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PubMed2025

High Prevalence of Potential Molecular Therapeutic Targets in Poorly Differentiated Thyroid Carcinoma.

Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid cancer with aggressive clinical course and peculiar clinical/pathological characteristics but lacking effective therapeutic options, when surgery is not curative. We aimed at the molecular characterization of PDTC with a specific focus on the identification of potential therapeutic targets. A series of PDTC cases was selected from a multi-institutional network. Fifty-nine samples underwent wide targeted DNA and RNA next-generation sequencing (NGS) testing and immunohistochemical analysis for mismatch repair (MMR) proteins. Gene fusion analysis was enriched by 25 additional samples. Prevalence of MMR protein loss was 11.9%. The most prevalent mutations were in NRAS (25%) and TP53 (25%), mutually exclusive. TERT promoter (TERTp) mutations were detected in 19.6% of cases (10/51). NRAS-mutated cases were enriched for mutations in genes belonging to the same pathway. TP53-mutated samples lacked TERTp co-mutations, but were associated with mutations in PTEN and in genes related to MMR system and/or loss of MMR proteins. TERTp mutations were the most prevalent alterations (28%, 7/25) in a third group that lacked NRAS or TP53 mutations. Four cases harbored gene fusions, including two cases harboring the TBL1XR1::PIK3CA fusion that has never been reported in thyroid cancer, so far. In conclusion, PDTC may be genomically segregated in subgroups with specific molecular characteristics. Overall, targetable gene fusions have a prevalence of 9% (4/42). Moreover, 47% of cases are potential candidates for individualized target therapies since they harbor mutations in genes coding for potentially targetable molecules and/or have defects in the MMR system.

Humans↗
PubMed1994

Present views of the surgical treatment of non-small cell lung cancer.

There is consensus regarding a pretreatment minimal staging protocol for non-small cell lung cancer. We adopted the new TNM-classification and staging system. For the preoperative mediastinal exploration CT scan (with contrast) and mediastinoscopy are complemental explorations. We avoid to operate on patients with multiple involved mediastinal lymph nodes (N2) or with involved contralateral (N3) or supraclavicular lymph nodes (N3). The final goal is a complete or potentially curative resection including mediastinal lymphadenectomy. The survival of the patient is mainly dependent of the N-status. When N2 disease is unsuspectedly discovered at operation, complete resection with mediastinal lymphadenectomy is performed. The subgroup with the best prognosis is the group with negative mediastinoscopy, lobectomy for central tumor and minimal N2, intracapsular. Multimodal therapy is investigated via multi-institutional trials. Chest wall involvement by lung cancer (T3) does not imply a hopeless prognosis. En-bloc resection of lung and partial chest wall is performed if possible. The 5 year survivors share common features: asymptomatic before operation, non-smokers, no riberosion, squamous cell carcinoma, chest wall resection limited to two ribs and N0-status. For Pancoast-tumors (T3) we follow the Paulson treatment protocol. After the usual staging, the candidates for surgery receive preoperative radiotherapy, followed by complete en-bloc resection, and eventual postoperative radiotherapy in case of incomplete resection. Careful follow-up of all patients operated for lung cancer is necessary, as the incidence of a metachronous lung cancer is as high as 10% for the long survivors. When a second or third primary lung cancer appears, reoperation is the treatment of choice in the absence of metastases or other contraindications. In most cases a complete curative resection is possible. Pulmonary resections have to be complete, but as conservative as possible, eventually with broncho- and angioplasty.

Adult↗
PubMed1995

Thoracoscopic staging and surgical therapy for esophageal cancer.

Esophageal cancer continues to be a major health problem with an associated poor prognosis. New technology is being applied to the staging of this cancer. The new staging system requires assessment of depth of wall penetration and lymph node status prior to resection. To determine penetration and node status with a high degree of accuracy generally requires some combination of chemotherapy, magnetic resonance imaging, endoesophageal ultrasound, and/or surgical staging. Several variables need to be considered in planning the surgical approach to the patient with esophageal cancer: the intent of the surgeon to either cure or palliate, the anatomic location of the tumor, and the method of reconstruction. Surgery is optimal for localized esophageal cancer. Neoadjuvant chemoradiation has increased survival in specific subgroups. Phase 2 trials have shown the safety and efficacy of chemoradiation. Randomized multi-institutional trials are needed to verify the encouraging results of recent phase 2 trials.

Chemotherapy, Adjuvant↗
PubMed1983

Immunology of head and neck cancers.

