Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer.

Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. Although it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically engineered mouse line lacking functional Muc4 (Muc4ko), and then crossed these animals with the NDL (Neu DeLetion mutant) model of ErbB2-induced mammary tumorigenesis. We observed that Muc4ko animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4ko/NDL female mice exhibit similar latencies and growth rates as Muc4wt/NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4ko/NDL mice. Interestingly, histological analysis of lung lesions from Muc4ko/NDL mice revealed a reduced association of disseminated cells with platelets and white blood cells. Moreover, isolated cells derived from Muc4ko/NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4wt/NDL cells than Muc4ko/NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation.

Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination.

The lethality of the aggressive brain tumor glioblastoma multiforme (GBM) results in part from its strong propensity to invade surrounding normal brain tissue. Although oncogenic drivers such as epidermal growth factor receptor activation and Phosphatase and Tensin homolog inactivation are thought to promote the motility and invasiveness of GBM cells via phosphatidylinostitol 3-kinase activation, other unexplored mechanisms may also contribute to malignancy. Here we demonstrate that several components of the planar cell polarity (PCP) arm of non-canonical Wnt signaling including VANGL1, VANGL2 and FZD7 are transcriptionally upregulated in glioma and correlate with poorer patient outcome. Knockdown of the core PCP pathway component VANGL1 suppresses the motility of GBM cell lines, pointing to an important mechanistic role for this pathway in glioblastoma malignancy. We further observe that restoration of Nrdp1, a RING finger type E3 ubiquitin ligase whose suppression in GBM also correlates with poor prognosis, reduces GBM cell migration and invasiveness by suppressing PCP signaling. Our observations indicate that Nrdp1 physically interacts with the Vangl1 and Vangl2 proteins to mediate the K63-linked polyubiquitination of the Dishevelled, Egl-10 and Pleckstrin (DEP) domain of the Wnt pathway protein Dishevelled (Dvl). Ubiquitination hinders Dvl binding to phosphatidic acid, an interaction necessary for efficient Dvl recruitment to the plasma membrane upon Wnt stimulation of Fzd receptor and for the propagation of downstream signals. We conclude that the PCP pathway contributes significantly to the motility and hence the invasiveness of GBM cells, and that Nrdp1 acts as a negative regulator of PCP signaling by inhibiting Dvl through a novel polyubiquitination mechanism. We propose that the upregulation of core PCP components, together with the loss of the key negative regulator Nrdp1, act coordinately to promote GBM invasiveness and malignancy.

Disseminated miliary tuberculosis of the skin in patients with AIDS: report of four cases.

We present clinical, bacteriologic, and pathological findings for four patients with AIDS and cutaneous miliary tuberculosis. All patients had generalized tuberculosis with hematogenous dissemination to multiple organs including the skin. Microscopic examination of the skin lesions revealed ill-formed or no granulomata, extensive necrosis, and numerous acid-fast bacilli. Mycobacterium tuberculosis was detected in the skin lesions by cultures for three patients and by polymerase chain reaction for one. Three of the isolates were resistant to at least isoniazid and rifampin, and one was susceptible to these drugs. The outcome was rapidly fatal for the three patients with multidrug-resistant tuberculosis. This report draws attention to the reappearance of a once-rare manifestation of disseminated tuberculosis which, in the setting of advanced human immunodeficiency virus disease, may offer the first indication of infection with multidrug-resistant M. tuberculosis and a poor prognosis.

A randomized clinical trial in bronchogenic small-cell carcinoma evaluating alternating maintenance therapy of vincristine, adriamycin, procarbazine, and etoposide (VAPE) with cyclophosphamide, CCNU, and methotrexate (CCM) versus CCM maintenance alone in complete responders following VAPE induction and late intensification.

Initially, 109 evaluable patients with locally advanced or metastatic small cell lung cancer (SCLC) were treated with vincristine, Adriamycin, procarbazine, and etoposide (VAPE). Partial (PR) or nonresponders (NR) were crossed to CCM (cyclophosphamide, CCNU, and methotrexate) and then to HMiVe (hexamethylmelamine, mitomycin C, vinblastine) sequentially at maximum response. Complete responders (CR) were intensified by 50% with VAPE primarily and randomized to VAPE, alternating with CCM or CCM alone during maintenance. CR patients with limited disease received local thoracic irradiation and prophylactic cranial irradiation (PCI), whereas those with extensive disease received PCI alone. There were 45 patients (41%) who achieved a CR to chemotherapy, and 27 patients were eligible for randomization. Of 12 CR patients randomized to alternating therapy (VAPE/CCM), the median survival was 25.9 months compared to 12.9 months for 15 CR patients randomized to continuous CCM (P = .049). In addition, 35 patients achieved a PR (32%) and 29 were NR (27%). Overall median survivals were significantly different for the CR patients (13.0 months) as compared to PR (7.6 months) and NR patients (6.4 months). Late intensification did not appear to add substantially to survival while contributing to toxicity. In summary, VAPE is a new outpatient regimen for SCLC, which is highly effective as an induction regimen with moderate hematologic toxicity and predominantly gastrointestinal nonhematologic toxicity.

