ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer.

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.

Associations between asthma trigger reports, mental health conditions, and asthma morbidity among world trade center rescue and recovery workers.

Aim: There is limited information regarding asthma triggers in World Trade Center (WTC) rescue and recovery workers (RRW) or how mental health conditions affect the perception of triggers. Methods: We included 372 WTC workers with asthma. The Asthma Trigger Inventory (ATI) assessed triggers along five domains: psychological, allergens, physical activity, infection, and pollution. We administered the Structured Clinical Interview to diagnose post-traumatic stress disorder (PTSD), major depression and panic disorder (PD). The Asthma Control Questionnaire (ACQ) and Mini Asthma Quality of Life Questionnaire (AQLQ) measured asthma control and quality of life, respectively. Linear regression models were fitted to examine the association of ATI total and subdomain scores with mental health conditions as well as the percent of ACQ and AQLQ variance explained by ATI subscales. Results: The most common triggers were air pollution (75%) and general allergens (68%). PTSD was significantly associated with psychological triggers (partial r2=0.05, p < 0.01), physical activity (partial r2=0.03, p < 0.01) and air pollution (partial r2=0.02, p = 0.04) subscales while PD was significantly associated with air pollution (partial r2=0.03, p = 0.03) and general allergens (partial r2=0.02, p = 0.03). ATI subscales explained a large percentage of variance in asthma control (r2=0.37, p < 0.01) and quality of life scores (r2=0.40, p < 0.01). Psychological subscale scores explained the largest portion of the total variability in ACQ (partial r2= 0.11, p = 0.72) and AQLQ (partial r2=0.14, p = 0.64) scores. Conclusion: RRW with mental health conditions reported more asthma triggers and these triggers were associated with asthma morbidity. These data can help support interventions in RRW with asthma.

A systematic review of care delivery models and economic analyses in lymphedema: health policy impact (2004-2011).

A project of the American Lymphedema Framework Project (ALFP), this review seeks to examine the policy and economic impact of caring for patients with lymphedema, a common side effect of cancer treatment. This review is the first of its kind undertaken to investigate, coordinate, and streamline lymphedema policy initiatives in the United States with potential applicability worldwide. As part of a large scale literature review aiming to systematically evaluate the level of evidence of contemporary peer-reviewed lymphedema literature (2004 to 2011), publications on care delivery models, health policy, and economic impact were retrieved, summarized, and evaluated by a team of investigators and clinical experts. The review substantiates lymphedema education models and clinical models implemented at the community, health care provider, and individual level that improve delivery of care. The review exposes the lack of economic analysis related to lymphedema. Despite a dearth of evidence, efforts towards policy initiatives at the federal and state level are underway. These initiatives and the evidence to support them are examined and recommendations for translating these findings into clinical practice are made. Medical and community-based disease management interventions, taking on a public approach, are effective delivery models for lymphedema care and demonstrate great potential to improve cancer survivorship care. Efforts to create policy at the federal, state, and local level should target implementation of these models. More research is needed to identify costs associated with the treatment of lymphedema and to model the cost outlays and potential cost savings associated with comprehensive management of chronic lymphedema.

A preliminary randomized controlled study to determine the application frequency of a new lymphoedema bandaging system.

BACKGROUND: Bandaging plays an important role in the treatment of lymphoedema. OBJECTIVE: To investigate efficacy and safety of the 3M™ Coban™ 2 compression system (Coban 2 system) with different application frequencies in comparison to short-stretch bandaging. METHODS: A multicentre, randomized, prospective study was performed with 82 patients suffering from arm or leg lymphoedema stage II or late stage II. Patients were allocated to traditional short-stretch bandaging five times per week or to the Coban 2 system applied two, three or five times per week for 19 days. Limb volume and adverse events were recorded at each study visit. The primary endpoint was percentage volume reduction. RESULTS: The highest lymphoedema volume reduction was achieved with the Coban 2 system applied two times per week. A mean reduction of 18·7% (SD 14·5) in legs and 10·5% (SD 8·3) in arms was achieved. More frequent bandage changes of three and five times per week did not demonstrate additional benefits. Short-stretch bandaging five times per week showed a mean volume reduction of 10·9% (SD 5·2) and 8·2% (SD 3·1) for legs and arms, respectively. Bandage slippage was low for all treatment groups. A relevant change in overall mobility was achieved during the use of the Coban 2 system. The adverse reactions were in agreement with already known side-effects and did not differ remarkably between the treatment groups. CONCLUSION: The 3M™ Coban™ 2 compression system applied twice weekly demonstrated a high rate of volume reduction and a good safety profile. Oedema reduction was still effective with 4 days between bandage change, which allows a constant therapeutic effect in routine practice. This should give the patient a high degree of independence and mobility.