Despite the ever growing collection of data concerning the function of the immune system in patients with epidermoid carcinoma of the head and neck, the precise mechanism by which these tumors effect the body's surveillance against foreign antigen is as yet unidentified. If these specific immunological characteristics of the cancer cell can be identified, laboratory analysis of these "markers" could lead to detection and treatment of cancer in its earliest stages. Included in this chapter is a review of the embryological development of the immune system, a description of the components of the immune system and their responses to invasion by tumor antigen. Measurements of immuno responsiveness of the individual are important in determining the pretreatment state of immuno-competence and in predicting prognosis following treatment. Measurements of T-lymphocyte functions and their response to immuno-manipulations can also aid in predicting which patients will benefit from immunotherapy. Finally, categorization of the multiple forms of immunotherapy including active, specific and non-specific, and adoptive mechanisms are discussed. More recent methods of related immunotherapy trials will also be mentioned. As of this writing, the trials of immunochemotherapy have not produced any conclusive results due to the lack of multi-institutional trials and limited quantities of immunotherapeutic agents for these clinical trials.

Adjuvants, Immunologic↗
PubMed1980

Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan.

A multi-institutional collaborative study was conducted concerning the course of pregnancy and delivery and the incidence of abnormal infants delivered of epileptic women. Of 657 women receiving antiepileptic drugs, 73% delivered live infants, 14% had miscarriage or stillbirth, and 13% underwent induced abortion. In contrast to the above findings, 80% of 162 patients not receiving antiepileptic drugs delivered live infants and 4% had miscarriage or stillbirth. The latter outcome was significantly increased in the medicated patients. In this series, 63 (9.9%) of 638 live births were malformed, 55 (11.5%) being from medicated mothers and 3 (2.3%) from nonmedicated mothers. The incidence of fetal malformation in medicated mothers was thus five times as high as that in nonmedicated mothers. Cleft lip and/or palate and malformations involving the cardiovascular system were found frequently in the infants from medicated mothers. General background factors that might exert teratogenic effects on pregnant patients with epilepsy were studied, and the potential toxicity of antiepileptic drugs to the fetus was also analyzed. In this regard, consideration should be given to whether the patient has partial epileptic seizures, whether the patient herself exhibits any malformation, or whether her previous pregnancy resulted in an abnormal outcome. The incidence of fetal malformation was the highest (12.7%) in the medicated patients who had epileptic seizures during the pregnancy. It is presumed on the basis of the results of analysis of the data that a combination of more than three drugs and a daily dose greater than a certain minimal level is likely to produce malformed infants.

Abnormalities, Drug-Induced↗
PubMed1981

Outcome of intensive care. An application of a predictive model.

The development of a scoring system to estimate equivalency of illness between individuals has been undertaken. A model has been formulated to calculate probability of survival from each of 225 potential "conditions" apt to occur in patients admitted to intensive care areas. The presence or absence of each factor was noted on admission to a university hospital ICU. The relation between conditions noted in observations on a sample of patients, and survival allows assignment of a weight to each complication on the basis of which a "Condition Index Score" (CIS) or prognosis index can be objectively calculated. Potential uses of CIS are to: (1) establish objective criteria for admission to and discharge from intensive care, and for transfer to tertiary care centers; (2) compare quality of care (outcome vs. CIS) between different intensive care facilities; (3) serve as basis for multi-institutional studies concerning critically ill patients; (4) compare outcomes in groups of patients with equal CIS who are and are not treated in ICUs; and (5) establish appropriate numbers of critical care beds for any hospital or area by CIS criteria.

Critical Care↗
PubMed1989

National Pediatric Trauma Registry.

The National Pediatric Trauma Registry (NPTR) is a multi-institutional database designed to compile information concerning all aspects of pediatric trauma care. The registry is designed and operated in a manner that maximizes data accuracy and provides this information to all participating investigators. The growth of the database has allowed the NPTR to provide the first accurate epidemiologic description of pediatric trauma as a national disease, as well as to develop national norms for pediatric trauma care. The registry presently contains 10,177 patients, and is undergoing revisions (phase II) to allow a more focused evaluation of various aspects of the clinical care and rehabilitation of the pediatric trauma patient.

Child↗
PubMed1988

An organized multi-institutional interdisciplinary evaluation of role of radiation therapy alone or combined with chemotherapy in treatment of adenocarcinoma of the gastrointestinal tract.

