Sexual intercourse during pregnancy and its association with spontaneous preterm birth.

This study investigated whether sexual intercourse during pregnancy is associated with spontaneous preterm birth (SPTB). We included 77 women with SPTB and 145 women with a term birth. A total of 195 (87.8%) women had sexual intercourse during pregnancy, which was comparable between the groups. Primiparas with SPTB tended to report more often having sexual intercourse 3 - 4 times a week compared to primiparas with a term birth (8.8% vs. 0%, p =.082). We advise not to completely discourage sexual intercourse among pregnant women. Yet, high sexual intercourse frequency could be associated with SPTB.

The association between vaginal hygiene practices and spontaneous preterm birth: A case-control study.

BACKGROUND: Spontaneous preterm birth (SPTB) is a major cause of neonatal morbidity and mortality worldwide and defining its risk factors is necessary to reduce its prevalence. Recent studies have pointed out that bacterial vaginosis, a disturbance in the vaginal microbiome, is associated with SPTB. It is hypothesized that vaginal hygiene practices can alter the vaginal microbiome and are therefore associated with SPTB, but there are no studies investigating this matter. METHODS AND FINDINGS: A case-control study was conducted between August 2018 and July 2021 in two affiliated university medical centers in Amsterdam, the Netherlands. We included a total of 79 women with a SPTB and compared them with 156 women with a term birth. Women with uterine anomalies, a history of cervical surgery or major congenital anomalies of the fetus were excluded. All participants filled in a questionnaire about vaginal washing with water, soap or gel, the use of intravaginal douches and vaginal steaming, both before and during pregnancy. Most women washed vaginally with water, 144 (61.3%) women before pregnancy and 135 (57.4%) women during pregnancy. A total of 43 (18.3%) washed with soap before and 36 (15.3%) during pregnancy. Before pregnancy, 40 (17.0%) women washed with vaginal gel and 27 (11.5%) during pregnancy. We found that the use of vaginal gel before pregnancy (aOR 2.29, 95% CI: 1.08-4.84) and even more during pregnancy, was associated with SPTB (aOR 3.45, 95% CI: 1.37-8.67). No association was found between washing with water or soap, intravaginal douching, or vaginal steaming and SPTB. CONCLUSIONS: Our findings suggest that the use of vaginal gel is associated with SPTB. Women should be informed that vaginal use of gels might not be safe.

On optical forces in spherical whispering gallery mode resonators.

In this paper we discuss the force exerted by the field of an optical cavity on a polarizable dipole. We show that the modification of the cavity modes due to interaction with the dipole significantly alters the properties of the force. In particular, all components of the force are found to be non-conservative, and cannot, therefore, be derived from a potential energy. We also suggest a simple generalization of the standard formulas for the optical force on the dipole, which reproduces the results of calculations based on the Maxwell stress tensor.

Immunohistochemical correlates of response to recombinant interleukin-2-based immunotherapy in humans.

We have evaluated immunohistochemical characteristics of tumors and the infiltrating cells in patients treated with various immunotherapy regimens. Forty-eight patients with advanced malignancies were treated with high dose i.v. recombinant interleukin-2 alone or in combination with cyclophosphamide, recombinant tumor necrosis factor, recombinant interferon-alpha, antimelanoma antibody 9.2.27, adoptively transferred tumor infiltrating lymphocytes, or lymphokine-activated killer cells. Thirty-four patients with metastatic melanoma and two patients with breast carcinoma underwent excision of one or more s.c. metastases either before, during, or after treatment. Twelve patients with metastatic renal cell carcinoma underwent pretreatment nephrectomy and these tumors were also studied. Tumor cells were evaluated for class I (HLA-A,B,C) and II (HLA-DR) antigen expression and the mononuclear infiltrate was characterized using an avidin-biotin immunoperoxidase technique. All melanomas were class I antigen positive. Fifty-three % of biopsied metastatic melanoma lesions, 58% of primary renal cell carcinomas, and neither of the two breast carcinomas expressed class II antigen prior to therapy. The pretreatment expression of class II antigens by a tumor was not predictive of a clinical response to recombinant interleukin 2-based therapy. After treatment, however, seven of seven biopsied regressing individual metastases intensely expressed DR antigen on over fifty percent of the cells while only three of ten nonresponding lesions did so. Regressing lesions were permeated with macrophages and both CD4 and CD8 T-cell subsets. There were no CD1 or NKH-1 positive infiltrating cells detected in any lesion. The response to recombinant interleukin 2-based immunotherapy is associated with T-cell as well as macrophage infiltration. DR antigen expression by tumor cells and T-cell infiltrate appear in individual lesions to be associated with this response.

