Molecular features and clinical outcome of lung malignancies in very young people.

INTRODUCTION: We describe the clinical features, outcome and incidence of druggable targets of lung cancers in patients ≤ 40 years old. MATERIALS & METHODS: Young patients were compared with two other groups (41-64 and ≥ 65 years). Neuroendocrine tumors, adenocarcinoma and non-adenocarcinoma/unspecified non-small-cell lung cancer were analyzed separately. Molecular characteristics of adenocarcinoma were evaluated in a subset of young patients. RESULTS: Of 2847 patients with lung cancer, 100 were ≤ 40 years old. The young group contained more women, never-smokers and patients presenting with advanced disease. The commonest tumor in young patients was adenocarcinoma. In total, 19 of 34 young patients with adenocarcinoma had tumors with specific molecular alterations. CONCLUSION: Lung cancers in young patients have distinctive features but outcomes similar to those in older patients.

Phase ib of sorafenib in combination with everolimus in patients with advanced solid tumors, selected on the basis of molecular targets.

BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.

Implementing an Integrative Oncology Paradigm in Cancer Care: The Tuscan Regional Healthcare System.

Introduction: Recent cancer research highlighted specific patient needs, with a growing interest in integrative oncology (IO). Design: This is a narrative review concerning the Tuscan Healthcare System, which represents a virtuous example of progressive integration of complementary medicine in conventional cancer care. Results: The main steps of the process are described, with a specific focus on the 2021 Diagnostic and Therapeutic Care Pathway on Integrative Oncology. Conclusions: Implementing an IO service may contribute to respond to patients' demand for complementary therapies, also providing safety and equity of therapeutic access within public health care systems.

"Waiting and the waiting room: how do you experience them?" emotional implications and suggestions from patients with cancer.

Waiting can increase discomfort. The goal of this study was to identify moods and fears of cancer patients while in a waiting room and to capture their concrete suggestions for an anthropocentric transformation of waiting itself. A 15-item questionnaire was given to 355 patients who came to our Out-patient Oncology Clinic. Eighty-three percent of patients felt that waiting has an emotional cost, 35% were upset by talking about their condition with others while waiting, and 26% suffered a major emotional impact seeing other sick people and witnessing their clinical decline. Eighty-nine percent of patients suggested that alternative activities, such as meetings with professionals, doctors, and psychologists, be organized during the waiting period; 65% suggested fun activities (music therapy, drawing courses, library, TV). Most patients asked to have the freedom to leave the waiting room. This option, feasibly by means of IMs/"beepers," would limit their sense of having a lack of freedom or being robbed of their time. This study highlighted the complexity and heterogeneity of emotional implications that waiting causes in patients with cancer and collected many patients' suggestions about how to create a constructive, free, and personalized waiting period, overcoming the boredom, distress, and psychological suffering it causes.

Safety, tolerability and biological effects of long-term metronomic administration of non-cytotoxic anti-angiogenic agents.

BACKGROUND: alpha-Interferon, thalidomide and celecoxib inhibit tumour angiogenesis by differing mechanisms. PATIENTS AND METHODS: In a randomized phase II trial to assess tolerability and safety, we assigned patients with advanced slow-growing solid tumours to 1 of 6 two- or three-drug combinations: alpha-interferon 0.5 million IU b.i.d., thalidomide (100 mg b.i.d. reduced to 100 mg daily), or celecoxib (400 mg daily reduced to 200 mg). Circulating endothelial cells and progenitors (CECs, CEPs) and vascular endothelial growth factor were also studied. RESULTS: From January 2002 to September 2005, 62 patients were enrolled. Four months after initiating treatment, 3 (4%) had partial response, 40 (64%) had stable disease and 19 (30%) had disease progression. Median duration of clinical benefit (partial response/stable disease) was 11.3 months. Patients receiving a third drug had significantly less stable disease plus partial response (chi(2) test, p = 0.002) than those receiving two drugs. The treatments were generally well tolerated, but neurotoxicity (G3 lethargy) occurred in 6 patients. Baseline CEPs were lower (p = 0.004) in patients with clinical benefit at 6 months than those without benefit. After 2 months of treatment CECs were lower than at baseline (p = 0.018) in patients without clinical benefit, and CEPs were higher than at baseline (p = 0.003) in patients with benefit. CONCLUSIONS: In pretreated patients with advanced slow-growing solid tumours, long-term metronomic administration of two-drug combinations of alpha-interferon, thalidomide or celecoxib was well tolerated and had antitumour activity. Low baseline CEPs in patients with subsequent clinical benefit suggest that CEC count may identify patients likely to benefit from long-term metronomic anti-angiogenic treatment.