Adenocarcinomas of the gastrointestinal tract have generally been considered to be radioresistant. In 1974-1975, following an early lead from the Mayo Clinic (Rochester, MN), the Gastrointestinal Tumor Study Group initiated a series of clinical trials of radiation therapy and chemotherapy as surgical adjuvant programs for patients with pancreatic and rectal cancer and for the treatment of locally unresectable gastric and pancreatic adenocarcinomas. The first protocols for pancreatic cancer included a controlled trial of radiation therapy and chemotherapy following pancreatoduodenectomy or total pancreatectomy and also a randomized trial of high-dose radiation therapy, with or without chemotherapy, compared to a lower dose of radiation therapy combined with chemotherapy for patients with locally unresectable tumors. In the treatment of locally incurable gastric cancer, radiation therapy plus chemotherapy was compared to chemotherapy alone, while the rectal trial was a randomized comparison of radiation therapy; chemotherapy; the combination of radiation therapy and chemotherapy; and no further treatment following surgical extirpation. In all cases, the agent used during the course of radiation was 5-fluorouracil. Subsequent trials in pancreatic cancer compared radiation combined with either 5-fluorouracil or doxorubicin and included a pilot study of hyperfractionated radiation therapy combined with 5-fluorouracil. Confirmatory trials were undertaken and are still under analysis in gastric cancer and in rectal cancer. A follow-up trial in pancreatic cancer was developed to establish the importance of the radiation therapy component of combined modality therapy in the treatment of patients with locally unresectable disease. A final study examined the potential for radiation therapy of the liver and systemic chemotherapy in the prevention of metastatic adenocarcinoma of the colon.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1989

[Immunity of gut-associated lymphoid tissue and the role of the oral immunotherapy in multi-disciplinary treatment of the digestive organ cancer].

In order to augment antitumor immunity of gut-associated lymphoid tissue in digestive organ cancer, oral administration of various biological response modifiers were studied using mice transplanted with cecal tumor. Among them OK-432 was the most effective and clinical application of oral OK-432 was studied. Autoradiogram and immunofluorescence studies showed the absorption of orally administered OK-432 from the gut. In phase I study oral OK-432 was much less toxic than other administration routes. Phase II study showed that oral OK-432 at various doses augmented antitumor immunity of the lymphocytes of peripheral blood and regional lymph node. In a multi-institutional study on postoperative adjuvant immunotherapy, 1011 gastric cancer patients were accumulated and randomized to compare the effects of oral and intradermal OK-432. In patients who underwent curative operation, 1-, 2- and 3-year survival rates (%) were 95, 88 and 82 for oral OK-432 group (n = 255), 88, 83 and 80 for the placebo group (n = 260), and 89, 79 and 73 for intradermal OK-432 group (n = 261). There was significant differences among cumulative survivals of three groups, and this life-prolonging effect of oral OK-432 was remarkable for stage II or III patients. These results demonstrate that oral immunotherapy with OK-432 is useful as an immunotherapy of digestive organ cancers.

Administration, Oral↗
PubMed1990

Pulmonary hypertension in connective tissue disease. Clinical analysis of sixty patients in multi-institutional study.

Clinical features and prognosis of sixty patients with connective tissue disease accompanied by pulmonary hypertension (PH) (26 MCTD, 20 SLE, and 14 PSS) reported retrospectively by multi-institutions were compared. Though the obtained data were incomplete and lacking in uniformity, no significant difference in the clinical features among the three diseases were observed except high incidence of pulmonary fibrosis and low % VC in PSS and PH patients. Statistically significant difference, however, was observed between live and dead patients of three diseases gathered in post sternal pain, pulmonary diastolic murmur, right ventricular hypertrophy on ECG and mean pressure of pulmonary artery. Higher incidence of anti-nRNP antibody was observed in SLE with PH and PSS with PH patients than with the general population. A quicker occurrence of PH and shorter survival time were observed in MCTD patients with PH than in SLE and PSS patients with PH.

Adult↗
PubMed1994

A comprehensive multi-institutional study of empiric therapy with flomoxef in surgical infections of the digestive organs. The Kyushu Research Group for Surgical Infection.

The effect of flomoxef as empiric therapy for surgical infections of the digestive organs was analyzed in 103 patients, most of whom (94.2%) had intra-abdominal infections. Surgical procedures were performed on 73 patients contemporaneously with the flomoxef therapy. Flomoxef is an oxacephem and has a potent and broad bactericidal spectrum against aerobes and anaerobes. It provokes fewer adverse reactions than latamoxef such as vitamin K deficiency and platelet dysfunction. Flomoxef was administered intravenously at a dose 1-4g/day for more than 3 days without any other antimicrobial agent. The clinical response was classified into 3 groups; cured, improved and failed, and both the cured and improved responses were defined as satisfactory. A satisfactory response was obtained in 99 patients (96.1%). Regarding bacteriological response, the overall eradication rate was 81.3%. Adverse reactions including abnormal laboratory data occurred in only two patients. One had abdominal pain, and the other had a mild elevation of transaminases, and both were mild and easily reversible. Therefore, flomoxef is considered to have the potential of becoming one of the most effective agents in empiric therapy for surgical infections of the digestive organs.