Diffuse pulmonary lymphangiomatosis.

Angiomatous lesions of the lung are uncommon and not well characterized. We describe nine cases of a distinct lymphatic vascular lesion that we have termed "diffuse pulmonary lymphangiomatosis." Extrathoracic lymphangiomatous lesions were not identified. The patients comprised seven males and two females with a mean age at presentation of 10 years (age range, 1 month to 33 years). Six patients were younger than 10 years of age. Symptoms included "wheezing" or "asthma" (44%) and dyspnea (22%) present for 3 months to 20 years. Chest radiographs showed bilateral interstitial infiltrates, often greatest in the lower lobes. Pleural or pericardial effusions were present or developed in six patients. Pulmonary function tests showed in two patients and mixed obstruction and restriction in five patients. Open lung biopsies (nine patients) and autopsy (one patient) showed anastomosing endothelial lined spaces along pulmonary lymphatic routes (especially pleural and interlobular septal) accompanied by asymmetrically spaced bundles of spindle cells, which were prominent in six cases. Hemosiderin deposition often was present in the spindle cell areas and in the adjacent lung. The lining cells were positive for factor VIII-related antigen (eight cases) and Ulex europaeus I agglutinin (four cases). The spindle cells were reactive with antibodies to vimentin (nine cases), desmin (six cases), actin (seven cases), progesterone receptor (seven cases), and proliferating cell nuclear antigen (one case); they were negative for estrogen receptor (seven cases), keratin, (eight cases), and HMB-45 (eight cases). Diffuse pulmonary lymphangiomatosis was progressive in eight cases and was most aggressive in the youngest children. Two of the children have died, one of pulmonary hemorrhage and the other after heart-lung transplantation. Diffuse pulmonary lymphangiomatosis is distinct from lymphangiectasis, lymphangioleiomyomatosis, pulmonary capillary hemangiomatosis, Kaposi's sarcoma, and kaposiform hemangioendothelioma. Due to its distribution and histology, a lymphatic origin of the lesion is favored.

Combined modality treatment for tumoral calcinosis.

Tumoral calcinosis is a rare syndrome marked by periarticular and intramuscular calcifications. We present the case of a 13-year-old black girl who has received treatment since age 2 for tumoral calcinosis with bilateral shoulder involvement.

A phase II clinical trial evaluating the use of two sequential, four-drug combination chemotherapy regimens in ambulatory bronchogenic adenocarcinoma patients.

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.

Results of acute zone III extensor tendon injuries treated with dynamic extension splinting.

Motivated by the favorable results of dynamic splinting in the treatment of more proximal extensor tendon injuries, we explored the use of dynamic splinting in the treatment of zone III extensor tendon lacerations. Twenty-two tendon repairs in 19 patients were available for review. On the basis of degree of extension lag and pulp-to-palm distance, 14 repairs were rated as excellent, 6 as good, and 2 as fair. Using total active motion at 10 weeks, the proximal interphalangeal and distal interphalangeal joints averaged 170 degrees. There was one mild boutonniere deformity. The results of this prospective study show that carefully monitored dynamic splinting is safe in the treatment of zone III lacerations. When results were compared with the results of our method of static splinting used prior to this prospective study, patients returned to full activities with good-to-excellent results 8 weeks earlier instead of at 16 to 18 weeks.

Complications experienced in the rehabilitation of zone I flexor tendon injuries with dynamic traction splinting.

A retrospective review of all flexor tendon repairs done between January 1985 to June 1987 determined the complication rate with our method of rehabilitation. One hundred sixty-three flexor tendon lacerations in 83 patients were reviewed. Follow-up ranged from 6 to 42 months. All patients participated in the same 12-week rehabilitation protocol. All patients had passive motion exercises of the interphalangeal joints in the first 2 weeks. We believe that passive stretching of zone I injuries during the first 2 weeks contributed to the zone I complication rate. Of the 20 patients with zone I tendon-to-tendon repairs, 7 patients had significant complications. The 35% complication rate found with zone I injuries has prompted us to modify our postoperative rehabilitation protocol in zone I injuries.

