Prediction of postoperative pain from assessment of pain induced by venous cannulation and propofol infusion.

BACKGROUND: Postoperative pain may lead to delayed mobilization, persisting pain, and psychosocial distress. There are no simple and reliable techniques for prediction of postoperative pain. This study was designed to evaluate if pain induced by venous cannulation or propofol injection can be used to predict postoperative pain. METHODS: This prospective study included 180 patients scheduled for laparoscopic cholecystectomy. Pain intensity associated with peripheral venous cannulation and administration of propofol preoperatively and pain intensity, and use of opioid postoperatively was recorded. RESULTS: Patients scoring cannulation-induced pain intensity > 2.0 VAS units were given postoperative opioid more often (65% vs. 36%; P < 0.001), earlier (12 min vs. 90 min; P < 0.001), and in higher doses (4.8 mg vs. 0 mg; P < 0.001), and also reported higher levels of postoperative pain intensity (5.8 vs. 2.9 VAS units; P < 0.001). There were also significant (P < 0.01) correlations with postoperative pain intensity (rs = 0.24), time to opioid administration (rs = -0.26), and total dose of opioid (rs = 0.25). Propofol-induced pain intensity correlated significantly (P < 0.05) with postoperative pain intensity (rs = 0.19). CONCLUSION: Pain intensity associated with venous cannulation and propofol infusion can easily be evaluated at bedside before surgery without specific equipment or training. Patients scoring > 2.0 VAS units on venous cannulation were found to have 3.4 times higher risk of postoperative pain after laparoscopic cholecystectomy. Low pain intensity associated with venous cannulation and propofol infusion indicate lower risk of postoperative pain.

Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.

Background: Nivolumab was the first immuno-oncology agent available for the treatment of lung cancer in Canada. In the present study, we evaluated the real-world benefit of nivolumab in Canadian patients with lung cancer. Methods: Patients included in the cohort were identified from a registry of patients treated through expanded access to nivolumab before and after Health Canada approval. Demographics were collected from the application forms. Outcome data for the duration of treatment and survival were collected retrospectively. Results: In contrast to the randomized clinical trial populations, our study cohort included patients who were older (median age: 66 years; range: 36-92 years) and who had an Eastern Cooperative Oncology Group performance status of 2 (8.9%). Despite the poorer-prognosis cohort, median overall survival was 12.0 months, which is comparable to the survival demonstrated in the randomized phase iii trials of nivolumab in lung cancer. Median time to treatment discontinuation was 3.45 months and was similar for all patient subgroups, including poorer-prognosis groups such as those with a performance status of 2, those 75 years of age and older, and those with brain metastases. Conclusions: Nivolumab given in a real-world clinical setting was associated with results similar to those reported in the phase iii clinical trial setting.

Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Invasive carcinoma of the uterine cervix following diagnosis and treatment of in situ carcinoma. Record linkage study within a National Cancer Registry.

56117 women registered in the Swedish National Cancer Registry with the diagnosis carcinoma in situ of the uterine cervix were followed up and the risk for developing an invasive carcinoma of the uterine cervix was studied. The studied cohort provided 453 362 women years at risk. The primary treatment for carcinoma in situ in Sweden is generally conization. Hysterectomy is carried out in relatively few cases and intracavitary radium treatment was given to a limited number during the period studied. Cryosurgery and laser conization were of less quantitative importance during this period. The incidence rates of invasive carcinoma of the uterine cervix were compared with expected rates calculated from the National Cancer Registry. The ratio between observed and expected number of cases of invasive carcinomas of the uterine cervix is roughly 2.5 from the first year of observation after treatment of the in situ carcinoma until 20 years. There seems to be a distinct difference in risk for development of an invasive carcinoma of the uterine cervix for different age groups. In age group 50 years and older at time for treatment of the in situ lesion, 66 cases of invasive cancer were observed against 10.7 expected - O/E = 6.2. In ages 49 years or less, 145 cases were observed compared with 77.4 expected - O/E = 1.9. The conclusion from this study is that women treated for an in situ lesion are at a higher risk for an invasive carcinoma than the common female population and should be carefully followed up for a long time after treatment of the in situ lesion.

Mixed müllerian tumours of the uterus--prognostic factors: a clinical and histopathologic study of 147 cases.

