Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.

BACKGROUND: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS: A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION: Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.

Erythema nodosum-like lesions during BRAF inhibitor therapy: Report on 16 new cases and review of the literature.

IMPORTANCE: BRAF inhibitors have been licensed for the therapy of BRAF-mutated melanoma. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as therapy side-effects that may lead to treatment discontinuation. OBJECTIVE: To identify and characterize cases with BRAF inhibitor-associated erythema nodosum-like inflammatory skin lesions and development of an algorithm for their management. DESIGN AND SETTING: Retrospective chart review of melanoma patients treated with BRAF inhibitors in 14 departments of Dermatology in Germany and Austria and PubMed search for cases in the literature. RESULTS: Sixteen patients were identified who developed erythema nodosum-like lesions under BRAF inhibitor therapy; 14 had received vemurafenib and two dabrafenib plus trametinib. The most frequently involved body sites were the legs. Histopathology was performed in five cases and revealed panniculitis in three and vasculitis in two patients respectively. Arthralgia and fever were associated symptoms in 44% and 31% of patients respectively. Inflammatory symptoms led to discontinuation of treatment in three patients, while in the majority of cases symptomatic management was sufficient. Skin lesions finally resolved despite continued BRAF inhibitor therapy in seven patients. In the literature, 19 additional patients with similar cutaneous appearance under BRAF inhibitors could be identified. An algorithm for the management of such lesions is proposed. CONCLUSION: Erythema nodosum-like skin lesions histologically correspond to panniculitis and/or vasculitis. Symptomatic treatment may be sufficient. However, additional work-up and interruption of BRAF inhibitor therapy may be necessary in severe cases which are commonly associated with systemic symptoms.

Differential influence of vemurafenib and dabrafenib on patients' lymphocytes despite similar clinical efficacy in melanoma.

BACKGROUND: Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system. PATIENTS AND METHODS: Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays. RESULTS: Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples. CONCLUSION: While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.

[Cutaneous side effects of anti-tumor therapy with BRAF and MEK inhibitors]. / Kutane Nebenwirkungen der medikamentösen Tumortherapie mit BRAF- und MEK-Inhibitoren.

BACKGROUND: BRAF and MEK inhibitors are new targeted therapies which are used in the treatment of malignancies, in particular of malignant melanoma. SIDE EFFECTS: Cutaneous side effects are common during the treatment with both types of inhibitors. These side effects include inflammatory reactions such as maculopapular and papulopustular exanthema, hand-foot syndrome, panniculitis, paronychia, photo- and radio-sensitization. As a class effect, BRAF-inhibitors induce proliferative disorders of keratinocytes and melanocytes, such as palmoplantar hyperkeratosis (as part of the hand-foot syndrome), verruciform and acanthoma-like lesions, follicular and Grover disease-like hyperkeratoses, keratoacanthomas, squamous cell carcinomas and atypical melanocytic nevi with transition to secondary melanomas. Furthermore, hair alterations and xerosis are possible. CONCLUSIONS: Treatment with BRAF and MEK inhibitors requires close dermatologic monitoring of the patient. This manuscript summarizes the most frequent cutaneous side effects and their management.

[Alopecia due to chemotherapeutics, hedgehog inhibitors, targeted antibody therapies and immune checkpoint inhibitors : Pathogenesis, clinical picture, diagnostics and prophylaxis]. / Alopezie durch Chemotherapeutika, Hedgehog-Inhibitoren, zielgerichtete Antikörpertherapien und Immuncheckpointinhibitoren : Pathogenese, Klinik, Diagnostik und Prophylaxe.

BACKGROUND: The incidence and severity of alopecia vary mainly depending on the chemotherapeutic agent used or other drug groups. The pathogenetic characteristics of the different forms of alopecia are reflected in the clinical presentation and, in some cases, in the resulting recommendations for prophylaxis. OBJECTIVES: To provide an overview of the pathogenesis, clinical presentation, diagnosis and prophylaxis of alopecia with chemotherapeutic agents, hedgehog inhibitors, targeted therapies and immune checkpoint inhibitors. MATERIALS AND METHODS: Based on the current S3 guideline "Supportive therapy", an extensive literature search was carried out. RESULTS AND CONCLUSION: Chemotherapy-induced hair loss (CIA) occurs in up to 65% of cases. Anagen effluvium is observed as early as 1-3 weeks after the start of treatment and is reversible in most cases. Alopecia associated with inhibitors of the Sonic Hedgehog signaling pathway (HHIA) such as vismodegib or sonidegib are observed in up to 60% of cases. They are characterized by telogen effluvium. BRAF or immune checkpoint inhibitors lead significantly less frequently to alopecia (BRAFA, CPIA). According to taxane-based chemotherapy protocols, scalp cooling can help to prevent higher-grade CIA. If CIA or other forms of alopecia are expected, early contact with self-help organizations and early prescriptions for wigs should be offered.