Dendritic cell sarcoma: an analytic overview of the literature and presentation of original five cases.

Interdigitating and follicular dendritic cell sarcoma (DCS) are very rare diseases, with approximately 184 cases being reported thus far, and their best treatment modality is still on debate. This is a review of all the cases of dendritic cell sarcoma reported from 1981 until April 2006. This review is enriched with the original contribution of five cases occurred at our Institution from 1994 to 2006. The review of the literature pointed out that radical surgery alone was curative in approximately two thirds of these cases, the relapsing rate in patients who received adjuvant treatments being higher than 30%. We pinpoint new five cases of dendritic cell sarcoma (three FDCS and two IDCS). Both the analytic revision of the literature and our data suggest that localized DCS may be effectively treated by radical surgery and do not support the use of adjuvant treatments after radical excision.

Complementary and Integrative Medicine to Reduce Adverse Effects of Anticancer Therapy.

BACKGROUND: To address the side effects of anticancer treatments, the Clinic for Complementary Medicine and Diet in Oncology was opened, in collaboration with the oncology department, at the Hospital of Lucca (Italy) in 2013. AIM: To present the results of complementary medicine treatment targeted toward reducing the adverse effects of anticancer therapy and cancer symptoms, and improving patient quality of life. Dietary advice was aimed at the reduction of foods that promote inflammation in favor of those with antioxidant and anti-inflammatory properties. METHODS: This is a retrospective observational study on 357 patients consecutively visited from September 2013 to December 2017. The intensity of symptoms was evaluated according to a grading system from G0 (absent) to G1 (slight), G2 (moderate), and G3 (strong). The severity of radiodermatitis was evaluated with the Radiation Therapy Oncology Group (RTOG) scale. Almost all the patients (91.6%) were receiving or had just finished some form of conventional anticancer therapy. RESULTS: The main types of cancer were breast (57.1%), colon (7.3%), lung (5.0%), ovary (3.9%), stomach (2.5%), prostate (2.2%), and uterus (2.5%). Comparison of clinical conditions before and after treatment showed a significant amelioration of nausea, insomnia, depression, anxiety, fatigue, mucositis, hot flashes, joint pain, dysgeusia, neuropathy, and all symptoms. Moreover, in a subgroup of 17 patients in radiotherapy undergoing integrative treatment, the level of toxicities and the severity of radiodermatitis were much lower than in the 13 patients without integrative treatment. Twenty-one cancer patients (6.2%) either refused (18) or discontinued (3) conventional anticancer treatment against the recommendation of their oncologist; after the integrative oncology (IO) visit, 7 (41.2%) out of 17 patients with follow-up decided to accept standard oncologic treatments. CONCLUSIONS: An IO clinic may contribute to reducing the adverse effects of anticancer therapy and improving the quality of life of cancer patients.

A 15-min premedication for 1-h paclitaxel infusion: optimizing patients' care.

BACKGROUND: Paclitaxel is a plant product highly active in numerous cancers, but anaphylactic-like hypersensitivity reactions with it have been reported in about 28% of patients receiving the drug. Thirty to sixty minutes are needed to give a standard premedication with steroids and diphenhydramine, leading to patients and nurses' discomfort and stealing time from other infusional treatments. PATIENTS AND METHODS: Eighty-nine patients with advanced NSCLC never pre-treated with taxanes, received paclitaxel followed by gemcitabine on days 1, 8, 15 q4wks. Premedication consisted of prednisone 25 mg/os on day 0 and hydrocortisone plus clorfenamina maleato given intravenous on day 1 by a 15 min infusion immediately before paclitaxel administration. RESULTS: Hypersensitivity reactions occurred in 3/341 (0.8%) cycles. In all three cases we observed severe dyspnoea and bronchospasm, that required treatment discontinuation but one was probably due to gemcitabine and another had a protracting time after premedication. CONCLUSIONS: A 15-min premedication infusion administered immediately before paclitaxel appeared to be highly effective in patients treated with 1h-infusion paclitaxel.

Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails.

PURPOSE: To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy. PATIENTS AND METHODS: Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group. RESULTS: The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose of 1,300 microg/m(2) were neutropenia, asthenia, and self-limited increase of aminotransferases never requiring treatment interruption. CONCLUSION: Trabectedin administered as a 3-hour infusion at 1,300 microg/m(2) is a safe new drug with promising activity in relapsed ovarian cancer, showing a 43% objective response rate in patients with platinum-sensitive disease, which favorably compares with other salvage treatments and warrants additional development either alone or in combination.

A proper schedule of weekly paclitaxel and gemcitabine combination is highly active and very well tolerated in NSCLC patients.

BACKGROUND: In a previous phase I dose-escalation study, we showed a weekly administration of paclitaxel (TAX) and gemcitabine (GEM) to be active and very well tolerated in non-small-cell lung cancer (NSCLC) patients, with the lack of interaction between drugs. The dose of GEM 1500 mg/m(2) and TAX 100 mg/m(2) was selected for phase II studies due to its predictable kinetic behaviour and less severe thrombocytopenia. PATIENTS AND METHODS: Fifty-four chemo-naïve patients with advanced NSCLC (53 patients: stage IV) received TAX (100mg/m(2) i.v. infusion over 1h) followed by GEM 1500 mg/m(2) over 30 min) on days 1, 8, 15 and 21 of a 28-day cycle. RESULTS: The objective response rate was 46% (95% CI 32-61), median OS of 10.4 ms (95% CI 6.5-4.3), and a 1-year survival rate of 53%. Grades 3 and 4 haematological toxicity consisted of non-febrile neutropenia and thrombocytopenia in 13 and 4% of the cycles, respectively. Grade 3 non-haematological toxicities were observed in three patients (asthenia, diarrhoea and neuropathy), and were always reversible. CONCLUSIONS: This weekly schedule of TAX and GEM is highly active in chemo-naïve NSCLC patients and confirms the low toxicity profile already observed in a previous phase I study.

Afatinib for the first-line treatment of patients with metastatic EGFR-positive NSCLC: a look at the data.

INTRODUCTION: Epidermal growth factor receptor (EGFR) mutations are detected in about 10-15% of Caucasian and 30-40% of Asian patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In patients harbouring EGFR mutations, the treatment with different available EGFR tyrosine kinase inhibitors (TKIs) showed to be more effective and safe than platinum-based chemotherapy regimens. Areas covered: The current evidences about the role of afatinib for patients with EGFR-positive NSCLC are reviewed and discussed. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating afatinib in EGFR-positive NSCLC. Expert commentary: Afatinib is the third EGFR TKI approved for the treatment of NSCLC harbouring EGFR mutations, showing high efficacy in this setting of patients.

Afatinib in first-line setting for NSCLC harbouring common EGFR mutations: new light after the preliminary results of LUX-Lung 7?

The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) changed dramatically the history of non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Several randomized prospective trials confirmed the superiority of these target agents about survival and response rate when comparing with platinum-based chemotherapy. Knowledge about EGFR mutations increased gradually during the development of target agents and different clinical trials. EGFR mutations cannot be considered all equal, but different entities should be considered in our clinical practice: exon 19 deletions, exon 21 mutation (L858R) and uncommon mutation (exon 20, exon 18 and double mutation). Nowadays, we dispose of three different EGFR TKIs (afatinib, erlotinib and gefitinib) approved for the treatment for first-line treatment of patients di NSCLC carrying EGFR, that was compared only by indirect analysis, producing data not always clear and convincing. This research highlight is an overview of data about EGFR TKIs in first-line setting, focusing on differences about exon 19 deletions and L585R mutation in patients treated with different TKIs. In addition, we report the preliminary results of the first head-to-head randomized clinical trial between two different EGFR TKIs, the LUX-Lung 7 (LL7) that compared afatinib and gefitinib showing interesting results.

[Immunotherapy in non-small cell lung cancer: evolution of knowledge and clinical advances]. / L'immunoterapia nel NSCLC: evoluzione delle conoscenze e dei progressi clinici.