Intermittent pneumatic compression therapy: a systematic review.

Intermittent pneumatic compression (IPC) therapy is an effective modality to reduce the volume of the lymphedematous limbs alone or in conjunction with other modalities of therapy such as decongestive therapy. However, there is no consensus on the frequency or treatment parameters for IPC devices. We undertook a systematic review of contemporary peer-reviewed literature (2004-2011) to evaluate the evidence for use of IPC in the treatment of lymphedema. In select patients, IPC use may provide an acceptable home-based treatment modality in addition to wearing compression garments.

Corrigendum for health-related quality of life and hospitalizations in chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension: And analysis from the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211053196.].

Cytology of immunologic memory. A morphologic study of lymphoid cells during the anamnestic response.

Pairs of rats were immunized with keyhole limpet hemocyanin (KLH) and simultaneously labeled with thymidine-methyl-(3)H or 5-iodo-2'-deoxyuridine-(125)I. From 10-50 days later, their lymphoid organs were examined 3 days after anamnestic stimulation with KLH or after primary injection of BGG. Light and electron microscopic study of the labeled cells revealed that immunologic memory resided in the mature resting monoribosomal lymphocyte which, upon stimulation, transformed to an immature polyribosomal lymphocyte and mitotically active blast cell. These latter elements differentiated into plasma cells directly or after mitosis.

Renal homotransplantation in rats. I. Allogeneic recipients.

Within 3-6 hr after the reestablishment of the circulation, a characteristic pathology developed in renal homotransplants. Blood monocytes and lymphocytes adhered to large thin-walled vessels of the septa carrying interlobular arteries, traversed their walls, and aggregated in the connective tissue spaces around them. Within 3 days, the number and size of the extravascular cells markedly increased, filling the septa completely and spreading from them centrifugally to occupy the intertubular spaces throughout the cortex. The composition of these aggregates at first was a mixture of lymphocytes and monocytes, and later consisted of large blast cells, macrophages, a few plasma cells, and polymorphonuclear leukocytes. Mitotic activity was seen 2 days after surgery among the large blast cells and increased to a maximal level a day later. Coevally with these changes, the thin-walled septal vessels, intertubular veins and capillaries, and finally, arteries and arterioles, in that order, were damaged. Focal injury of tubules was slight 24 hr after homografting; widespread cortical necrosis had developed 5-7 days later. At no time up to 7 days were concentrations of immunoglobulins detected by fluorescence microscopy in the transplanted kidneys. The morphologic manifestations and temporal sequences of renal homograft destruction suggested that several mechanisms acted synergistically to eliminate the transplant. The initial injury appeared to be the result of an interaction between host lymphoid cells and target endothelium, a phenomenon akin to allogeneic inhibition; followed by spreading ischemia; additional contact injury to tubules; and nonspecific inflammation associated with necrobiotic tissue.

Density of surface immunoglobulin and capping on rat B lymphocytes. I. Changes with aging.

The rate of capping and shedding of cross-linked surface immunoglobulins (SIg) was slower in old Lewis rats (greater than 24 mo) than in young Lewis rats (3-4 mo). Analysis of spleen cell populations with the fluorescence-activated cell sorter indicated that with aging there was a loss of cells with a high density of SIg. Cells with the highest density of SIg capped and shed cross-linked SIg faster than cells with a low density of SIg. The alteration in density of SIg may account for the difference in capping kinetics. Colchicine treatment increased the rate of capping of lymphocytes from young animals, but had no effect on the capping kinetics of lymphocytes from old animals.