One hundred and forty-seven women with uterine mixed Müllerian tumours (UMMT) treated at Radiumhemmet from 1936 through 1981 were reviewed. The prognostic value of clinical and histopathologic data was analysed with bivariate and multivariate techniques. Stage, age and abdominal pain were found to be significant predictors of survival. Surgery and combined radiotherapy (intracavitary + external irradiation) gave in stage I, a lower local failure rate (p = 0.006) and better overall survival (p = 0.001) than surgery in combination with either intracavitary or external irradiation.

Evaluation of screening for cervical cancer in Sweden: trends in incidence and mortality 1958-1980.

Papanicolaou screening for cancer of the uterine cervix was introduced in Sweden in the late 1950's. Screening programmes covering the age groups 30-49 years were organized in various countries between 1965 and 1973. The approximate number of smears rose from 100 000 in 1960 to one million in 1970, in a female population of four million. Almost 60 000 cases of in situ carcinoma and 17 100 invasive carcinomas of the uterine cervix were registered in Sweden between 1958 and 1980. The age-standardized incidence of invasive carcinoma fell in this period by about 40%. Within the screened cohorts and age groups, the incidence was reduced by two-thirds and there was a parallel fall in mortality from the disease. At least part of these reductions seemed to be explained by the intensity of screening.

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Retinoic acid enhances the cytotoxic effects of gemcitabine and cisplatin in pancreatic adenocarcinoma cells.

INTRODUCTION: Retinoids, which are derivatives of vitamin A, are important factors involved in the control of biologic functions such as cell growth and differentiation, development, and carcinogenesis. We have shown previously that the naturally occurring retinoids all-trans-retinoic acid (ATRA) and 9-cisretinoic acid (9cRA) induce growth inhibition followed by apoptosis in pancreatic adenocarcinoma cells in vitro. AIM: To evaluate the efficacy of retinoids in combination with the chemotherapeutic drugs gemcitabine and cisplatin. METHODOLOGY: In vitro growth inhibition and induction of apoptosis by different combinations of retinoids and cytotoxic drugs were studied by using the T3M-4 and BxPc-3 cell lines. For in vivo studies, T3M-4 cells were injected subcutaneously in nude mice. RESULTS: Pre-treatment of pancreatic adenocarcinoma cells with ATRA or 9cRA before the addition of the drugs resulted in significant reduction in cell number compared with treatment with the drugs alone. Pre-treatment with 9cRA followed by gemcitabine or cisplatin alone also resulted in a strong increase in the percentage of cells undergoing programmed cell death, or apoptosis. Furthermore, there was an indication that the combination of ATRA and gemcitabine caused increased apoptosis in vivo. CONCLUSION: Our results clearly suggest the need for additional studies exploring the potential role of the combination of retinoids and gemcitabine in the management of pancreatic cancer.

Paget's disease of the vulva: the Radiumhemmet series 1975-1990.

Twenty-eight patients with a diagnosis of 'extramammary Paget's disease of the vulva' were referred to the Radiumhemmet, Karolinska Sjukhuset, Stockholm, during the period 1975-1990. A clinical and histopathologic retrospective review was undertaken. Six patients had associated malignancies (21.4%). The disease was considered primary invasive in three cases, whereas three patients later developed an invasive cancer. Surgery-local resection, hemivulvectomy or vulvectomy-was performed in 24 cases. Twelve patients, in which surgery was supposed to be radical with respect to free margins, had a significantly longer recurrence-free survival than 12 patients in which the surgical margins were dubious.

Malignant mixed müllerian tumors of the ovary: histopathologic and clinical review of 36 cases.

Among 2,895 malignant ovarian tumor cases referred to Radiumhemmet, Stockholm from 1975 through 1995, 36 were certified to be malignant mixed müllerian tumors. The overall prognosis was poor with only 18% five-year actuarial survival (median survival 16.6 months). Five patients are still surviving after 75, 68, 117, 121, and 168 months, respectively. Fifteen women treated with melphelan, doxorubicin (adriamycin) and cisplatin (MAP) had a five-year actuarial survival of 33.3% and a median survival of 19.8 months. In a multivariate analysis taking into account stage, age, radiation, type of chemotherapy, histopathologic type and completeness of surgery, the most important predictors for survival were stage (stages I-II vs stages III-IV, P < 0.05), histopathologic type (homologous vs heterologous, P < 0.05), and type of chemotherapy (MAP or CAP vs other types, P < 0.05). We concluded that homologous tumor and chemotherapy containing cisplatin, doxorubicin, and melphalan, as well as early stage of the tumor, provided the optimal survival rate.