Further experience in rehabilitation of zone II flexor tendon repair with dynamic traction splinting.

A review of all flexor tendon repairs in the "no man's land" performed from January of 1985 to June of 1987 was done to evaluate the efficacy of our method of rehabilitation. There were 60 fingers (57 patients) with complete laceration of the flexor digitorum profundus and flexor digitorum superficialis tendons in zone II. Fingers with phalangeal fractures, joint injuries, or significant skin loss were excluded. Follow-up ranged from 12 to 48 months. Rehabilitation consisted of a 12-week protocol using the U.S. military combined regimen of controlled motion. Features from the technique of controlled active extension against rubber band passive flexion as well as those of controlled passive extension and passive flexion were incorporated. The palmar pulley modification of Kleinert's dynamic traction splint was utilized. Strickland's total active motion formula was employed to determine results. The results were classified into the four categories of excellent, good, fair, and poor. Fifty-two fingers (86 percent) were rated excellent, 4 fingers (7 percent) were rated good, 1 finger (2 percent) was rated fair, and 3 fingers (5 percent) were rated poor.

Anatomic course of the medial cutaneous nerves of the arm.

The medial antebrachial cutaneous nerve and the medial brachial cutaneous nerve were dissected in twenty fresh cadaver extremities. These nerves have a variable number of cutaneous branches ranging from four to twelve, with an average of eight. Branches always originated medially in both nerves and ran in an anterolateral direction. In all the medial antebrachial cutaneous nerves, there were three to five terminal branches directly overlying the medial epicondyle and supplying the skin over the olecranon. The course of this nerve is predictable relative to the basilic vein and the medial epicondyle. There was a ninety percent incidence of communication between the medial brachial cutaneous nerve and the intercostobrachial cutaneous nerve. The standard incision used for surgery of the ulnar nerve at the elbow will cut the terminal branches of the medial antebrachial cutaneous nerve one hundred percent of the time, and the terminal branches of the medial brachial cutaneous nerve eighty percent of the time, if they are not identified. A posterior approach for transposition of the ulnar nerve would avoid damage to these nerves.

Microsurgical revascularization of ischemic rat femoral heads.

To demonstrate whether revascularization could be surgically induced in avascular bone the femoral heads of female albino rats were excised and drilled through and through. The femoral heads were then placed in the opposite thigh and by use of microvascular techniques the femoral artery was divided and lengthened with a 1 cm artery or vein graft, and reanastomosed after passing one end through the drilled hole in the transplanted femoral head. Arterial blood flowed through the graft within the drilled femoral head on its way to its normal distribution down the leg. Technetium 99m MDP methylene diphosphate, tetracycline labeling, latex injection, and histologic review were used to demonstrate new vessel growth. All grafts patent at the end of the experiment were associated with tetracycline labeling, positive technetium 99m methylene diphosphate counts and latex-filled vessels in the matrix of the femoral heads. Histologically the vascularized femoral heads showed evidence of neovascularization and new bone formation.

Intraarticular fractures of the distal radius: a cadaveric study to determine if ligamentotaxis restores radiopalmar tilt.

Nineteen fresh cadaver wrists were divested of all dorsal and palmar tissues to the wrist capsule and extrinic and intrinsic ligaments. A Frykman VII type fracture was established across the radiocarpal and radioulnar joints. The dorsal and palmar wrist ligaments were left intact. The forearms were stabilized in an arm board and an external fixation device and traction applied through a Kirschner wire at the base of the third metacarpal. Three positions of wrist flexion; neutral, 15, and 30 degrees, with 10 and 20 pounds of traction were used to attempt to reestablish radiopalmar tilt. Only when the entire palmar ligamentous structures were transected at the radius was radiopalmar tilt reestablished. Ligamentotaxis alone is not a reliable method to reestablish radiopalmar tilt in intraarticular distal radius fractures.

Cavitation and other atypical manifestations of Pneumocystis carinii pneumonia.

In the 1980s, under the impact of the acquired immune deficiency syndrome, Pneumocystis carinii Pneumonia (PCP) has become the prime infectious manifestation of this condition. In addition to the well-recognized "classic" features of this disease, several unusual manifestations are being recognized with increasing frequency. We presently review and illustrate the following "atypical" manifestations of PCP: (1) interstitial lung responses that include diffuse alveolar damage, bronchiolitis obliterans, interstitial fibrosis, and lymphoplasmacytic infiltrates; (2) striking localized processes frequently exhibiting granulomatous features; (3) extensive necrosis and cavitation; and (4) extrapulmonary dissemination of the disease. Close clinico-pathologic correlation and attention to roentgenographic detail are invaluable aids in arriving at the correct diagnosis.