HLA association with response and toxicity in melanoma patients treated with interleukin 2-based immunotherapy.

Peripheral blood lymphocytes from 146 patients with metastatic melanoma undergoing interleukin 2 (IL-2)-based immunotherapy were characterized for HLA A, B, Cw, DR, DQw, and DRw specificities. Patients had been enrolled into sequential treatment protocols with either IL-2 alone (28) or in combination with tumor-infiltrating lymphocytes (TILs) (86), alpha-interferon (26), lymphokine-activated killer cells (16), radiation therapy (7), cyclophosphamide (3), tumor necrosis factor (1), and interleukin 4 (1) for a total of 168 courses of therapy. HLA phenotype was then correlated with response rate and toxicity to IL-2. We noted: (a) a significant difference in the frequency of A11 (20.5% versus 10.2%; P < 0.05) allele between melanoma patients and the North American Caucasian population; (b) a significantly higher frequency of A11 phenotype among responders (40.5%) than in the melanoma patient population (20.5%; P < 0.01), which was even more obvious among patients responding to TIL therapy (47.4% versus 22.1%; P < 0.05); within TIL patients, responders also had an increased frequency of A19 (42.1% versus 25.6%; P < 0.05); (c) a correlation between the number of TILs received and response rate (P < 0.005); and (d) an association between DR4 haplotype and decreased tolerance to IL-2 among the patients receiving TILs (P = 0.01). These results suggest that, in melanoma patients, some HLA Class I specificities may predict for a greater likelihood of response to IL-2-based therapy, while HLA Class II phenotype correlates with tolerance to the combination of TIL and IL-2 therapy.

A prospective randomized trial evaluating prophylactic antibiotics to prevent triple-lumen catheter-related sepsis in patients treated with immunotherapy.

During a 15-month period, 92 patients undergoing 129 treatment episodes of immunotherapy with interleukin-2 (IL-2) alone or with immune cells underwent insertion of central venous catheters (CVCs) in the Surgery Branch, National Cancer Institute. Before each catheter insertion patients were prospectively randomized into one of three treatment groups; therapy with intravenous (IV) placebo using D5W, IV oxacillin, or change of the catheter to a new site every 72 hours. The mean duration of catheterization was 3.8 +/- 1.1 days. No patient in the oxacillin arm developed catheter-related sepsis, while eight patients in the control arms (five, line change, three, placebo) developed catheter-related sepsis (P2 = .050). Seven episodes of catheter-related sepsis were due to Staphylococcus aureus and one was due to Staphylococcus epidermidis. Catheter colonization was reduced significantly in the oxacillin arm versus control arms (P = .0001). Staphylococcus aureus, Staphylococcus epidermidis, and other coagulase-negative Staphylococci were sensitive to oxacillin in 89%, 60%, and 50% of cultures, respectively. No evidence of bacterial overgrowth, candida colonization, or candidemia was observed in these patients. Thus this trial demonstrates that treatment with prophylactic oxacillin can decrease the incidence of catheter-related sepsis in patients undergoing immunotherapy with interleukin-2 (IL-2). To our knowledge this is the first prospective randomized trial to evaluate the prophylactic use of systemic antibiotics in the prophylaxis of CVC sepsis.

Genetically marking human cells--results of the first clinical gene transfer studies.

