A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases from colorectal cancer.

BACKGROUND: Isolated hepatic perfusion (IHP) with melphalan is an established approach for patients with unresectable metastatic liver lesions. This study determined the safety and maximum tolerated dose (MTD) of 5-FU with oxaliplatin via IHP. METHODS: Standard 3 × 3 Phase I design. Subjects with unresectable isolated CRC liver metastases scheduled for HAI pump were eligible. IHP used fixed-dose oxaliplatin with escalating 5-FU doses. Toxicity (CTCAE v 4.0) and response (RECIST), progression-free survival, and overall survival (OS) were assessed. Systemic and IHP plasma PK of 5-FU, anabolites, and platinum were determined. RESULTS: All 12 patients had received ≥ 1 line of pre-IHP chemotherapy. There were 4 grade 3 serious adverse events (33.3 %) and 1 grade 4 event (8.3 %). Also, 2 dose-limiting toxicities occurred at DL2 at 300 mg/m(2), resulting in expansion of DL1 at 200 mg/m(2) 5-FU, the eventual MTD. At 6-month follow-up, 9 patients (82 %) demonstrated partial response, while 2 (18 %) exhibited stable disease. Also, 64 % of patients demonstrated a >50 % decrease in CEA. The 1- and 2-year OS probabilities were 90.9 and 71.6 %, respectively, with median follow-up of 24 months. IHP exposures (AUC0-60 min) were 10.9 ± 4.5 µgPt h/mL, 49.3 ± 30.7 µg h/mL 5-FU (DL1), and 70.5 ± 35.5 µg h/mL 5-FU (DL2). Systemic exposure (AUC0-inf) relative to IHP exposure was negligible for both platinum (1.1 ± 1.5 %) and 5-FU (0.09 ± 0.10 %). CONCLUSIONS: The MTD for IHP was 200 mg/m(2) 5-FU with 40 mg/m(2) oxaliplatin. Systemic exposure to the agents was minimal during IHP. The response and survival observed warrants assessment in a larger phase II trial.

Ultrastructure of hyaline, border, and vacuole cells in chick inner ear.

The sense organ for hearing in birds, the basilar papilla, is capable of replacing lost or damaged hair cells and supporting cells through regeneration. Potential candidates for precursor-cell populations include cells within the auditory receptor epithelium and nonsensory cells inferior to the sensory epithelium. Ultrastructural characteristics of hyaline cells, border cells, and vacuole cells, nonsensory cells which border or lie inferior to the receptor epithelium proper, were studied with transmission electron microscopy. Data were obtained from normal neonatal and adult chickens. Several rows of epithelial cells separate hyaline cells from inferiorly located organ supporting cells and hair cells. Ultrastructural characteristics and location of these epithelial cells differentiate them from organ supporting cells and hyaline cells; consequently, we have termed them "border cells." Synaptic specializations are observed between neural elements and border cells, and gap junctions are found between adjacent border cells, between border cells and neighboring organ supporting cells, and between juxtaposed border and hyaline cells. Hyaline cells, in contrast to border cells, are highly specialized. Dense bundles of filaments are present in hyaline cells from the basal one-half of the papilla, and an unusual structure, a rough tubular aggregate, is present in hyaline-cell cytoplasm. Pre- and postsynaptic specializations are observed between neural elements and hyaline cells, and gap-junctional complexes link neighboring hyaline cells. Vacuole cells lie inferior to the hyaline cells and rest on the inferior fibrocartilaginous plate. They are unspecialized morphologically. Their only remarkable morphological feature is the abundance of spherical vacuoles within their cytoplasmic matrix.

Analysis of residual disease following preoperative radiotherapy versus initial surgery in endometrial carcinoma.

A clinicopathologic study of residual disease following pre-operative radiotherapy (RT) in 67 patients and initial surgery in 40 patients with early invasive endometrial carcinoma is presented. In 10%, extrauterine spread was found at operation. In 10% of patients, the histologic type, and in 19% the grade of tumor, differed between the curettage and hysterectomy specimens. Pre-op RT altered the depth of myometrial invasion and frequency of vascular invasion, but there was no evidence that irradiation itself affected the histologic type or grade of tumor. The patients with residual tumor after pre-op RT had significantly more cancer-related deaths than those without residual disease. The high risk factors were deep myometrial invasion and residual disease outside the uterus. Vascular invasion did not affect the prognosis in this series. The importance of surgical-pathologic staging by initial surgery is discussed.

Neuronal tracing with DiI: decalcification, cryosectioning, and photoconversion for light and electron microscopic analysis.

