Behavioral factors to modulate immunotherapy efficacy in cancer.

Immune checkpoint inhibitors, including anti-PD-1 and anti-CTLA-4 therapies, are used to (re)activate the immune system to treat cancer. Despite promising results, a large group of patients does not respond to checkpoint inhibition. In the vulnerability-stress model of behavioral medicine, behavioral factors, such as stress, exercise and classical pharmacological conditioning, predict cancer incidence, recurrence and the efficacy of conventional cancer treatments. Given the important role of the immune system in these processes, certain behavior may be promising to complement immune checkpoint inhibition therapy. Here, we discuss the preliminary evidence and suitability of three behavioral mechanisms, i.e. stress modulation, exercise and classical pharmacological conditioning for the benefit of immunotherapy. It is crucial to study the potential beneficial effects of behavioral strategies that support immunotherapeutic anti-tumor effects with rigorous experimental evidence, to exploit behavioral mechanisms in improving checkpoint inhibition efficacy.

Eye-tracking analyses of physician face gaze patterns in consultations.

Face gaze is a fundamental non-verbal behaviour and can be assessed using eye-tracking glasses. Methodological guidelines are lacking on which measure to use to determine face gaze. To evaluate face gaze patterns we compared three measures: duration, frequency and dwell time. Furthermore, state of the art face gaze analysis requires time and manual effort. We tested if face gaze patterns in the first 30, 60 and 120 s predict face gaze patterns in the remaining interaction. We performed secondary analyses of mobile eye-tracking data of 16 internal medicine physicians in consultation with 100 of their patients. Duration and frequency of face gaze were unrelated. The lack of association between duration and frequency suggests that research may yield different results depending on which measure of face gaze is used. Dwell time correlates both duration and frequency. Face gaze during the first seconds of the consultations predicted face gaze patterns of the remaining consultation time (R2 0.26 to 0.73). Therefore, face gaze during the first minutes of the consultations can be used to predict face gaze patterns over the complete interaction. Researchers interested to study face gaze may use these findings to make optimal methodological choices.

Evaluation of tests of exocrine and endocrine pancreatic function in older patients with cystic fibrosis.

In order to determine the value of noninvasive tests in the analysis of pancreatic function in cystic fibrosis, 14 older cystic fibrosis patients were studied by a set of noninvasive tests of exocrine and endocrine pancreatic function. The tests, comprising trypsin, total amylase, pancreatic isoamylase, lipase, pancreatic polypeptide (PP), glucose and insulin in fasting serum, PP, glucose and insulin in postprandial serum, and p-aminobenzoic acid (PABA) excretion in urine, were compared to fecal fat excretion after discontinuation of pancreatic enzyme supplementation. Eleven of the 14 patients were found to have a fecal fat excretion of more than 7 g/day. Serum levels of trypsin, pancreatic isoamylase and lipase, and the urinary excretion of PABA showed significant negative correlations with fecal fat excretion. Endocrine pancreatic function was abnormal in the majority of patients with fibrocystic disease. Although serum trypsin, postprandial PP, and urinary PABA excretion were the most sensitive tests for severe exocrine pancreatic insufficiency, the differences in sensitivity were rather modest. Therefore, the type of test to be selected for clinical use is mainly dependent upon factors as accessibility, simplicity, patient's acceptability, and costs.

Significance of screening in treatment and survival in bronchial carcinoma.

In a retrospective study, the influence of the way bronchial carcinoma was detected was evaluated with respect to the possibility of surgery and to survival rates. From the 324 patients detected through mass screening (category I) 69.8% were suitable for surgery, whereas only 41.4% of the 736 patients detected because of pulmonary symptoms (category II) were deemed surgery-eligible. In category I, the type of surgical interventions were 65% (bi)lobectomy and 22.4% pneumonectomy. In category II, these figures were 23.4% and 53.6%, respectively. During the surgery, 10.6% turned out to be unresectable in category I, whereas 22.0% were in category II. There was also a marked difference in survival after 5 and 10 years. For category I, the 5-year survival rate was 23.4%, the 10-year survival 10.9%. In category II, these figures were 8.6% and 4.2%, respectively. The 5-year survival rate of all nonsurgically treated patients was 1% regardless of the method of diagnosis.