The rapid development of both knowledge and techniques in molecular biology have made it possible to engineer genetic constructs and transfer them into cells of individuals with various diseases. Such gene therapies may alleviate or perhaps even cure diseases for which no adequate treatment now exists. One potential application is to treat genetic disease by inserting a normal gene into cells in individuals with a "malfunctioning" gene. The added genetic information could allow these cells to function properly and might reduce or eliminate the sequelae of the disease. Such genetic manipulation could also be used to combat other diseases using the same general technique. For example in cancer patients, various cytokine genes inserted into tumor cells may serve as components of a tumor vaccine because such cytokine-secreting tumor cells can induce a significant T-cell response in experimental animal models when compared with non-gene-modified tumors, ultimately leading to a systemic immune response. In addition to treating patients, transferred genes also can serve as markers to obtain important information about the fate of otherwise indistinguishable cells. For example, we used a genetic marker to label tumor-infiltrating lymphocytes (TILs) to monitor their in vivo survival and ability to "home" to tumor sites. Gene markers also were transferred into autologous bone marrow cells to study the mechanism of tumor relapse. This review will focus primarily on studies using gene markers to track TILs after transfer. We will focus on the following issues: (a) that TILs are potent antitumor cells, mediating partial and complete responses in patients with melanoma; (b) the importance of the initial gene marked TIL study; (c) safety considerations in the use of gene marking/gene therapy; (d) results of gene-marked TIL studies; and (e) other gene-marked cells.

Potent antitumor effects of intra-arterial injection of fibroblasts genetically engineered to express IL-12 in liver metastasis model of rat: no additional benefit of using retroviral producer cell.

Interleukin-12 (IL-12) mediates significant antitumor effects in animal models but associated with dose-dependent toxicity in human. To achieve local expression of IL-12 at the tumor site without systemic toxicity, we performed intra-arterial administration of fibroblasts genetically engineered to produce IL-12 protein with or without retrovirus (CRIP- IL-12 or 3T3-IL-12) in liver metastasis model. Rat breast cancer cells ( MADB - 106) were injected into the portal vein of syngeneic Fisher rats on day 0, and fibroblasts were injected into the hepatic artery on day 7. On day 21, liver weight and number of liver tumors were examined. As controls, CRIP cells expressing retrovirus carrying lacZ marker gene (CRIP-lacZ) or saline (Hanks balanced salt solution, HBSS) were injected. Administration of CRIP-IL-12 significantly reduced tumor metastasis in liver measured by number of foci (CRIP- IL-12: 45.2 +/- 36.7, CRIP-lacZ: >250, HBSS: >250, P<.05) and by liver weight (CRIP-IL-12: 13.0+/-2.5 g, CRIP-lacZ: 30.4+/-8.5 g, HBSS: 26.0+/-7.6 g, P<.05). 3T3-IL-12, which produced only IL-12 protein but not IL-12 retrovirus, also had significant antitumor effects equivalent to CRIP-IL-12. Intra-arterial injection of IL-12--producing fibroblasts into the liver may be an effective therapy for liver tumors reducing systemic toxicity, and could be developed for clinical application.

Acute gastric mucosal injury associated with the systemic administration of interleukin-4.

METHODS: Seventy-three patients with advanced malignancy were treated with the recombinant lymphokine interleukin-4 either as the sole immunotherapeutic reagent or in combination with recombinant interleukin-2. RESULTS: Twelve of 84 courses of therapy were complicated by gastroduodenal erosion or ulceration. Three of these courses were associated with significant bleeding, which required multiple red blood cell transfusions and endoscopic therapy. No treatment-related deaths occurred. Eleven of 57 courses administered with concomitant indomethacin and 11 of 62 courses administered with ranitidine resulted in gastroduodenal mucosal injury. No acute change in gastric acid output occurred after one dose of interleukin-4 in patients prospectively evaluated with an indwelling nasogastric tube. An intravenous ranitidine infusion appropriately reduced acid output in these patients. In contrast, we have treated over 650 patients with interleukin-2 and indomethacin without interleukin-4, none of whom developed signs or symptoms of gastroduodenal ulceration. CONCLUSIONS: These observations suggest that systemically administered cytokines may exert an effect on the integrity of the gastroduodenal mucosa.