The molecule 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) is a fluorescent dye which diffuses within cell membranes. The properties of DiI diffusion and fluorescence are maintained in aldehyde-fixed tissue, thereby allowing selective neuronal tracing post mortem. We describe three modifications of this tracing method. First, while DiL diffuses along neuronal membranes the tissue can be decalcified in EDTA at 37 degrees C. Tracing in decalcified tissue extends the possible application of the DiI technique to the investigation of neuronal tissue enclosed in bony structures. Second, we describe a protocol that allows sectioning of DiI-injected tissue on a cryostat with minimal subsequent spread of DiI in dried sections. Third, we demonstrate that DiI label of fluorescent neurons in cryosections as well as Vibratome sections can be photo-oxidated and converted to a stable diaminobenzidine reaction product. The photo-converted DiI label is electron dense and allows analysis of labeled cell bodies and processes at the electron microscopic level. DiI does not stay confined to the surface cell membrane in fixed tissue but reaches internal organelles, presumably via membranes of the endoplasmic reticulum, and concentrates in microsomal structures adjacent to mitochondria. Photoconversion of DiI label is compatible with gold immunocytochemistry. Long-term incubation and subsequent photoconversion of post-mortem DiI-labeled neurons provides remarkable tissue preservation at the ultrastructural level.

An inexpensive variable-frequency microwave system for hyperthermia.

A microwave hyperthermia system is described which uses surplus communications equipment. The most costly components of the microwave system, the signal generator and amplifier, were obtained through the Federal Surplus Supply System. The cost of the entire system, including 2450 MHz applicator and temperature monitoring system, is under $1200. Extensive testing has demonstrated the capability of heating several cm3 mouse tumors to a temperature of 42.5 degrees C. Depth of heating can be varied by adjusting the frequency of the oscillator or by adjusting the output attenuator.

Methicillin-resistant Staphylococcus aureus infection in palliative care.

Our objective was to assess the impact of methicillin-resistant Staphylococcus aureus (MRSA) infection in palliative care. The study was conducted at three hospices in south London, totalling 118 beds, and the following two methods were used. Firstly, a retrospective review of the notes of patients who were known to be MRSA positive at admission or were subsequently found to be MRSA positive was taken. Secondly, a prospective study of factors influencing bed occupancy in one hospice was conducted. The proportion of admissions who were MRSA positive ranged from 4% to 8% in the three hospices. Seven of the 43 patients who had MRSA suffered clinically significant infections. Risk factors for colonization and bacteraemia were similar to the general population. Sites of infection were variable and multiple and treatment regimes for eradication were variable, with varying outcomes. MRSA infection appeared to delay admission because of the need for single rooms, of which there are few Time spent cleaning rooms after discharge or death also reduced the number of available beds. It was concluded that MRSA infection is associated with significant morbidity in a small number of palliative care patients. Beds unavailable because of MRSA should be considered in bed occupancy figures, otherwise bed occupancy may appear artificially low. The psychological and financial impact of the infection in palliative care patients needs further evaluation.

Bladder and rectal complications following radiotherapy for cervix cancer.

One-hundred and thirty-two patients with cervix carcinoma who were treated with whole pelvis irradiation and two intracavitary applications had bladder and rectal dosimetry during brachytherapy with contrast agents placed into the bladder and rectum prior to orthogonal simulator radiographs. Doses were computer calculated at points A and B, F (bladder), R1 (rectum), and R2 (rectosigmoid). Late occurring bladder and rectal complications were graded on a severity scale of 1 to 3, and 14% had grade 2 or 3 injuries (9% developed fistulas). Statistical evaluation of the data showed that severe bladder and rectal injuries occur more commonly in stage IIIA and IIIB disease and in those receiving high external beam doses (5000 rad +). Analysis of variance tests revealed a significant correlation of brachytherapy dose to points R1 and R2 with severe rectal injuries but there was not a correlation of dose to F with bladder injuries. Nor was there correlation of injuries with dose to point A or the milligram-hour dose. We conclude that our technique for rectal dosimetry is adequate but that an improved technique of bladder dosimetry is needed. Also, when combining whole pelvis irradiation with two intracavitary applications (4000 rad to point A), the whole pelvis dose should probably not exceed 4000-4500 rad.

Histologic grading in the clinical evaluation of laryngeal carcinoma.

A histologic grading system based on tumor differentiation was applied in a study of 73 patients with epidermoid carcinoma of the larynx treated at the Milton S. Hershey Medical Center of the Pennsylvania State University from 1971 through September 1977. The supraglottic and subglottic primary tumors were more likely to be poorly differentiated than the glottic carcinomas. In general, the more poorly differentiated the primary tumor, the more advanced was the stage of disease, and the higher the incidence of cervical node metastasis. After treatment, grade 3 patients have a higher incidence of treatment failure and cancer death than grade 1 or 2 patients. The findings suggest that a histologic grading system is an important adjunct to the clinical evaluation.