Background. The value of chemotherapy after standard postoperative external beam radiation in the treatment of malignant gliomas remains controversial. Despite recent recommendations from the Brain Tumor Cooperative Group that chemotherapy should be considered part of the standard treatment of patients with highgrade astrocytomas, several recent trials have questioned the efficacy of this approach.

Methods. Using results from 16 randomized clinical trials involving more than 3000 patients, the authors compared the survival rates of patients who received radiation alone or radiation with chemotherapy. The combined data were analyzed using the statistical method of meta-analysis as described by DerSimonian and Laird.

Results. The estimated increase in survival for patients treated with combination radiation and chemotherapy was 10.1% at 1 year (95% confidence interval, 6.8, 13.3%) and 8.6% at 2 years (5.2, 12.0%). These absolute increases in survival (treated-control [TC]) in patients treated with chemotherapy represent relative increases (T-C)/C of 23.4% at 1 year (15.8, 30.9%) and 52.4% at 2 years (31.7, 73.2%). This survival advantage is conferred by several different chemotherapeutic agents. When the prognostic variables of age and histology are factored into the analysis, however, the data suggest that the survival benefit from chemotherapy occurs earlier in patients with anaplastic astrocytoma (AA) than in patients with glioblastoma.

Conclusions. The authors concluded that chemotherapy is advantageous for patients with malignant gliomas and should be considered part of the standard therapeutic regimen. Additional randomized trials using optimal radiation and chemotherapy may still be needed to precisely define which subgroups of patients, based on prognostic variables, will benefit most from chemotherapy after radiation.

Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults

The term "Sjogren's syndrome" (SS) is frequently used to describe the occurrence of keratoconjunctivis sicca and xerostomia in association with an autoimmune disorder. However, well-defined criteria for the classification of SS have not been established, and this diagnosis is being applied to a wide spectrum of conditions, ranging from clear "autoimmune" disease in some patients, to sicca complaints without evidence of a systemic immune process in elderly patients. Here, we review the clinical and laboratory features of patients referred for evaluation of sicca symptoms. In particular, we emphasize the need for care in choosing the site for minor salivary gland biopsy, and we describe the histologic features that aid in the evaluation of these biopsy specimens. In an attempt to identify a population of patients whose conditions might have a common etiopathogenesis and, thus, a common treatment program, we propose the following criteria for a diagnosis of SS: 1) objective evidence of keratoconjunctivis sicca, as documented by rose bengal or fluorescein dye staining; 2) objective evidence of diminished salivary gland flow; 3) minor salivary gland biopsy, obtained through normal mucosa, with the specimen containing at least 4 evaluable salivary gland lobules, and having an average of at least 2 foci/4 mm2; 4) evidence of a systemic autoimmune process, as manifested by the presence of autoantibodies, such as rheumatoid factor and/or antinuclear antibody. The diagnosis of "definite SS" would be made when all 4 criteria are met; the diagnosis of "possible SS" would be made when 3 criteria are present. Specific exclusions for this diagnosis are preexisting lymphoma, graft-versus-host disease, sarcoidosis, and acquired immunodeficiency disease.(ABSTRACT TRUNCATED AT 250 WORDS)

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780290501

Sjögren's syndrome. Proposed criteria for classification

Significance: Extensive research during the last quarter century has revealed that reactive oxygen species (ROS) produced in the body, primarily by the mitochondria, play a major role in various cell-signaling pathways. Most risk factors associated with chronic diseases (e.g., cancer), such as stress, tobacco, environmental pollutants, radiation, viral infection, diet, and bacterial infection, interact with cells through the generation of ROS. Recent Advances: ROS, in turn, activate various transcription factors (e.g., nuclear factor kappa-light-chain-enhancer of activated B cells [NF-κB], activator protein-1, hypoxia-inducible factor-1α, and signal transducer and activator of transcription 3), resulting in the expression of proteins that control inflammation, cellular transformation, tumor cell survival, tumor cell proliferation and invasion, angiogenesis, and metastasis. Paradoxically, ROS also control the expression of various tumor suppressor genes (p53, Rb, and PTEN). Similarly, γ-radiation and various chemotherapeutic agents used to treat cancer mediate their effects through the production of ROS. Interestingly, ROS have also been implicated in the chemopreventive and anti-tumor action of nutraceuticals derived from fruits, vegetables, spices, and other natural products used in traditional medicine. Critical Issues: These statements suggest both “upside” (cancer-suppressing) and “downside” (cancer-promoting) actions of the ROS. Thus, similar to tumor necrosis factor-α, inflammation, and NF-κB, ROS act as a double-edged sword. This paradox provides a great challenge for researchers whose aim is to exploit ROS stress for the development of cancer therapies. Future Directions: The various mechanisms by which ROS mediate paradoxical effects are discussed in this article. The outstanding questions and future directions raised by our current understanding are discussed. Antioxid. Redox Signal. 16, 1295–1322.