Immune function and dysfunction. A primer for the radiologist.

Freedom from infection is the result of many tiers of immune defenses that harmoniously interact to rid the body of microorganisms and their products, which are perceived as foreign. The ability to distinguish self from nonself is embodied in lymphocytes, which serve both effector and regulatory functions. Through the elaboration of cytokines and immunoglobulins, lymphocytes recruit nonspecific immune effectors, focus their activity, and modulate the intensity of the immune response. The phylogenetically more primitive complement system serves a similar function. Although congenital defects in immune function occur, by far the most common causes of immunodeficiency are acquired and occur in patients treated for cancer with myelosuppressive, cytolytic drugs and in transplant recipients treated with immunosuppressants. HIV infection and malnutrition are responsible for even larger numbers of immunocompromised patients worldwide. The nature and severity of infections that occur as a result of immunodeficiency vary as a function of the immune effector targeted and the degree to which it is dysfunctional. Granulocytopenia is well tolerated unless the absolute number of circulating cells falls below 500/mm3. Profound granulocytopenia and deficits of neutrophil function are often manifest as bacterial or fungal infections. Complement deficiency predisposes to infection with encapsulated bacteria such as pneumococci, meningococci, and Haemophilus influenzae. T cells play such a central role in the immune response that their derangement is associated with susceptibility to almost any potential pathogen. These patients often succumb to mortal opportunistic infections. Recent advances in hybridoma and recombinant DNA technology have provided us with immunologic reagents that enable us to manipulate the immune response. Anti-CD3 monoclonal antibody has permitted salvage of solid organ transplants in well-defined clinical settings. Monoclonal antibodies against TNF-alpha and lipopolysaccharide may alter the consequences of gram-negative sepsis. Alternatively, recombinant cytokines have been associated with clinically significant tumor regression in selected patients, presumably by enhancing the nascent antitumor immune response. The development of immunologic reagents such as these in concert with our growing understanding of the immune system may translate to improved care for immunocompromised patients.

Penetration of recombinant interleukin-2 across the blood-cerebrospinal fluid barrier.

Recombinant interleukin-2 (rIL-2) is an immunotherapeutic agent with efficacy against certain advanced cancers. The penetration of rIL-2 across the blood-cerebrospinal fluid (CSF) barrier was studied in 12 cancer patients who had no evidence of tumor involvement of the central nervous system. At different times during treatment with intravenous rIL-2, CSF was withdrawn either continuously for 8 to 26 hours via a lumbar subarachnoid catheter (in eight patients) or by a single lumbar puncture (in four). Bioassay showed the appearance of rIL-2 in lumbar CSF 4 to 6 hours after the first intravenous dose, a rise over 2 to 4 hours to a plateau of 3 to 9 U/ml, and clearance to less than 0.1 U/ml by 10 hours after the last dose. An abnormally elevated CSF albumin level in two of the twelve patients indicated alteration of the blood-brain barrier. There were no abnormalities in the CSF glucose level or white blood cell count. The CSF pharmacokinetics contrast with the rapid elimination of rIL-2 from plasma and demonstrate significant blood-CSF barrier penetration. These data support the possibility of achieving CSF levels of rIL-2 that are adequate to maintain activity of lymphokine-activated killer cells after parenteral administration, and argue for rIL-2-associated disruption of the human blood-brain barrier in some patients.

The effect of intravenous interleukin-2 on brain water content.