Surgery of pulmonary metastases.

From 1954 to 1985, 150 metastases were removed in 80 patients (55 males, 25 females) with an age range from 8 to 82 years. The role of pulmonary resection for metastatic lesions of the period 1954 to 1975 (group I) was compared to the period 1976 to 1985 (group II). In group I, 48 metastases were resected in 35 patients and in group II, 102 metastases in 45 patients. The surgical mortality in the total population was 1%. The average interval from diagnosis of the primary neoplasm to diagnosis of thoracic metastases was 4 years in both groups. Primary neoplasm localization did not differ in the 2 groups. In both groups approximately 50% of the patients were without symptoms. Wedge resection and lobectomy were the most frequent procedures followed by segmentectomy and pneumonectomy. The median post thoracotomy survival was 21 months in group I and 36 months in group II. Although the tumor-free interval, presenting symptoms and surgery did not differ in the 2 groups, the actuarial 5-year survival in group I was 31%, and 53% for group II. Neither sex, age nor the lung resection type significantly affected the therapeutic results. Good prognostic factors were a non-seminomatous testicular tumor as the primary tumor, a tumor-free interval longer than 60 months and a tumor-doubling time longer than 136 days. Poorer results were obtained in the presence of N2 metastases, and of a large tumor volume. It seems that with the increased effectiveness of chemotherapy, especially in non-seminomatous testicular tumor, the role of surgery is changing. Surgery is now also indicated to resect metastases unresponsive to chemotherapy and to obtain histology of stabilized lesions after chemotherapy.

En bloc resection for bronchogenic carcinoma with chest wall invasion.

The incidence rate of chest wall invasion in operated bronchogenic carcinoma is about 3%. From 1973 to 1984, 12 patients in our hospital underwent en bloc lung and partial chest wall resection for bronchogenic carcinoma with local invasion of the thoracic wall. All were male, between 49 and 74 years of age. Chest wall or back pain was the most prominent complaint. The duration of symptoms varied from 2 to 20 months. In 10 the tumour was peripherally and in 2 centrally located. Mediastinoscopies, selectively performed were negative. In 11 patients there was a squamous cell and in 1 an adenocarcinoma. 10 lobectomies and 2 pneumonectomies were performed. Macroscopic size of the tumour ranged from 3 to 17 cm, the number of partially resected ribs ranged from 1 to 4. There was 1 operative death (8%). 3 patients died within 5 months and 3 other patients within 14 months. 5 patients are still alive, 2 more than 5 years (17%). The survival is unfavourably influenced by lymph node involvement. The majority of patients became free of pain one month after surgery.

The therapeutic approach to intrathoracic metastases of non-seminomatous testicular tumour.

Before the era of chemotherapy an extensively metastasized non-seminomatous testicular tumour was nearly always fatal. Only 10 cases of spontaneous regression of thoracic metastasis have been reported. With chemotherapy, a much better outlook has been achieved, however, in 10% of the cases, chemotherapy resistant thoracic masses remain after treatment. In 70 to 80% of those cases with normal tumour markers, mature teratoma is found. In this paper, three patients with non-seminomatous testicular tumour and thoracic opacities resistant to conservative treatment are reported. One patient showed a complete disappearance of 9 out of 10 thoracic opacities 6 months after a short chemotherapy course, which had seemed to be ineffective. After a short period of reduction, the remaining opacity demonstrated continued tumour growth with a significantly longer tumour doubling time. The other two patients showed enlarged thoracic opacities despite combination chemotherapy and normal tumour marker levels. At the time of thoracotomy and complete surgical resection of the tumours all patients had normal tumour marker levels. Mature teratoma without genuine malignant cells was found microscopically. At this time all patients are free of metastases, 18, 3.5 and 2 year post thoracotomy. We suggest complete extirpation of the chemotherapy resistant lesions because, mature teratoma may give rise to compression and because in the cases with notwithstanding normalization of tumour markers and active tumour histology has to be obtained to restart combination chemotherapy.