Early switch from run-in treatment with vemurafenib plus cobimetinib to atezolizumab after 3 months leads to rapid loss of tumour control in patients with advanced BRAFV600-positive melanoma: The ImmunoCobiVem phase 2 randomised trial.

AIM: ImmunoCobiVem investigated whether a planned switch to atezolizumab after achieving tumour control during run-in with vemurafenib + cobimetinib improves progression-free survival (PFS) and overall survival (OS) compared to continuous targeted therapy (TT) in patients with previously untreated advanced BRAFV600-mutated melanoma. METHODS: In this multicenter phase 2 study, patients received vemurafenib plus cobimetinib. After 3months, patients without progressive disease (PD) were randomly assigned (1:1) to continue vemurafenib + cobimetinib (Arm A) or switch to atezolizumab (Arm B) until first documented PD (PD1). Primary outcome was PFS1 (time from start of run-in until PD1 or death). OS and safety were also assessed. RESULTS: Of 185 patients enroled between November 2016 and December 2019, 135 were randomly assigned after the run-in period (Arm A, n = 69; Arm B, n = 66). Median PFS1 was significantly longer in Arm A versus Arm B (13.9 versus 5.9months; hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.37-0.84; PStratified=0.001). Median OS was not reached in either arm (HR 1.22; 95%CI, 0.69-2.16; PStratified=0.389); 2-year OS was higher in Arm B versus Arm A (67%; 95%CI, 53-78 versus 58%; 95%CI, 45-70). Grade 3/4 AEs occurred in 55% of patients in Arm A and 64% in Arm B; treatment-related AEs led to discontinuation of any drug in 7% and 9% of patients, respectively. CONCLUSION: In patients with BRAFV600-mutated advanced melanoma who achieve tumour control with TT, early switch at 3months to atezolizumab led to rapid loss of tumour control but provided a numerical OS benefit at 2years compared with continued TT.

[Adjuvant systemic treatment of melanoma]. / Adjuvante systemische Therapie des Melanoms.

Despite intensive clinical and research efforts during the last decades the prognosis for patients with stage IV melanoma still remains fatal. An efficient adjuvant treatment for patients with a high risk of relapse and metastases is one of the most urgent fields in clinical research. Systemic adjuvant chemotherapy was not beneficial in terms of relapse-free or overall survival improvement in several clinical trials. Treatment with IFN-α-2a and -2b treatment was the first and as yet only adjuvant therapy which has been proven to show a benefit in controlled studies and to gain approval in Germany in the indications for adjuvant therapy. Current clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon and on the other hand on testing new compounds, such as the CTLA4 inhibitor ipilimumab or a vaccination against the MAGE-A3 peptide.

[Current aspects of adjuvant therapy of malignant melanoma]. / Aktuelle Aspekte der adjuvanten Therapie des malignen Melanoms.

Despite intensive clinical and research efforts during recent decades, the prognosis of patients with stage IV melanoma still remains poor. Finding effective adjuvant treatment for patients with a high risk of relapse and metastasis is one of the most urgent needs in clinical research. Systemic adjuvant chemotherapy administered in several clinical trials offered no benefit in terms of improved relapse-free or overall survival. Interferon alpha-2a and -2b treatment was the first treatment in the adjuvant setting which has shown a treatment benefit and received approval in Germany. Today clinical research focuses on improved treatment schedules with conventional interferon compared to pegylated interferon as well as on new compounds such as CTLA4 inhibitors like ipilimumab or a vaccination against the MAGE-A3 peptide.

[Skin changes as a result of targeted therapies in oncology patients: cutaneous side effects of targeted therapies in oncology patients]. / Hautveränderungen durch "targeted therapies" bei onkologischen Patienten: Kutane Nebenwirkungen zielgerichteter Therapie bei onkologischen Patienten.

The growing number of patients treated with modern targeted therapies that cause specific cutaneous side effects is drawing attention to the optimal management of these side effects. Experience to date has shown that good management allows the majority of patients to receive the treatment as planned. As a result of the link between dermatological side effects and the success of treatment than can be assumed to exist for many substances, interdisciplinary collaboration between dermatologists and professionals from other disciplines working in the field of oncology is becoming increasingly important.

Assessment of potential risk factors associated with ischaemic colitis.