Heterogeneity of antibody-forming cells. An electron microscopic analysis.

Cell suspensions from draining lymph nodes of immune and nonimmune rats were reacted in vitro with (125)I-labeled antigens. In light microscopic radioautographs of smears, 17% of the immunized cells were tagged by specific antigen; 2.0% of control cells were positive. In electron microscopic radioautographs, 90% of the labeled elements from immune donors were lymphocytes, blast and plasma cells; 10% were monocytes-macrophages or other elements, including naked nuclei. 15% of the labeled cells from control materials were lymphocytes and plasma cells, while 85% were monocytes-macrophages and naked nuclei. Within cell suspensions derived from immunized animals there were almost twice as many lymphocytes marked by isotope as plasma cells, and the lymphocytes ranged in morphology from mature monoribosomal elements to immature polyribosomal cells. Antibody-forming cells fixed labeled antigen at their surfaces. The monocyte-macrophage class was distinguished by a high mean grain count and by distribution of grains within cytoplasmic vacuoles and lysosomes.

The role of thymus and bone marrow cells in delayed hypersensitivity.

Adoptive transfer experiments were performed to define the immunological role of thymus and bone marrow cells in the induction of delayed hypersensitivity (DH). The results indicated the following, (a) Bone marrow from immune donors contained cells capable of being stimulated by antigen to initiate the expression of DH. (b) Bone marrow from nonimmune or tolerant donors contained cells that were needed to complete the expression of DH after the infusion of immune lymph node cells. (c) Normal bone marrow and thymus cells cooperated in the irradiated recipient to induce the most vigorous skin reactions to specific antigen; these reactions were seen only when the recipients were stimulated by antigen. Either cell type alone was ineffective. (d) In the presence of tolerant bone marrow cells, thymus cells from immune donors gave a more vigorous response than did thymus cells from normal or tolerant donors. (e) There was suggestive evidence that thymus cells were the source of trigger elements that initiated DH. (f) Antigen in the irradiated recipient was necessary to induce DH after infusion of bone marrow cells alone, or bone marrow and thymus cells together.

Cell-mediated cytotoxicity during rejection and enhancement of allogeneic skin grafts in rats.

Cell-mediated cytotoxicity (CMC) in spleens and lymph nodes of allografted rats was determined by release of (51)Cr from labeled target cells incubated with aggressor lymphoid cells. CMC was first detected in grafted adult rats on day 5, peaked on days 7 and 8, and declined rapidly to background levels by days 9 to 11. In allografted neonates and in cyclophosphamide-treated or neonatally thymectomized adults CMC was a fraction of that observed in normal adult rats. Enhancing antibodies deferred in vivo peak activity of CMC in allografted neonates for 3-4 days, and blocked in vitro the action of aggressor lymphocytes by binding to target cells. Enhancing antibodies had no effect on the cytotoxicity of aggressor cells, but horse antibodies to rat thoracic duct cells inhibited in vitro CMC of aggressor cells.

Immunologic competence of thoracic duct cells. I. Delayed hypersensitivity.

Delayed hypersensitivity was produced in donor Lewis rats by sensitization with soluble protein antigens emulsified in complete Freund's adjuvant. Cells of their thoracic duct lymph were collected for varying periods of time and transferred intravenously to isogenic Lewis recipients. With this model the following conclusions were reached: 1. Delayed hypersensitivity was transferred by thoracic duct cells. 2. The longer the drainage of the thoracic duct, the fewer cells were needed to achieve a successful transfer. With continuing drainage the proportion of small lymphocytes decreased and large cells increased. There was, therefore, a better correlation between successful transfer of delayed hypersensitivity and the number of large cells transfused than between positive skin reactions and transfer of small lymphocytes. 3. Prolonged fistula of the thoracic duct did not diminish the skin reaction of sensitized donors to specific antigen. 4. Delayed hypersensitivity was elicited in recipients 3 wk after transfer of sensitized cells. There was evidence that delayed hypersensitivity was enhanced in recipients, possibly because of prior skin testing. 5. Total body X-irradiation abolished the lesions of passively transferred delayed hypersensitivity. Recovery of positive skin tests was observed 19 to 20 days later. 6. The lesions of delayed hypersensitivity were probably mediated by cells. There was no evidence that a circulating high affinity antibody played a role in this type of immunologic reaction.