Evaluation of short-course preoperative irradiation in the treatment of resectable bronchus carcinoma: long-term analysis of a randomized pilot-study.

A randomized pilot-study on patients with resectable non small-cell lung carcinoma was conducted from December 1971 to May 1976 inclusive. Patients were randomly assigned to receive preoperative irradiation to the mediastinum followed by surgery (RT + S), or to be treated by surgery only (SO). A total of 33 patients clinically staged as T1-2, N0, M0 histologically confirmed bronchus carcinoma were entered onto the study. Sixteen patients were assigned to RT + S and 17 patients received SO. There were 3 operative mortalities, all of them in the SO group. A total of 28 patients, 14 in each group are evaluable, with a minimum period of observation of 7 years. Preoperative irradiation consisted of a Telecobalt photon-beam applied to the mediastinum as anterior and posterior portals. The thoracic spine was protected on the posterior portal by a narrow lead block. A total dose of 20 Gy calculated in the mid plane was given in 5 equal fractions each of 4 Gy administered on 5 consecutive days: Monday through Friday; patients were operated on the following Monday after the week-end. Surgical treatment was similar for both groups and consisted of lobectomy or pneumonectomy, depending on the size and site of the primary tumor. Analysis of the survival data showed an absolute crude 5 years survival rate of 58% for patients who received RT + S versus 43% for SO. The corrected actuarial 5 and 10 years survival rates are 78 and 69% for the group that received RT + S, and 67 and 55% for the group treated by SO, respectively. Nineteen patients were treated more than 10 years ago. Four of 8 (50%) treated by RT + S are alive with no evidence of disease (NED), and 3/11 (28%) treated by SO are alive with NED. The median survival period for the group that received RT + S is 72 months versus 30 months for the group treated by SO. Analysis of the adequacy of surgical resection based on histological examination of the operative specimen showed higher incidence of radical resection in the group that received RT + S (57 versus 28.5%). It is concluded that the treatment protocol of preoperative radiation therapy as outlined is well tolerated and the results are encouraging.

Chest wall resection for bronchogenic carcinoma.

The incidence rate of chest wall invasion in bronchogenic carcinoma is difficult to estimate, but is possibly as high as 5%. These cancers can be locally extensive without systemic dissemination. From 1973 to 1982, 9 patients in our hospital underwent en bloc pulmonary and partial chest wall resection for bronchogenic carcinoma with local invasion of the thoracic wall. All the patients were male, their ages ranging from 49 to 67 years. Pain was the most prominent symptom. Bronchoscopy examination revealed no tumors in 7 of the 9 patients, in one a tumor was seen in the apex of the right lower lobe and in another in the apex of the right upper lobe. Seven lobectomies and 2 pneumonectomies were performed. The macroscopic size of the tumour ranged from 3 to 17 cm, the number of partially resected ribs ranged from 1 to 4. In 8 cases squamous cell carcinoma was found, in one adenocarcinoma. After operation 7 patients were classified as T3N0M0 and 2 as T3N1M0. One T3N0M0 patient died shortly after operation due to a lung embolism. Two out of the 6 patients with T3N0M0 neoplasm survived more than 5 years, none of the patients with T3N1M0 neoplasm survived more than 3 months. Late deaths were due to recurrent carcinoma in the chest wall (2 cases), cerebral metastasis (1 case), cardiac failure (1 case) and unknown causes (2 cases). In cases where the lymph nodes are not involved, the survival rate is not unfavorably influenced by chest wall invasion. In the literature the mean operative mortality rate is 12%, the median survival time approximately one year and the mean 5-year survival rate 18%; resection is also of great importance in relieving pain.