Carcinoma of the fallopian tube. A clinical and histopathologic review. The Radiumhemmet series.

A histopathologic and clinical review of the Radiumhemmet series of primary fallopian tube carcinoma (PFTC) treated from 1923 to 1991 revealed that 128 cases fulfilled the diagnostic criteria for PFTC. These cases were staged according to the new FIGO staging rules for PFTC. Survival was studied with respect to prognostic factors such as age, stage, histologic subgroups, degree of differentiation and mode of treatment. The mean age at diagnosis was 56 years. Seventy-four per cent were found to be in stage Ia-IIa and 26 % in stage III-IV. Forty-five per cent were nulliparous and 22 % had evidence of previous pelvic inflammatory disease. Treatment modalities changed during the studied period. Thirty-three per cent of patients underwent surgery with total abdominal hysterectomy and bilateral salpingo-oophorectomy while 67 % were incompletely operated. A trend towards improvement in results was noticed-however, it was not statistically significant. Among the 14 prognostic variables tested in the multivariate analysis the first in rank were stage (P = 0.001) and degree of differentiation of the tumors (P = 0.070). Patients receiving chemotherapy had superior survival rates compared with those without chemotherapy (P = 0.0006) and patients with cisplatinum-containing chemotherapy did better than those without cisplatin.

The pulse wash instrument. A new sampling method for uterine cervical cancer detection.

A new sampling method for uterine cervical cancer detection is described. In this method, sampling of cytologic material is done by using a pulse wash instrument. Liquid jets with a diameter of 0.2 mm at a speed of 20 m/s create a successful rinsing effect of cervical epithelial cells due to the high kinetic energy produced. Because cells are suspended in the flushing liquid it is possible to collect material for additional cytochemical, immunocytochemical, and microbiologic diagnostic techniques in addition to a conventional smear technique. Compared to a conventional Papanicolaou smear technique performed in 75 women at two cervical atypia clinics at the Karolinska Hospital, the pulse wash technique is suggested to result in a more representative cellular sample, thus offering a method to decrease false negative diagnoses in uterine cervical cancer detection.

Medical induction prior to surgical evacuation of hydatidiform mole: is there a greater risk of persistent trophoblastic disease?

A retrospective study was undertaken to assess whether stimulation of uterine contractility prior to surgical evacuation of a molar pregnancy will lead to an increased frequency of persistent trophoblastic disease. Forty-seven patients treated with chemotherapy for persistent trophoblastic disease after a hydatidiform mole between 1971 and 1988 were evaluated. The use of medical methods in this study group was compared to a control group of 219 patients with hydatidiform mole not requiring further treatment. A medical method, mainly treatment with prostaglandins, was used in 61.7% in the study group compared to 35.2% in the control group. This difference was, however, due to different stage distribution in the groups. Persistent disease was significantly correlated to uterine size and medical methods were mainly used in patients where uterine size corresponded to 15 weeks gestation or more. In this subset of patients, a medical method was used in the same frequency in both groups. Thus, large uterine size seems to be an independent risk factor. We conclude that stimulation of uterine contractility, which in Sweden is frequently used before surgical evacuation of the uterus in patients with hydatidiform mole and large uteri, carries no additional risk.

A case-control study of oral contraceptive use in women with adenocarcinoma of the uterine cervix.

To evaluate oral contraceptive (OC) use as a possible cause of the changed ratio between adenocarcinoma and squamous cell carcinoma of the uterine cervix a case-control study was performed. The OC use among 23 women with adenocarcinoma of the uterine cervix was compared with that of a matched group of 46 women with squamous cell carcinoma. No differences in percentage of OC use, duration of such use or period of OC use in relation to diagnosis could be demonstrated between the two groups compared.

Endometrial stromal sarcoma of the uterus. A clinical and histopathological study. The Radiumhemmet series 1936-1981.