Lung cancer represent the leading cause of cancer related-death worldwide. Although cytotoxic chemotherapy and targeted agents improved survival, the median overall survival for patients with metastatic disease remains poor. Docetaxel is still the corner stone of the second-line treatment, although associated with an unfavourable safety profile. Recent advances in the understanding of cancer immune escape system lead to the development of novel immunotherapies agent that can restore patient's immune response to cancer cells. Unlike vaccines, immune checkpoints inhibitors have shown promising results in non-small cell lung cancer patients. Especially, nivolumab and pembrolizumab, monoclonal antibodies against PD-1, provides as single agent therapy in chemotherapy refractory patients objective response rates ranging from 15%-25%, the majority of which arose quickly and were ongoing 1 year after starting treatment. Furthermore, the toxicity profile differs from that of cytotoxic chemotherapy and is much better tolerated. PD-L1 expression is a promising biomarker for selection and stratification of patients, although its prognostic and predictive role remains to be defined. Several trials are currently ongoing to define the role of immune checkpoint inhibitors in the treatment of patients with non-small cell lung cancer, their combination with cytotoxic chemotherapy or targeted agents and the efficacy and safety of double blockage of PD-1/PD-L1 and CTLA4. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating immune checkpoint inhibitors and NSCLC, considering the measured outcomes as progression free survival (PFS), overall survival (OS), and the overall response rate (ORR).

Improved health perception after genetic counselling for women at high risk of breast and/or ovarian cancer: construction of new questionnaires--an Italian exploratory study.

BACKGROUND: Subjects referred to genetic counselling for cancer may have heightened perceptions of illness and death, even though they are healthy and this may cause anxiety and reluctance to follow through with consultation. We investigated such perceptions before and after counselling and genetic testing for cancer in a cohort of Italian women. We sought to understand the situation of the women referred by designing questionnaires administered to women at high risk of breast and/or ovarian cancer (those who had had a pathogenic mutation identified in a family member via diagnostic testing). We also assessed women after the diagnosis of breast cancers, but free of disease, to help determine risks in their families. METHODS: The first questionnaires were administered before initial counselling, and the second were completed within 20 days after the counselling. When a genetic test was proposed, the individual was asked to fill in a third questionnaire; the final questionnaire was administered after the person had received the results of the genetic test. RESULTS: We evaluated 204 subjects. Before counselling, 89 % of the subjects were worried about their risk of disease, 52 % felt "different" because of their personal and family history, and 39 % declared that their life choices were influenced by their fear of cancer. After counselling, 82 % of the subjects felt more relived about their pre-existing fears and stated that this process of being seen in a clinic with genetic expertise had clarified the meaning of disease risk for them, and for 50 %, this experience had positively influenced their life choices. Thirty percentage of the subjects had a positive test; all of them felt safer in being cared for by specifically trained staff. Fifty percentage had a less informative test (e.g. "wild-type" gene found); 84 % of them were not worried by the uncertainty, and overall, 96 % considered counselling to be very useful. CONCLUSION: Candidates for genetic counselling frequently had heightened their perception of being ill, which influenced their ability to make life decisions. Genetic counselling often improves this perception, especially in subjects who have negative tests and this knowledge facilitates their life plans. After testing, most women felt satisfied and safer because of being properly followed by professionally trained and sympathetic staff. In conclusion, knowledge of the real individual risk, the presence of a professional team, and the possibility of entering a programme of controlled screening enable patients rather than living in fear and uncertainty to be less anxious about their state of health and to live with the knowledge that they are doing everything possible to care for themselves, aided by a specialized team, and that, if necessary, they would be able to take part in investigational studies.

A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors.

PURPOSE: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors. EXPERIMENTAL DESIGN: This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg. RESULTS: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962. CONCLUSIONS: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146-54. ©2015 AACR.

Modulation of epidermal growth factor receptor status by chemotherapy in patients with locally advanced non-small-cell lung cancer is rare.

