cell lines were exquisitely sensitive to infection by very low doses of GLV-1h68. Orthotopic parotid tumors exhibited more aggressive behavior compared with flank tumors. A single intratumoral injection of GLV-1h68 induced significant tumor regression without observed toxic effects in flank and parotid tumor models; controls demonstrated rapid tumor progression.nnnCONCLUSIONnThese promising results demonstrate significant oncolytic activity by an attenuated vaccinia virus for infecting and lysing salivary gland carcinomas, supporting future clinical trials.

Radiation therapy for leukemia cutis

PURPOSEnLeukemia cutis (LC) is the infiltration of the epidermis, dermis, or subcutis by neoplastic leukocytes, resulting in clinically identifiable cutaneous lesions. Electron-based radiation therapy (RT) is often used in the treatment of LC; however, modern studies of RT are lacking. We reviewed our experience to analyze treatment response, disease control, and toxicity associated with RT in order to develop treatment recommendations for patients with LC.nnnMETHODS AND MATERIALSnFifteen patients who underwent treatment for LC at our institution from November 1994 to August 2009 were identified and their medical records were reviewed and analyzed.nnnRESULTSnLC presented after a median of 2 (range 0-24) months from acute myeloid leukemia diagnosis. Median survival from time of LC presentation was 23 months (range 0.5-137 months). Thirteen courses of radiation were administered to 12 patients: 9 total skin electron beam (TSEB) therapy and 4 focal treatments. Of patients receiving TSEB, 89% had diffuse LC involvement and 67% were in marrow remission. By contrast, only 25% of patients receiving focal therapy had diffuse LC involvement and only 25% were in marrow remission. Median TSEB dose was 1600 (range 600-2400) cGy. Fifty percent of patients had a complete response to RT but 1-year local control was only 33%. All patients who developed a skin relapse either had active marrow disease at the time of RT or marrow recurrence shortly thereafter. Median survival since RT was 5 (range 0.5-136) months. RT was well tolerated without significant acute effects; however, 1 patient receiving chemotherapy developed radiation recall 1 month after RT.nnnCONCLUSIONSnPatients with LC have aggressive disease with few long-term survivors. Definitive treatment with TSEB should be utilized only in cases of marrow remission with focal electron therapy reserved for palliation of symptomatic lesions. Long-term prognosis and durable cutaneous remission is dependent on systemic disease control.