Parenteral treatment with interleukin-2 (IL-2) is effective against certain advanced cancers outside the central nervous system. Prior to commencement of Phase II trials in patients with brain tumors, the neurological and neuroradiological features of 10 patients treated with intravenous administration of repeated doses of IL-2 were studied. Three patients had malignant gliomas, and seven patients had extracranial cancer without evidence of intracranial metastasis. All were treated with intravenous doses of 10(5) U/kg three times daily for up to 5 days. The patients with gliomas received cranial computerized axial tomography (CT) scans before IL-2 therapy was initiated and during the later stages of treatment. The patients with extracranial cancer underwent T2-weighted magnetic resonance (MR) imaging before and later during therapy. After two to 11 doses of IL-2, the patients with gliomas had marked neurological deterioration that was associated with a mild to marked increase in peritumoral edema and mass effect visible on CT scans. With cessation of treatment and appropriate supportive care, all returned to their pretreatment state. The patients with extracranial cancer were either neurologically unchanged or underwent minor transient changes in mental status (lethargy and confusion). In these patients, the MR signal intensity was quantified and compared in eight anatomic regions of interest. In six of the seven patients, there were increases in gray and white matter signal intensity consistent with increased cerebral water content. The percentage changes (means +/- standard error of the means) were 12.6% +/- 7.3% in the gray matter and 17.0% +/- 6.2% in the white matter. This study demonstrates that treatment with a high parenteral dose of IL-2 is not tolerated by patients with gliomas due to increased cerebral edema. In patients with extracranial cancer but no brain disease, parenteral IL-2 induces an increase in the cerebral water content of both gray and white matter.

A comparison of locoregional depot and systemic preparations of 9-aminocamptothecin for treatment of liver metastases in a rat tumor model: superior antitumor activity of sustained-release preparation.

BACKGROUND: Locoregional therapy of hepatic-metastatic disease may overcome the limitations of systemic therapy by allowing tumor drug dose intensification without increasing systemic toxicity. This may result in improved efficacy. We have demonstrated that the novel topoisomerase I inhibitor 9-Aminocamptothecin (9-AC) when dissolved in Ethiodol acts as a sustained release preparation, with good antitumor activity. Its benefit as a depot hepatic intraarterial (i.a.) therapy for hepatic metastases was compared to systemic therapy with an aqueous colloidal dispersion (CD) preparation of 9-AC in a rat model, since a lack of demonstrable benefit of the locoregional therapy, would argue against further clinical evaluation. METHODS: Fisher rats underwent direct intraportal injection of 2 x 10(5) MADB106 adenocarcinoma cells and were treated 6 to 7 days later with: (a) bolus i.a. 9-AC (60 micrograms) in 60 microliters of Ethiodol; (b) bolus i.a. CD/9-AC (60 micrograms) in 200 microliters water; (c) bolus i.a. Ethiodol only (60 microliters), or (d) CD/9-AC (60 micrograms) in 200 microliters water, via a mini-osmotic pump pumping at 1 microliter/hr for 7 days intraperitoneally (i.p.). Livers were harvested 10 to 12 days later, and the number of metastases on the surface were counted blindly. RESULTS: Bolus hepatic i.a. 9-AC/Ethiodol was found to be significantly superior in reducing the number of hepatic metastases, when compared to the aqueous CD preparation administered in the same manner, or by continuous infusion via mini-osmotic pump i.p. (p < 0.01). Systemic therapy was also associated with substantial toxicity. CONCLUSIONS: These results suggest that locoregional therapy of hepatic neoplasms with 9-AC/Ethiodol would be associated with clinical efficacy far exceeding that associated with its systemic administration.

New biologic agents come to bat for cancer therapy.

Biologic therapies are playing an increasingly important role in the treatment of patients with cancer. A better understanding of immune responses to tumors now exists, and more defined reagents are now available including new recombinant cytokines, cultured lymphoid cells of defined specificity, and most recently, vectors containing specific genes that can be introduced either into tumor cells or lymphoid effectors. During this past year, we have observed the reporting of new cytokines identified and tested in humans and the advent of cytokine gene therapy. The successful application of these new reagents either singly or in combination will require significant ingenuity, resources, and intuition over the next decade.

Recurrent metastatic renal cell carcinoma presenting as a bleeding gastric ulcer after a complete response to high-dose interleukin-2 treatment.