Experimental allergic glomerulonephritis induced in the rabbit with homologous renal antigens.

Rabbits immunized to several homologous renal antigens developed a variety of autoantikidney antibodies. Some of these antibodies reacted with the host's glomeruli and appeared to cause glomerulonephritis. Passive transfer of sera from some of these nephritic rabbits into normal, unilaterally nephrectomized rabbits led to the induction of nephritis. The production of autoantibody to glomeruli was transitory in most instances in spite of continued immunization. In some rabbits immunized to whole kidney homogenate, extracts or sediment, antibodies were found fixed to renal tubular basement membranes where an ultrastructural lesion was demonstrated. Rabbits also produced antikidney antibody apparently to tubular cytoplasmic components which did not fix to kidney in vivo and were of no pathogenetic significance. Immunization with autologous renal basement membranes induced a small autoantibody response in half the rabbits. This response was not associated with detectable renal injury.

IgE-mediated chemotaxis of rat basophilic leukemia cells towards specific antigen.

We evaluated chemotactic properties of four sublines of rat basophilic leukemia cells using blindwell Boyden chamber assays. After sensitization with a mouse monoclonal IgE directed against dinitrophenyl (DNP), cells from sublines 2H3-C and 926a underwent chemotaxis toward DNP-bovine serum albumin (BSA) and sublines RBL-1 and 4A did not. Chemotactic responses required specific IgE and were determined by the IgE antigen specificity used for sensitization. The threshold for chemotaxis was on the order of 10(-10) M DNP-BSA. Release of incorporated [3H]-serotonin did not always parallel chemotactic responses, which suggests that chemotaxis and secretion may be two unlinked processes that occur during basophil activation. Our results predict a possible in vivo mechanism whereby specific chemotactic responses of basophils and other FcR epsilon-bearing cells are mediated via specific IgE bound to membrane FcR epsilon.

The production of vesicular stomatitis virus by antigen- or mitogen-stimulated lymphocytes and continuous lymphoblastoid lines.

A variety of lymphoid cell populations were examined in terms of their ability to replicate vesicular stomatitis virus (VSV), a lytic, RNA-containing virus maturing at the cell surface. The number of cells capable of producing VSV was estimated in terms of infectious centers by the virus plaque assay (VPA), and morphologically by electron microscopy (EM). The lymphoid cells examined in this study included: (a) lymph node cells from delayed hypersensitive guinea pigs stimulated by specific antigen, (b) mouse spleen cells activated by selective bone marrow-derived (B) cell and thymus derived (T) cell mitogens, and (c) cells of human and murine continuous lymphoblastoid or lymphoma lines. In unstimulated cultures of guinea pig lymph node cells there is a background of approximately 1 in 1,000 cells which produces VSV; in purified protein derivative (PPD)-stimulated cultures the number of cells producing virus was 1.6% in the VPA and 1.9% by EM. These cells were large lymphocytes with some morphological features of transformed lymphocytes but were not typical blast cells. A few macrophages were associated with virus in both stimulated and control cultures. These observations indicate that (a) cells responsive to antigens, as detected by a marker virus, were lymphocytes; (b) cells other than lymphocytes (macrophages) were capable of replicating VSV even without antigenic stimulation; and (c) the correlation of results obtained by VPA and morphologic examination was usually quite good. Of the total number of mouse spleen cells stimulated with concanavalin (Con A), a T cell mitogen, 4.5 (EM)-5.7% (VPA) were associated with VSV. These were characteristic transformed lymphocytes, similar to phytohemagglutinin (PHA)-stimulated human lymphocytes. In contrast Escherichia coli lipopolysaccharide (LPS)-treated mouse spleen cultures contained lower numbers of virus plaque-forming cells. The majority of such cells associated with virus displayed extensive rough endoplasmic reticulum. Two cultured murine lymphomas containing lymphocytes with the theta surface marker (L5178Y and EL-4) showed a 15-100-fold higher incidence of virus-producing cells than leukemias (L1210 and C57Bl/6) which did not carry this marker. Similarly, the L2C guinea pig leukemia, a known B cell leukemia, yielded a low percent of virus plaque-forming cells (<2%). However, MOPC-104, a plasma cell tumor presumed to be of B cell origin, was found to be an efficient virus producer. There was a wide variation in the efficiency of VSV replication among human lymphoblastoid lines. One line, Wil-2, produced 80% infectious centers after 24 h of exposure to VSV, and all cells were associated with virus at the EM level. The relationship between the virus-producing cells and different lymphocyte subpopulations as well as the efficiency of the two assays for studying virus-producing lymphocytes is discussed.