The pathology of treated Pneumocystis carinii pneumonia.

Post-mortem examinations were conducted in 28 patients with the acquired immune deficiency syndrome (AIDS) and biopsy-proven Pneumocystis carinii pneumonia (PCP) who had been treated with trimethoprim-sulfamethoxazole (Bactrim, intravenous infusion [Roche]) and/or pentamidine isethionate. According to the evolution of the pulmonary process, the cases were classified into three groups. Group I ("fulminant" PCP) was composed of eight patients who died during the first week of the disease. Although treatment had eradicated most of the organisms, one third of the alveolar space volume, on the average, was filled by foamy exudates characteristic of PCP. This accounted for the respiratory insufficiency and death of these patients. Group II ("nonresolving" PCP) was comprised of nine patients who died within eight days and 2 months of diagnosis. PCP was less severe than in group I, but fatal respiratory insufficiency was the result of fibroblastic organization of the intraalveolar exudates (fibrosing alveolitis). In seven of the nine patients (78%), the latter resulted from oxygen toxicity; in the remaining two patients (22%) PCP, per se, was the original stimulus for the fibrosis. Patients in group II also had a high incidence of thromboembolic pulmonary lesions. Group III ("cured" PCP) was composed of 11 patients who responded dramatically well to therapy but died months or years later of other manifestations of AIDS. In group III patients, the roentgenographic picture at diagnosis was consistently less severe than in groups I and II.

Tumoral calcinosis. Case report with treatment failure.

Periarticular calcifications are the hallmark of a rare entity: tumoral calcinosis. We have followed for 90 months a nine-year-old black girl with involvement of both shoulders. Seven initial local excisions of the mass on the right shoulder were attempted without complete removal and prompt recurrence after each attempt. The entire lesion on the right side, including a cutaneous ulceration, was managed by en masse surgical excision. Preoperative inpatient medical management in the form of low calcium and low phosphorus diet was unsuccessful. Postoperatively, she has remained free of ulceration; however, after two and a half years, the right mass has again increased in size with compression of the brachial plexus. This recurrence occurred despite strict dietary control starting immediately postoperatively. Although there are many advocates of surgical excision of these lesions and, more recently, several cases reported of successful medical management, we find that often a combination approach is necessary to effectively treat tumoral calcinosis and reduce the rate of recurrence.

Primary choriocarcinoma of the lung: report of a case treated with intensive multimodality therapy and review of the literature.

Primary choriocarcinomas of the lung are extremely rare. Like choriocarcinomas elsewhere, they possess rapid growth ability and a high propensity to metastasize. There is minimal information available on the treatment of lung choriocarcinoma. In the case reported herein, neoadjuvant chemotherapy with 5-fluorouracil (5-FU) infusion, etoposide, and cisplatin induced a partial response permitting complete excision of a massive tumor of the right upper lobe involving the chest wall and superior vena cava. The patient relapsed with a metastasis to the brain that was surgically excised. Contralateral lung metastases were soon noted and responded well to systemic chemotherapy; yet the patient died of a new brain metastasis. To our knowledge, this is the first example of a primary choriocarcinoma of the lung treated with intensive multimodality therapy. The latter seems to offer a potential benefit if certain guidelines are followed.

Primary bronchopulmonary fibrosarcoma of childhood and adolescence: reassessment of a low-grade malignancy. Clinicopathologic study of five cases and review of the literature.

In children, primary tumors of the lung constitute a unique subset of quasineoplastic and unequivocally neoplastic lesions whose benign or malignant potential is not always predictable on the basis of morphologic findings. One such neoplasm in the latter category is the primary bronchopulmonary fibrosarcoma (PBPF). This clinicopathologic, ultrastructural, and immunohistochemical study documents our experience with five PBPFs in newborns and children up to 11 years of age at diagnosis. The tumors were either endobronchial or intraparenchymal in location. A uniform population of interlacing bundles and sheets of densely arranged spindle cells with variable mitotic activity was observed microscopically in each case. Ultrastructurally, the cells had the features of fibroblasts and vimentin was the only immunohistochemical marker identified. Despite the disturbing pathologic findings, the four children with more than 1 year of follow-up have survived well 4 to 9 years after surgical resection. Our results are compared with the 21 cases of PBPF reported in the literature and the differential diagnosis is discussed.