Immunotherapy with high-dose recombinant interleukin-2 is an effective therapy for selected patients with metastatic renal cell carcinoma (RCC). Objective responses (complete or partial) are observed in about 15% of treated patients. The overall and disease-free survival of patients with a complete response are significantly prolonged. Although RCC is known to spread hematogenously, isolated RCC metastasis to the stomach is a rare event. Recurrent RCC, after a complete response to interleukin-2, presenting clinically as an isolated gastric metastasis, has not been reported to date. In this report, we describe the clinical course of a patient with metastatic RCC who had a complete response to high-dose interleukin-2 and was disease free for 4 years before presenting with massive upper gastrointestinal hemorrhage due to an isolated gastric metastasis. The patient remained disease free for 3 years after resection of the metastasis. Metastatic RCC to the stomach, although rare, should be suspected in any patient with a history of RCC who presents with gastrointestinal symptoms. In the absence of diffuse disease, aggressive therapy, including surgical resection, is appropriate for isolated gastric metastasis, because prolonged survival is possible.

HLA-DQ1 is associated with clinical response and survival of patients with melanoma who are treated with interleukin-2.

AIM: The risk of developing melanoma, the natural history of this disease, and the response to therapy with biological reagents may be determined, in part, by a patient's human leukocyte antigen (HLA) phenotype. In order to study this, the relationship between HLA type and clinical response to therapy with interleukin-2 (IL-2) was evaluated. METHODS: We retrospectively determined the HLA phenotype of 82 patients with metastatic melanoma who were treated with IL-2-based therapy. Fresh or frozen lymphocytes were serologically typed by standard lymphocytotoxicity techniques (NIH or Amos modified). The treatment regimens included IL-2 alone or with tumour infiltrating lymphocytes, lymphokine activated killer cells, cyclophosphamide, interferon-alpha, and tumour necrosis factor-alpha. Initially, the relationship between clinical response and each HLA antigen was evaluated by performing a two-tailed Fisher exact test. Associations with a P-value less than or equal to 0.10 without adjustment for multiple comparisons were considered worthy of further study. Independent confirmation of these apparent associations was obtained by studying the relationship between HLA phenotype and patient survival using Cox proportional hazards models. RESULTS: In the initial screening, a statistically significant association between clinical response and the expression of HLA-DQ1 was observed (unadjusted P2 = 0.0017). HLA-DQ1 was also independently associated with prolonged survival (P2 = 0.026). This positive association with survival was evident both for patients who responded to therapy and those who did not respond, as defined by > 50% tumour regression. CONCLUSIONS: Among patients with metastatic melanoma, HLA-DQ1 appears to be associated with clinical response to therapy using IL-2. This apparent association is confirmed by the observation that HLA-DQ1 is independently associated with prolonged survival in this group of patients.

Treatment of hepatic-metastatic colorectal cancer with a chemotherapeutic emulsion: interim results of a phase I trial.

BACKGROUND: Hepatic arterial infusion of 5-fluoro-2-deoxyuridine (FUdR) is associated with a 60% response rate among previously untreated patients who have hepatic-metastatic colorectal cancer. One obstacle to further dose escalation has been concomitant hepatic toxicity. We are evaluating a FUdR-containing chemotherapeutic emulsion to further dose intensify therapy without associated toxicity. METHODS: The in vitro pharmacokinetics of the emulsion were determined using high-pressure liquid chromatography (HPLC). The rate at which FUdR is released from emulsion into an overlying aqueous phase was determined in static and dynamic assays. Fifteen patients with hepatic-metastatic colorectal cancer were treated with intrahepatic arterial infusions of emulsion on a phase I dose-escalating clinical protocol. Serum collection determined systemic drug levels using HPLC. RESULTS: In vitro studies demonstrate that FUdR is slowly released from emulsion into overlying aqueous medium. The emulsion serves as a depot for FUdR. Therapy was well tolerated. Emulsion was sequestered in the liver after infusion in all treated patients. CONCLUSIONS: This Ethiodol-based, oil-in-water emulsion serves as a sustained-release preparation of FUdR. An Ethiodol-based oil-in-water emulsion is a clinically effective vehicle for delivering FUdR to hepatic-metastatic colorectal tumors.