PURPOSE: To determine whether epidermal growth factor receptor (EGFR) expression in non-small-cell lung cancer (NSCLC) is modulated by chemotherapy and to assess the agreement of EGFR status between mediastinal nodes and the primary tumor after chemotherapy. PATIENTS AND METHODS: Patients with NSCLC stage IIIa/b pN2/3 confirmed by mediastinoscopy or mediastinostomy were treated with at least three cycles of chemotherapy before undergoing surgery. EGFR expression was evaluated on mediastinal nodes at the time of initial diagnosis and on both the primary tumor and residual metastatic nodes after treatment. RESULTS: EGFR expression determined on 138 of 164 patients who underwent mediastinoscopy or mediastinostomy was 0 (22 patients), 1+ (27 patients), 2+ (28 patients), and 3+ (61 patients). Fifty-four patients of 164 received chemotherapy followed by surgery. Of the 89 of 138 patients with EGFR score of 2+/3+ at the time of diagnosis, 34 patients underwent surgery after induction chemotherapy. None changed to zero EGFR immunoreactivity, with 29 patients (88%) maintaining a score of 2+/3+. Of the 22 of 138 patients with no EGFR expression at the time of diagnosis, six underwent surgical resection after induction chemotherapy. Of these six patients, four changed their EGFR expression from an EGFR score of 0 to 2+/3+. After treatment, the agreement of EGFR status between tumor and nodes in the subgroup of patients with EGFR score 2+/3+ was 89% to 92%. CONCLUSION: Our data suggest a very good agreement of EGFR status before and after chemotherapy in EGFR-positive NSCLC. Induction chemotherapy can induce EGFR expression in occasional EGFR-negative tumors.

Inactivity of imatinib in gastrointestinal stromal tumors (GISTs) harboring a KIT activation-loop domain mutation (exon 17 mutation pN822K).

The development of gastrointestinal stromal tumors (GISTs) is largely driven by mutations in the KIT and PDGFRα genes. Imatinib mesylate is an oral small molecular tyrosine kinase inhibitor that mainly targets abl, c-KIT, and PDGFRα. Imatinib achieves disease control in approximately 70%-85% of patients with advanced GIST, and the median progression-free survival is 20-24 months. The efficacy of imatinib correlates with tumor kinase mutational status (exon 11 mutations mainly), and some mutations are known to be responsible for primary and secondary imatinib resistance. Beyond these, there are many other mutations that are considered rare and are associated with unknown clinical behavior. In the literature, there are poor and inconsistent data about the inhibitor sensitivity of mutations occurring in the activation-loop domain encoded by exon 17. In this article, we focus on a case of a patient suffering from GIST, harboring an extremely rare KIT activation-loop domain mutation (exon 17 mutation pN822K) treated with imatinib. A review of the literature is also presented.

Erlotinib efficacy in NSCLC patients with high polysomy of chromosome 7 and EGFR/KRas wild-type tumors.

BACKGROUND: More than even before, the efficacy of epidermal growth factors (EGFRs) tyrosine kinase inhibitors in non-small-cell lung cancer patients carrying EGFR wild-type tumors has been under investigation. EGFR wild-type patients represent a large and heterogeneous group of patients. In this setting, the role played by high polysomy of chromosome 7 still remains controversial. Indeed, previous reports did not discriminate between chromosome 7 high polysomy and EGFR amplification and/or did not investigate the concurrent presence of EGFR and KRas mutations. METHODS: We retrospectively collected data from 163 patients analyzed for EGFR status (mutation, amplification, chromosome 7 trysomy, and polysomy), in addition to KRas mutation, between 2000 and 2010 in our institute. Erlotinib was administered to 73 of them. Objective responses and progression-free survivals to erlotinib were evaluated. RESULTS: High polysomy of chromosome 7 characterized 17% (28 of 163) of EGFR/KRas wild-type tumors, independently of smoking status. In this group, 13 patients received erlotinib at progression. The treatment led one complete and four partial responses, and five stable diseases. Two patients progressed. One patient was lost to follow-up. The mean time to progression was 9 months. CONCLUSION: Among the EGFR wild-type population, when analyzed separately, high polysomy of chromosome 7 was the only molecular feature conferring clear signs of sensitivity to erlotinib. Therefore, the evaluation of high polysomy of chromosome 7 could become a helpful tool to predict for the benefit from epidermal growth factors tyrosine kinase inhibitors in selected cases.