[The triad: mediastinal chemodectoma, chondroma of the lung and esophageal leiomyoma]. / La triade: chémodectome du médiastin, chondrome du poumon et léiomyome de l'oesophage.

In 1958 a mediastinal tumor was discovered in an asymptomatic patient. The tumor was resected and diagnosed as a nonchromaffin chemodectoma. Additionally an oesophageal abnormality was discovered but not treated. At subsequent follow-ups the mediastinum never appeared normal and the heart size progressively increased. In 1974 a small opacity appeared in the left lung. In 1975 the patient was operated: a pulmonary osteochondroma, a pericarditis and an intrapericardial aortopulmonary chemodectoma were discovered. The oesophagus was not explored. In july 1979 an inoperable epidermoid carcinoma of the main bronchus of the left lung was discovered and the patient died in september 1979. There was no hypertension and no catecholamine excess. A post-mortem section was refused. After the recent description by Carney of the triad: extra-adrenal paraganglioma, lung chondroma and gastro-intestinal leiomyo(sarco)ma, we feel that our patient could present this syndrome and that the oesophageal tumor could be a benign leiomyoma. However the exact diagnosis of the oesophageal lesion is still unknown.

Interferons and bronchogenic carcinoma in juvenile laryngeal papillomatosis.

A squamous cell carcinoma of the bronchus developed in a patient during the course of juvenile laryngeal papillomatosis. This patient had received interferon treatment, which caused regression of the papillomas, but apparently had no influence on the progression of the bronchogenic squamous cell carcinoma. This suggests that interferons have an antiviral effect, but not an antitumor effect in the dosage used. No radiation therapy had been given in the past and no other carcinogenic factors are obvious. However, human papilloma viruses, which cause juvenile laryngeal papillomatosis, have been incriminated in the genesis of squamous cell carcinomas.

[Carcinoid tumors, adenoid-cystic carcinomas and muco-epidermoid carcinomas of the tracheo-bronchial tree (author's transl)]. / Carcinoïd tumoren, adenoïd-cystische carcinomen en muco-epidermoïde carcinomen van de tracheo-bronchiale boom.

A retrospective study of 25 cases with a so-called bronchial adenoma was made. Classification by this old-fashioned nomenclature included 76% carcinoid tumors, 20% adenoid-cystic carcinomas and 4% muco-epidermoid carcinomas of the trachea and bronchial tree. With regard to their malignant potential, the correlation between histological differentiation, invasiveness, metastatic spread and clinical evolution is discussed. An outline of the extent of therapy for each of the 3 types is given.

[Surgical treatment of pulmonary metastases (author's transl)]. / De chirurgische behandeling van longmetastasen.

From April 1954 till February 1976, pulmonary resections for metastases of primary extrapulmonary malignancies have been done on 35 patients, 21 men and 14 women with average age of 49 years 7 months. In about half of the cases the lung opacities were discovered occasionally. Three patients have undergone a second thoracotomy for a recurrent metastasis. Of the 48 resected metastatic lesions, 31 were located in the right and 17 in the left lung. Thirty were on resection unilateral and solitary. There was no operative mortality and the postoperative morbidity was neglectable. The cumulative 3- and 5-years survival percentages as obtained by the life-table method were 44.6 and 31.2. Better survival rates were found in the age group of 0-40 years and in the group of the sarcomas. Worse results were obtained when the primary tumor was invasive or associated with regional metastases. Resection of metastatic lung lesions larger than 5 cm diameter and especially the resection of multiple lesions gave poorer results. The time-interval between the primary operation and the pulmonary resection had no clear prognostic value. The factors determinating the palliative character of the pulmonary resection had a negative influence on the survival. None of the 9 patients with pulmonary metastasis and secondary intrathoracic lymphatic metastases did survive longer than 3 years. All these patients had a primary carcinoma. Out of this study no conclusions can be made as to the extension of the pulmonary resection.