Twenty-eight cases of endometrial stromal sarcoma treated from 1936 to 1981 at Radiumhemmet were reviewed. Histopathologically, 16 were classified as high-grade stromal sarcomas and 12 were of a low grade. A significant relation between mitotic count and relative survival within 10 years of the diagnosis was found (p less than 0.05) showing a more favorable outcome for patients with low counts compared with patients with higher counts. Primary treatment included surgery and radiotherapy in 21 cases. Two advanced cases were only irradiated and five cases were treated with surgery alone. Adjuvant radiotherapy seems to be of benefit in high-grade tumors, demonstrated in a 5-year survival rate of 73%, which exceeds most reported results. Five out of seven women dying of low-grade tumors were diagnosed in an advanced stage.

Delay in diagnosis of epithelial ovarian cancer.

OBJECTIVES: To investigate and analyze the process from first recognition of symptom(s) to final diagnosis at operation in patients with ovarian epithelial cancer. METHOD: The medical records of 160 women with ovarian cancer were studied and traced back to the doctor first consulted, in order to obtain information on patient- and doctor-related delay. RESULTS: Symptom duration was 12 weeks in patients with serous tumors and 7 weeks in patients with other histopathological classes; 56% were diagnosed within 4 weeks. Women in stages I and II were diagnosed faster than those in stages III and IV; 4% were diagnosed within 3 days because of an emergency operation; 30% were not diagnosed within 8 weeks. CONCLUSION: Diagnosis of ovarian cancer is difficult due to the vagueness of the symptoms which mislead both patients and doctors. Methods to enable earlier diagnosis must be sought.

Symptoms and diagnostic difficulties in ovarian epithelial cancer.

OBJECTIVE: To investigate and analyze symptoms in patients with different types of ovarian cancer. METHOD: Records of 160 women with ovarian cancer were studied in detail following the patients from first consultation to operation and diagnosis at Sodersjukhuset, Stockholm. RESULT: No specific group of symptoms could be linked to type or stage of ovarian cancer. Gastrointestinal symptoms were more common in patients with class 1C tumors. Only 21% complained of gynecological symptoms. Women with class 1C cancer had significantly more advanced disease than those with 2C-5C cancer as 77% had a stage III-IV tumor compared with 40% of class 2C-5C patients. CONCLUSION: Diagnosis of ovarian cancer is difficult due to the multitude of symptoms often appearing late in the disease. The majority of women did not experience symptoms in the genital organs. Methods to encourage early consultation should be investigated.

Radiotherapy in benign uterine bleeding disorders. The Radiumhemmet metropathia cohort 1912-1977. Short and long term results.

Radiotherapy was earlier a method of choice for treatment of benign bleeding disorders (metropathia), especially in women of high surgical risk. During the period 1912 to 1977 933 women with benign bleeding disorders were treated at Radiumhemmet with intracavitary brachytherapy or external irradiation or a combination of both. The result with regard to cure of the uterine bleedings was good (48%). Hormonal withdrawal symptoms after treatment were noted in 45% of the patients. In the long term follow up an increased risk of cardiovascular death was found in women treated before menopause. Malignant tumours occurred in 107 cases versus 90.2 expected (RR 1.19). The estimated ovarian dose of ionizing radiation varied from 3.5 Gy to 6.0 Gy for the three standard techniques. Two women gave birth to a healthy child 4 and 5 years after intracavitary radium treatment. The estimated absorbed dose to the ovaries in these two women were 1 Gy and 4 Gy, respectively.

Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance.

Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, de novo or acquired resistance to HDACi therapy is inevitable, and their molecular mechanisms are still unclear. To gain insight into HDACi resistance, we developed vorinostat-resistant clones from the hematological cell lines U937 and SUDHL6. Although cross-resistant to some but not all HDACi, the resistant cell lines exhibit dramatically increased sensitivity toward chloroquine, an inhibitor of autophagy. Consistent with this, resistant cells growing in vorinostat show increased autophagy. Inhibition of autophagy in vorinostat-resistant U937 cells by knockdown of Beclin-1 or Lamp-2 (lysosome-associated membrane protein 2) restores sensitivity to vorinostat. Interestingly, autophagy is also activated in parental U937 cells by de novo treatment with vorinostat. However, in contrast to the resistant cells, inhibition of autophagy decreases sensitivity to vorinostat. These results indicate that autophagy can switch from a proapoptotic signal to a prosurvival function driving acquired resistance. Moreover, inducers of autophagy (such as mammalian target of rapamycin inhibitors) synergize with vorinostat to induce cell death in parental cells, whereas the resistant cells remain insensitive. These data highlight the complexity of the design of combination strategies using modulators of autophagy and HDACi for the treatment of hematological malignancies.