The case histories of 1961 patients with inflammatory bowel disease (IBD), 1227 with Crohn's disease (CD) and 734 with ulcerative colitis (UC), have been studied for the incidence of extraintestinal malignant neoplasms. There were 54 extraintestinal cancers in 51 patients: 28 patients with CD and 23 with UC; 25 men and 26 women. There were 9 breast, 7 skin, 15 reticuloendothelial, 11 genitourinary, 3 lung, 3 perianal, 2 pancreatic islet cell, and several miscellaneous cancers. The number of patient-years from the onset of disease to the last date of follow-up was calculated for men and women with each form of IBD. The observed number (O) of neoplasms was recorded. The expected number (E) of neoplasms was derived from the Department of Health, Education, and Welfare (DHEW) incidence figures for the same neoplasms that occurred in a standard age- and sex-matched population. The O/E ratio was then calculated for each type of cancer as well as for the entire series. There were no statistically significant increases in overall O/E ratios of extraintestinal cancers for either CD (0.76) or UC (1.32). On the other hand, several specific types of cancer did appear to occur with a frequency that was significantly greater than expected. These cancers were classified into two groups. The first group included reticuloendothelial neoplasms. There was an excess of leukemias in UC (P less than 0.005) and an excess of lymphomas in both UC and CD (P less than 0.005). The second group included three squamous cell cancers of the perianal region, an incidence 30 times greater than expected, and two squamous cell cancers of the vagina, also in excess of the expected number. Lymphoma, leukemia, and squamous cell cancers have been reported to occur in excess in immunosuppressed or irradiated patients. It may therefore be speculated that the apparently increased incidence of these neoplasms in the patients with ileitis and colitis might be related to immunologic deficiencies associated with IBD, to the long-term administration of steroids or other immunosuppressive medications that were given to most of the patients or, possibly, to increased exposure to ionizing radiation. The apparently increased incidence of perianal and vaginal cancers of the squamous variety might be a consequence of the combined effects of chronic inflammatory disease involving these areas and primary immune suppression.

Balamuthia mandrillaris , a free-living ameba, causes rare but frequently fatal granulomatous amebic encephalitis (GAE). Few patients have survived after receiving experimental drug combinations, with or without brain lesion excisions. Some GAE survivors have been treated with a multi-drug regimen including miltefosine, an investigational anti-leishmanial agent with in vitro amebacidal activity. Miltefosine dosing for GAE has been based on leishmaniasis dosing because no data exist in humans concerning its pharmacologic distribution in the central nervous system. We describe results of limited cerebrospinal fluid (CSF) and serum drug level testing performed during clinical management of a child with fatal GAE who was treated with a multiple drug regimen including miltefosine. Brain biopsy specimens, CSF, and sera were tested for B. mandrillaris using multiple techniques, including culture, real-time polymerase chain reaction, immunohistochemical techniques, and serology. CSF and serum miltefosine levels were determined using a liquid chromatography method coupled to tandem mass spectrometry. The CSF miltefosine concentration on hospital admission Day 12 was 0.4 μg/mL. The serum miltefosine concentration on Day 37, about 80 hours post-miltefosine treatment, was 15.3 μg/mL. These are the first results confirming some blood-brain barrier penetration by miltefosine in a human, although with low-level CSF accumulation. Further evaluation of brain parenchyma penetration is required to determine optimal miltefosine dosing for Balamuthia GAE, balanced with the drug’s toxicity profile. Additionally, the Balamuthia isolate was evaluated by real-time PCR, demonstrating genetic variability in18S rRNA sequences and possibly signaling the first identification of multiple Balamuthia strains with varying pathogenicities.

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In this study of 25 central nervous system (CNS) tumor-bearing rats, the CNS biodistribution of intravenously administered, indium-labeled liposomes was investigated. In 16 animals, the blood-brain barrier and blood-tumor barrier were modified using intracarotid administration of etoposide. In control animals, analysis by autoradiography and well-counting experiments demonstrated uptake of liposomes in the tumor-bearing hemisphere (% injected dose/g tissue = 0.135) with minimal uptake in the non-tumor-bearing hemisphere (% injected dose/g tissue = 0.007), p < 0.01. Unilateral intracarotid etoposide administration enhanced liposome uptake in both hemispheres-0.215 and 0.023 (tumor-bearing and nontumor-bearing), respectively. The presence of meningeal tumor involvement in nontumor-implanted hemispheres increased liposomal uptake 10-fold. These findings may have clinical applicability in designing therapeutic protocols for the treatment of CNS tumors.

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