Elimination of syngeneic sarcomas in rats by a subset of T lymphocytes.

Established subcutaneous Moloney sarcomas (MST-1) of large size and long duration were eliminated from syngeneic rats by intravenous infusion of varying numbers of specific syngeneic effector T lymphocytes. Spleen cells from BN rats in which tumor had regressed were cultured in an in vitro mixed lymphocyte tumor cell culture (MLTC) to augment cytotoxicity of effector cells. In the MLTC a T cell subset was expanded in response to MST-1 antigens and transformed into blast elements. With these changes, there was an increase in the W3/25 antigen on the T cell surface, a decrease of W3/13 antigen, and an increase in the number of T cells with Ia antigens. The subset associated with elimination of established tumors was a blast T cell W3/25+, W3/13+, as detected by monoclonal antibodies to rat T antigens. The W3/25+ subset was poorly cytotoxic in vitro for MST-1 and apparently functioned in vivo as an amplifier or helper cell in the tumor-bearing host. The W3/25- population was a melange of cells that included (W3/13+, W3/25-) T cells, null cells, Ig+ cells, and macrophages, and was associated with enhancement of tumor in vivo, suggesting the presence of suppressor cells.

Production of ultrastructural membrane lesions by the fifth component of complement.

A direct quantitative relationship has been demonstrated between the number of cell bound C4,2 complexes or C5 molecules and the number of ultrastructural lesions visualized on the cell membrane subsequent to immune hemolysis. When bound C4,2 complexes exceeded bound C5 molecules, the number of ultrastructural lesions seen corresponded to the number of C5 molecules. However, in the reverse situation, with bound C5 molecules in excess of bound C4,2 complexes, the latter determined the number of lesions. During the complement-reaction sequence, the lesions first became visible in the nonlytic intermediate complex EAC1,4,2,3,5 and their number was unaffected when lysis was induced by C6-C9. Since the lesions were also demonstrable on the intermediate complex EC5,6,7, it is concluded that the protein C5 is responsible for their production. Once formed, the physical presence of the C5 molecule is no longer required for the manifestation of the lesions as indicated by persistence of lesions after removal of C5 protein by trypsin. The C5-dependent ultra-structural phenomenon has therefore been interpreted to represent a true structural change of the membrane which, however, is not accompanied by a permeability defect.

Thymus-dependent lymphocytes in tissue sections of rejecting rat renal allografts.

Lewis kidneys were grafted into BN recipients and examined at daily intervals up to 6 days after grafting with immunofluorescent reagents. A horse antiserum specific for T lymphocytes revealed an increasing number of T lymphocytes in the cellular infiltrates of rejecting allografts. These were detectable 1 day after grafting, reached a maximum 3 days later, and were relatively diminished at 6 days. In control isografts and nonimmunological inflammations of kidney, a small number of dispersed T lymphocytes was seen. A rabbit antirat thymocyte antiserum, given to allografted BN rats, prolonged survival of the grafts and decreased the cellular infiltrate and the number of T lymphocytes in the infiltrates. We conclude that in graft rejection there is a flow of T lymphocytes into areas of tissue damage and these T lymphocytes are immunologically reactive to graft antigens.