T. Jeffery Wieman

Clinical efficacy of becaplermin (rhPDGF-BB) gel☆

Abstract The results of four multicenter, randomized, placebo-controlled, parallel group studies of the efficacy of becaplermin gel are reviewed here. The four studies included a total of 922 patients, all of whom received a standardized regimen of good ulcer care. Patients were randomized to receive placebo gel, 30 or 100 μg/g becaplermin gel, or good ulcer care alone. In Studies 1 and 2, the incidence of complete healing was significantly higher in patients receiving becaplermin gel (30 μg/g, Study 1; 100 μg/g, Study 2) compared with that in patients receiving placebo gel. In Study 3, which was not powered for statistical analysis, the incidence of complete healing in patients treated with 100 μg/g becaplermin gel was approximately twice that of patients treated with good ulcer care alone. In Study 4, there was no significant difference in the incidence of complete healing in patients treated with becaplermin gel versus good ulcer care alone.

The effect of photodynamic therapy on the microcirculation

Photodynamic therapy (PDT) is a new form of cancer therapy involving tumor localization by photosensitizing drugs such as dihematoporphyrin ether (DHE). Light irradiation of drug-sensitized tissue results in photoactivation of DHE and tumor necrosis. The mechanism of action is incompletely understood but involves the generation of singlet oxygen which produces cytotoxic effects on tissues containing the compound. In addition, microcirculatory aberrations have been described during PDT. We have studied the acute effects of PDT on the microcirculation using in vivo television microscopy of the rat cremaster. This has enabled us to observe the effects of PDT on both paired and unpaired arterioles and venules using two different wavelengths of activating light (blue, 450-490 nm, and green, 530-560 nm). For both wavelengths of activating light, significant reduction in blood flow of all vessels was seen during PDT. This, in combination with the formation and embolization of platelet thrombi, resulted in stasis of blood flow in 80% of arterioles and 90% of venules. Observation for 2 hr after the completion of photoactivation revealed reperfusion in 20% of the arterioles but none of the venules. Blood flow was reduced by a combination of vasoconstriction and platelet thrombus formation. Reducing the total activating energy from 120J/cm2 to 24J/cm2 significantly reduced the response in venules and the incidence of stasis in both arterioles and venules. We conclude that the photoactivation of DHE results in significant vasoconstriction and thrombosis of normal vessels and that if these effects are seen at later times after DHE administration and in tumor neovasculature they may contribute to the mechanism by which PDT results in tumor necrosis.

Treatment of Hyperesthetic Neuropathic Pain in Diabetics Decompression of the Tarsal Tunnel

ObjectiveThe authors evaluated the causal relationship between entrapment of the posterior tibial nerve and neuropathic pain and describe the results of nerve decompression in a selected group of patients with intractable pain. Summary Background DataPainful metabolic neuropathy has, until recently, been thought to be an irreversible and essentially untreatable complication of diabetes. Recent studies have shown that metabolic deterioration is only one component of the disease process. MethodsA group of patients with intractable painful neuropathy and a positive percussion sign underwent posterior tibial nerve decompression. ResultsNerve decompression relieved the pain in the majority of treated patients. Return of other sensory function also was noted. ConclusionsPainful diabetic neuropathy of the lower extremities is potentially reversible. It appears to be caused partially by nerve entrapment and can be reversed by decompression.

Effect of metatarsal head resection for diabetic foot ulcers on the dynamic plantar pressure distribution

Diabetic neuropathic ulcers are thought to arise from repetitive injury during normal walking in areas of high plantar pressures. It has been suggested that metatarsal head (MTH) resection alleviates elevated pressures at the site of the ulcer and, thus, expedites healing and prevents recurrence. We investigated the effect of MTH resection on plantar pressure distribution and ulcer healing. Sixteen diabetic patients with neuropathic plantar ulcers present for a mean of 36 +/- 28 weeks undergoing MTH resection were studied. Plantar pressure distribution was measured preoperatively and postoperatively using the EMED-SF pressure sensor platform (Novel, Munich, Germany). The data showed that 68.8% of the patients had mean peak plantar pressures (MPPs) elevated (greater than 500 kilopascal (kPA)) at sites of plantar ulceration. The MPPs following MTH resection were significantly reduced irrespective of the site (p = 0.002). There was maximal MPP reduction following the resection of the 1st MTH (70%) and a lower reduction with 2nd-3rd MTH (39.9%) and 4th-5th MTH (45.8%) resections. We found no significant transfer of pressure to adjacent metatarsal heads following resection of the 1st MTH (p = 0.87), 2nd-3rd MTH (p = 0.11), and 4th-5th MTH (p = 0.75). All patients achieved complete ulcer healing within 8 +/- 2 weeks after surgery. We concluded that reduction of plantar pressure is crucial for plantar ulcer healing, and we have demonstrated definitively that MTH resection leads to reduced peak plantar pressure, thus, expediting ulcer healing.