/pdf/upsides-and-downsides-of-reactive-oxygen-species-for-cancer-4b2dwkkilo.pdf

Upsides and Downsides of Reactive Oxygen Species for Cancer: The Roles of Reactive Oxygen Species in Tumorigenesis, Prevention, and Therapy

Xerostomia is an unsatisfactory diagnostic criterion for the salivary component of Sjogren's syndrome (SS). To determine the diagnostic usefulness of the presence of focal sialadenitis in labial salivary gland (LSG) biopsy specimens, 362 patients suspected of having SS prospectively underwent a unique LSG biopsy procedure. The pattern and severity of LSG inflammation were compared with measurements of parotid flow rate, and the presence or absence of symptomatic xerostomia, major salivary gland enlargement, keratoconjunctivitis sicca (KCS), and other connective tissue diseases (CTD). LSG biopsy focus scores of >1 correlated more closely with the diagnoses of KCS alone and with KCS plus a CTD than did either reduced parotid flow rate or symptoms of xerostomia (P < 0.0005 and P < 0.05, respectively). Focal sialadenitis in an adequate LSG specimen is an objective criterion and a more disease-specific feature of SS than xerostomia or any other feature of salivary disease. The salivary component of SS should be redefined as the presence of LSG focal sialadenitis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780270205

Labial salivary gland biopsy in sjögren's syndrome

The practice of perioperative fluid therapy is variable, ranging from ‘high volume’ to ‘dry’ regimen. A review of the data on the effect of ‘high volume’ perioperative fluid therapy suggests that the resulting overhydration may have deleterious effects on cardiac and pulmonary function, and on recovery of gastrointestinal motility (postoperative ileus), tissue oxygenation, wound healing and coagulation. These observations call for randomized studies of the effects of ‘high’ vs ‘low’ volume replacement therapy on postoperative morbidity, in order to establish evidence-based guidelines for perioperative fluid management. Perioperative fluid replacement has been, and still is, the focus of much debate. This debate has primarily focused on the various types of fluid components available for replacement therapy, and not on the actual amount of fluid administered.

Pathophysiology and clinical implications of perioperative fluid excess

Eighty-one patients with recurrent primary or metastatic brain tumors were treated with carmustine (BCNU [1,3-Bis(2-chloroethyl)-1nitrosourea]) alone or carmustine and vincristine sulfate combined, and their responses analyzed. A response was defined as a clear clinical improvement unrelated to corticosteroid therapy. The overall response rate with carmustine was 48% and with the combination, 30%. In patients with glioblastoma, the response rates were 53% and 25%, respectively. The most responsive tumors were ependymomas; the least responsive, metastatic. The dose-limiting toxicity of carmustine was exclusively hematologic; of vincristine, exclusively neurologic, and severe enough to make drug effectiveness difficult to assess. We conclude that carmustine is an effective chemotherapeutic agent, with an acceptable level of toxicity, for the treatment of brain tumors. Vincristine did not enhance the effectiveness of carmustine and we have discontinued the use of these drugs in combination.

https://jamanetwork.com/journals/jama/articlepdf/345130/jama_222_5_004.pdf

The Chemotherapy of Brain Tumors: Clinical Experience With Carmustine (BCNU) and Vincristine

Forty-eight patients with primary or metastatic malignant tumors of the central nervous system (CNS) were treated with combination chemotherapy, consisting of procarbazine (100 mg/m2 × 14 days), CCNU (75 mg/m2), and vincristine (1.4 mg/m2 × 2, 1 week apart) (PCV) every 4 weeks. Most patients had undergone initial resection of primary tumors, postoperative radiotherapy, and a post irradiation interval of 3 months or more. Other patients harbored unbiopsied, newly-discovered primary or metastatic tumors. All patients were deteriorating neurologically when treatment began. Overall response rate for PCV combination therapy was 44%, no better than results obtained with single agent procarbazine or BCNU, the most effective drugs used alone in previous brain tumor chemotherapy studies.

Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors.

Sequential salivary scintigraphy, labial salivary gland biopsy, and measurement of stimulated parotid flow rate were performed in 50 patients suspected of having Sjogren's syndrome. The value of these tests in the diagnosis of this disease was compared. Salivary scintigraphy and labial salivary gland biopsy can be used together to diagnose the oral component of Sjogren's syndrome. Abnormal salivary scintigraphy correlated with both of the other tests and may be considered optional in the diagnostic evaluation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780220801

An evaluation of salivary scintigraphy in sögren's syndrome

Summary The fluid requirements and shifts after reconstruction of the abdominal aorta were analyzed retrospectively in one hundred patients and prospectively in ten patients. Nine per cent of the patients undergoing operation while receiving fluid regimen of balanced saline solution infused at 500 to 1,000 ml per hour and replacement of lost blood developed complications secondary to fluid overload. Distribution of retained fluid with this regimen was determined in six patients by clinical, laboratory, and isotopic measurements. The weight increased by 6 per cent, ECFV rose 33 per cent, and renal function and solute excretion increased markedly by the second postoperative day. In four patients a balanced saline solution was infused at a rate sufficient to maintain urinary output at 50 to 55 ml per hour during operation. Although this regimen reduced the volume of infused fluid by 50 per cent, it appeared to meet the obligatory ECFV loss, while preserving normal renal function and lessening the risks of systemic fluid overload.

Malcolm R. Powell

Papers

The Chemotherapy of Brain Tumors: Clinical Experience With Carmustine (BCNU) and Vincristine

Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors.

An evaluation of salivary scintigraphy in sögren's syndrome

Fluid requirements and shifts after reconstruction of the aorta