Adolescent↗
PubMed1982

Leukocyte-derived interferon (alpha) in human breast carcinoma. The American Cancer Society phase II trial.

A multi-institutional trials program was initiated to define the effects of interferons in disseminated human breast carcinoma. Interferon alpha, prepared from buffy coats, was administered intramuscularly at 3 x 10(6) U daily for an initial period of 28 days. Of 23 patients who entered the program, five had an objective partial response of 92 days mean duration at diverse sites of involvement. Patients who responded were significantly older (p = 0.05) than nonresponders. Dose escalation in eight patients did not result in any clear evidence of additional responses. Major toxicities were fatigue, anorexia with weight loss, and reversible leukopenia (less than 3.5 x 10(9) leukocytes/L in 16 patients). Natural killer cell and antibody-dependent cell-mediated cytotoxicity were significantly (p less than 0.05) enhanced 48 hours after interferon administration began but subsequently declined despite continued therapy. Serum beta 2-microglobulin concentration increased on day 15 (p less than 0.05) and remained significantly elevated on day 22 (p less than 0.005). Peak interferon titers (mean, 62 U) occurred 6 hours after interferon was started, varied widely between patients, and were higher and more persistent with dose escalation. Once an optimal dose is defined, prospectively randomized trials will define what role interferons may have in systemic therapy of breast carcinoma.

Adult↗
PubMed1991

A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder.

BACKGROUND: In carcinoma of the bladder, both intravesical chemotherapy and immunotherapy can induce tumor regression and reduce the rate of recurrence, but the relative merits of these two therapies are unclear. We conducted a multi-institutional study to address this question. METHODS: Patients with rapidly recurrent (stage Ta and T1) or in situ transitional-cell carcinoma of the bladder were randomly assigned to receive either doxorubicin administered intravesically or bacille Calmette-Guérin (BCG) administered both intravesically and percutaneously. The 262 eligible patients were followed for a median of 65 months. Complete responses to treatment of carcinoma in situ were confirmed by biopsy and cytologic analysis of the urine. RESULTS: For patients with Ta and T1 tumors without carcinoma in situ, the estimated probability of being disease free at five years was 17 percent after doxorubicin, as compared with 37 percent after immunotherapy with BCG (P = 0.015). The median times to treatment failure (termination of treatment, due to persistence, recurrence, or progression of disease) were 10.4 and 22.5 months, respectively. For patients with carcinoma in situ the complete-response probability estimates (i.e., the estimated probability of documented disappearance of disease) were 34 percent for doxorubicin (23 of 67 patients) and 70 percent for BCG (45 of 64 patients) (P less than 0.001); the median times to treatment failure were 5.1 and 39 months, respectively. The probability of being disease-free at five years survival among the patients with carcinoma in situ was 18 percent after treatment with doxorubicin and 45 percent after BCG therapy. Patients treated with BCG had a higher incidence of toxic systemic effects and a larger number of local irritative symptoms than patients treated with doxorubicin, but few of these adverse reactions were severe. CONCLUSIONS: As compared with intravesical doxorubicin, immunotherapy with BCG provides improved protection against the recurrence of superficial bladder cancer.

Administration, Cutaneous↗
PubMed1982

National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of a working formulation for clinical usage. The Non-Hodgkin's Lymphoma Pathologic Classification Project.

An international multi-institutional clinicopathologic study of 1175 cases of non-Hodgkin's lymphoma sponsored by the National Institute has been completed. Histologic slides and clinical records were examined from previously untreated patients seen during the period between July 1971 and December 1975 at four institutions, three in the United States and one in Italy. The reproducibility and clinical relevance of the six major classifications of the non-Hodgkin's lymphomas was tested by six "expert" pathologists, each a proponent of a major classification, and six very experienced pathologists not identified with one of the major classifications. Immunologic methods were not employed in the study design. A summary of the methods employed and the conclusions of the study is described. The major conclusion was that all six classifications were valuable and comparable in reproducibility and clinical correlations. The clinical significance of a follicular architecture, independent of cell type was confirmed. A working formulation of non-Hodgkin's lymphomas is described which separates the disease into ten major types utilizing morphologic criteria only. Subtypes are also described which allow translation of all of the major classifications into comparable groups. Histologic criteria are presented for each major type and equivalent terms are given for each type in the six major classifications. The formulation is not proposed as a new classification but a means of translation among the various systems and to facilitate clinical comparisons of case reports and therapeutic trials. The report contains commentaries by five of the "expert" pathologists on the value and conclusions of this unique study.