THE EFFECTS OF PHOTODYNAMIC THERAPY USING DIFFERENTLY SUBSTITUTED ZINC PHTHALOCYANINES ON VESSEL CONSTRICTION, VESSEL LEAKAGE AND TUMOR RESPONSE

Abstract— The effects of four different zinc phthalocyanines were studied during and after photodynamic therapy (PDT). Measurements of vessel constriction, vessel leakage, tumor interstitial pressure, eicosanoid release, and tumor response of chondrosarcoma were made in Sprague‐Dawley rats. Animals were injected intravenously with 1 μmol/ kg of mono‐, di‐, or tetrasulfonated zinc phthalocyanine, or 1 μmol/kg of a zinc phthalocyanine substituted with four tertiary butyl groups. Tissues were exposed to 400 J/cm2 670 nm light 24 h after photosensitizer injection. An additional group of animals was given indomethacin before treatment. The use of the monosulfonated and tertiary butyl substituted zinc phthalocyanines in PDT caused the release of specific eicosanoids, caused vessel constriction, and induced venule leakage and increases in tumor interstitial pressure. Tumor cures of 27% and 7% were observed. Photodynamic therapy using the disulfonated zinc phthalocyanine did not induce vessel constriction or the release ofeicosanoids, however; tumor cure was 43%. The use of thc tetrasulfonated zinc phthalocyanine caused intermediate effects between the mono‐ and disulfonated compounds. The administration of indornethacin to animals completely inhibited the effects of PDT using the monosulfonated compound but had minimal effects on treatment using the disulfonated compound. This suggests that the monosulfonated and disulfonated compounds act by different mechanisms of destruction.

Resection of the metatarsal head for diabetic foot ulcers

BACKGROUND Diabetic foot ulceration is a worldwide health problem. Approximately 15% of the 10 million diabetic patients in the United States will develop a foot ulceration at some time in their lives. The presence of a foot ulcer in this population is extremely debilitating and dramatically increases the risk of lower extremity amputation, accounting for approximately 67,000 lost limbs each year. Additionally, the costs associated with treating foot ulcers in diabetic patients is a major expense in the overall care of this patient group. METHODS An 11-year retrospective study was conducted to evaluate 101 consecutive patients with diabetic ulcers of the forefoot who were treated using resection of the metatarsal head as the primary means of obtaining wound closure. RESULTS The results indicate that 88% of the ulcers were healed by using this technique, and relatively more rapidly than would be expected when compared with historical norms. CONCLUSIONS Resection of the metatarsal head is a safe and relatively inexpensive procedure that facilitates closure of the lesion, helps to control infection, and prevents countless and costly amputations.

THE EFFECTS OF THROMBOXANE INHIBITORS ON THE MICROVASCULAR AND TUMOR RESPONSE TO PHOTODYNAMIC THERAPY

Abstract— Vascular stasis and tissue ischemia are known to cause tumor cell death in several experimental models after photodynamic therapy (PDT); however, the mechanisms leading to this damage remain unclear. Because previous studies indicated that thromboxane release is implicated in vessel damage, we further examined the role of throm‐boxane in PDT. Rats bearing chondrosarcoma were injected with 25 mg/kg Photofrin® (intravenously) 24 h before treatment. Light (135 J/cm2, 630 nm) was delivered to thc tumor area after injection of one of the following inhibitors: (1) R68070: a thromboxane synthetase inhibitor; (2) SQ‐29548: a thromboxane receptor antagonist; and (3) Flunarizine: an inhibitor of platelet shape change. Systemic thromboxane levels were determined. Vessel constriction and leakage were evaluated by intravital microscopy. Tumor response was assessed after treatment. Thromboxane levels were decreased more than 50% with SQ‐29548 as compared to controls. Thromboxane levels in animals given R68070 and Flunarizine remained at baseline levels. SQ‐29548 and R68070 reduced vessel constriction compared to controls, while Flunarizine totally prevented vessel constriction. R68070 and SQ‐29548 inhibited vessel permeability compared to PDT controls; Flunarizine did not. Animals given these inhibitors showed markedly reduced tumor cure. These results indicate that the release of thromboxane is linked to the vascular response in PDT.

Responsiveness of metastatic basal-cell carcinoma to chemotherapy. A case report

Basal cell carcinoma normally causes major morbidity only by direct extension of the tumor into adjacent tissues. Occasionally the tumor will metastasize to distant sites such as the lungs, the bones, regional lymph nodes, and the abdominal viscera. Over 100 cases of this disseminated disease are reported in the literature. Once a tumor has metastasized beyond the regional lymph nodes it is uniformly fatal. This article reports a case of basal cell carcinoma, metastatic to the lung, which was successfully treated with cisplatin. Three other cases treated similarly are reviewed, and the prospects for treatment of advanced basal cell carcinomas with chemotherapy are discussed.

The effects of thrombocytopenia on vessel stasis and macromolecular leakage after photodynamic therapy using photofrin.

Abstract— Several studies have reported thrombus formation and/or the release of specific vasoactive eicosanoids, suggesting that platelet activation or damage after photodynamic therapy (PDT) may contribute to blood flow stasis. The role of circulating platelets on blood flow stasis and vascular leakage of macromolecules during and after PDT was assessed in an intravital animal model. Sprague‐Daw‐ley rats bearing chondrosarcoma on the right hind limb were injected intravenously (i.v.) with 25 mg/kg Photofrin 24 h before light treatment of 135 J/cm2 at 630 nm. Thrombocytopenia was induced in animals by administration of 3.75 mg/kg of rabbit anti‐rat platelet antibody i.v. 30 min before the initiation of the light treatment. This regimen reduced circulating platelet levels from 300000/mm3 to 20000/mm3. Reductions in the luminal diameter of the microvasculature in normal muscle and tumor were observed in control animals given Photofrin and light. Venule leakage of macromolecules was noted shortly after the start of light treatment and continued throughout the period of observation. Animals made thrombocytopenic showed none of these changes after PDT in either normal tissues or tumor. The lack of vessel response correlated with the absence of thromboxane release in blood during PDT. These data suggest that platelets and eicosanoid release are necessary for vessel constriction and blood flow stasis after PDT using Photofrin.

Implications of a pre-existing tumor hypoxic fraction on photodynamic therapy

The presence of oxygen in tissue is a requirement for photodynamic therapy (PDT)-induced destruction of solid tumors, otherwise no cell death occurs. Since many tumors have been shown to have significant populations of hypoxic cells, it is of clinical interest to determine if pre-existing tumor hypoxia limits phototherapy. This question was examined using RIF tumors where tumor response to PDT of completely oxygenated tumors was compared to tumors with an induced hypoxic fraction. Tumor hypoxia was induced by using vasoactive drugs (epinephrine, chlorpromazine, or isoproterenol), given 30 min prior to PDT, or by a surgical method. PDT consisted of 5 mg/kg Photofrin II ip 24 hr prior to treatment and 135 J/cm2 630-nm light. The administration of the various vasoactive agents induced hypoxic fractions of 2.2 to 10%. The surgical method induced hypoxic fractions of 35%. Tumor response and cure in animals given vasoactive agents did not differ from controls, suggesting that low levels of pre-existing tumor hypoxia do not limit photodynamic therapy in this tumor model. Animals with tumors made hypoxic by a surgical method showed significantly reduced tumor response to PDT. Only 14% of these animals had tumors which became flat and necrotic by the day following PDT, compared to nearly 100% for animals given vasoactive drugs or controls. Furthermore, no tumor cure was observed in animals treated by this method. The higher level of tumor hypoxia in these animals likely represents one point where large proportions of PDT-resistant cells can survive after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)