Actuarial Analysis↗
PubMedDate not supplied

Reliability of basic cancer patient data.

Pooling patient data from multi-institutional medical chart review occurs commonly in the study of cancer and other diseases. To determine the consistency of reporting among institutions, we presented a test set of 25 standardized medical charts to coders at 18 Comprehensive Cancer Centers and compared their resulting codes. This study measures the reproducibility of coding by different persons, but does not assess the accuracy of the underlying medical record. Among 34 data items, we found high disagreement rates in coding stage of disease (14 per cent) and date of diagnosis (8 per cent). Primary site, histologic type and other key items had good reproducibility (disagreement rates less than or equal to 5 per cent). A number of minor disagreements indicated that detailed distinctions could not be reliably coded from medical charts.

Forms and Records Control↗
PubMed2024

Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

Humans↗
PubMed1995

Influence of competitive pulmonary blood flow on the bidirectional superior cavopulmonary shunt. A multi-institutional study.

BACKGROUND: It is common practice to interrupt all alternative sources of pulmonary blood flow ("competitive flow") at the time of a bidirectional superior cavopulmonary anastomosis (BCPA), although the merits of this have not been systematically studied. METHODS AND RESULTS: We reviewed the early and medium-term clinical and hemodynamic findings in 108 consecutive patients 3 weeks to 25 years old (median, 1.9 years) undergoing BCPA at one of three institutions. Preoperatively, pulmonary blood flow was dependent on antegrade ventricular flow (n = 50), systemic-to-pulmonary shunts (n = 33), or mixed sources (n = 25). Postoperatively, competitive sources of pulmonary blood flow were left patent in 43 of 108 patients (40%). There were four early (3.7%) and four late deaths, none related to persistence of competitive flow. After BCPA, patients with competitive flow had significantly higher systemic oxygen saturations at 1 hour (85% versus 79%), 24 hours (84% versus 78%), and at hospital discharge (84% versus 78%) and required a shorter period of artificial ventilation (median, 9 versus 24 hours) and intensive care (median, 2 versus 4 days). Oxygen saturations at late follow-up (median, 2.8 years; range, 1 to 7) did not differ (83% versus 82%). No patient developed pulmonary arteriovenous malformations. CONCLUSIONS: Competitive flow is well tolerated in the short and medium term after BCPA, and early postoperative systemic oxygen saturations are improved. The long-term influence of competitive flow on pulmonary arterial growth, arteriovenous malformation development, and ventricular function warrants investigation.

Adolescent↗
PubMed1991

Chemotherapy for retinoblastoma: where do we go from here? A review of published literature and meeting abstracts, including discussions during the Vth International Symposium on Retinoblastoma, October 1990.

The history of the application of chemotherapy in the management of retinoblastoma (RB) may conveniently be divided into three eras: initial enthusiasm (from early 1950s to mid 1970s), realism (from late 1970s to mid 1980s) and possibility (from mid 1980s to the future). Available data from each of these eras are reviewed in the clinical categories of: intraocular RB, micrometastatic RB and overt dissemination. The latter is further sub-classified into: orbital invasion, central nervous system involvement and systemic metastases. Experimental models are described with particular emphasis on future directions. Early reports led to initial optimism subsequently dampened by a more critical approach. Recent results with increasingly effective chemotherapeutic regimens offer the possibility of a valid contribution in each of the above clinical settings. A multi-modality approach is recommended optimizing a combination of the most active drugs with continuing refinements of other techniques. In selected patients with intraocular, and particularly bilateral RB, visual outcome may be enhanced by the combined use of non-surgical modalities. Adjuvant treatment of presumed micrometastases needs to be studied within risk categories defined by prognostic factors. Invasion of the ocular coats and/or of the optic nerve are the most relevant factors but there are continued difficulties in defining the extent of involvement and eligibility criteria for such a strategy. Overt dissemination has recently been demonstrated to be curable in each of the three subgroups above. Intensive regimens incorporating cyclophosphamide, vincristine, cisplatinum, etoposide and possibly doxorubicin, plus intrathecal agents in combination with radiation therapy and, in some instances supplemented by bone marrow transplantation have produced promising results. Multi-institutional collaboration has been encouraged by the recently formed International Committee for the Staging and Management of Retinoblastoma, opening the way for prospective clinical trials. At the same time both laboratory and clinical experimental studies are being pursued and may produce further improvements in currently available strategies.

Drug Therapy↗