Ischaemic colitis (IC) has been associated with a number of diverse disorders and risk factors, including irritable bowel syndrome (IBS) and constipation. We sought to assess, through a large-scale population study, the potential risk factors associated with IC. Patients with IC and matched controls without IC were identified using the medical and pharmacy claims data from the HealthCore Managed Care Database from 1st January 2000 to 31st May 2005. A multivariate conditional logistic regression model was developed to identify significant risk factors of IC. Interactions of age, sex, prior IBS diagnosis, and prior constipation diagnosis were further evaluated. We identified 1754 patients with IC and 6970 non-IC controls; 64% were women, and mean ages were 63 and 62 years respectively. The final parsimonious model comprised 19 independent variables associated with increased risk for IC including shock, dysentery, bloating, IBS, colon carcinoma, constipation, cardiovascular disease, dyspepsia, abdominal, aortic, or cardiovascular surgery, 12-month laxative, H(2) receptor blocker and oral contraceptive use. A significant interaction was observed between age and prior IBS on risk for IC. In conclusion, multiple risk factors for IC were identified and we confirmed that patients with IBS or constipation are at greater risk for IC.

Patients with irritable bowel syndrome or constipation have an increased risk for ischaemic colitis.

AIMS: To estimate the relative risk for ischaemic colitis in patients with and without irritable bowel syndrome or constipation, and to evaluate the role of irritable bowel syndrome and constipation as confounders in the relationship between commonly used gastrointestinal medications and ischaemic colitis. METHODS: Patient cohorts were identified with the use of longitudinal MarketScan research databases from 1 January 1999 to 31 December 2002. Patients in each study cohort were matched 1:1 with comparable control patients using a propensity score. A Cox proportional hazards models were used to estimate relative risk for ischaemic colitis. RESULTS: The relative risk for ischaemic colitis was 3.17 and 2.78 times higher for patients with irritable bowel syndrome and constipation, respectively, than for those without these disorders. Patients who were taking an antispasmodic, a proton pump inhibitor, or an H2-antagonist were at increased risk for ischaemic colitis [relative risk with 95% CI 2.73 (1.41-5.39), 2.00 (1.05-3.79), 2.75 (1.22-6.17) respectively]; however, when these results were adjusted for irritable bowel syndrome or constipation, the relative risks were attenuated and no longer statistically significant. CONCLUSIONS: Patients with irritable bowel syndrome or constipation demonstrated a two- to threefold increased risk for ischaemic colitis. Moreover, irritable bowel syndrome and constipation strongly confounded the relationship between gastrointestinal drug use and the risk for ischaemic colitis, suggesting that etiologic studies of ischaemic colitis risk must account for the presence of irritable bowel syndrome or constipation.

Hepatic arterial Fotemustine chemotherapy in patients with liver metastases from cutaneous melanoma is as effective as in ocular melanoma.

AIM: Hepatic metastases from melanoma are associated with poor prognosis. Systemic chemotherapy and biological treatments remain unsatisfactory. This study investigated the impact of hepatic arterial chemotherapy in patients with ocular and cutaneous melanoma. METHODS: In a retrospectively analysed observational study, 36 consecutive patients with hepatic metastases from ocular or cutaneous melanoma were assigned for surgical hepatic port-catheter implantation. Fotemustine was delivered weekly for a 4-week period, followed by a 5-week rest and a maintenance period every 3 weeks until progression. Overall survival, response and toxicity were analysed and compared. RESULTS: After port-catheter implantation 30/36 patients were finally treated (18 with ocular and 12 with cutaneous melanoma). A median of 8 infusions per patient were delivered (range 3-24). 30% thrombocytopenia grade >or=3, 7% neutropenia grade >or=3 but no nausea or vomiting grade >or=3 were encountered. Nine out of 30 patients achieved partial remission, 10/30 stable disease; 11/30 patients were progressive. Median survival for all treated patients was 14 months. Partial remission and stable disease were associated with a survival advantage compared to progressive disease (19 vs. 5 months). No significant difference in survival was observed for ocular versus cutaneous melanoma. Serum LDH was a significant predictor of both response and survival. CONCLUSIONS: Hepatic arterial Fotemustine chemotherapy was well tolerated. Meaningful response and survival rates were achieved in ocular as well as cutaneous melanoma. Careful patient selection in consideration of extra-hepatic involvement is crucial for the effectiveness of this treatment. Independent from the primary melanoma site, it is debatable if patients with highly elevated serum-LDH may benefit from this approach.

Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab.

INTRODUCTION: PD-L1 is established as a predictive marker for therapy of non-small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab. MATERIALS AND METHODS: Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings. RESULTS AND DISCUSSION: The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab.

Red cell filterability determined using the cell transit time analyzer (CTTA): effects of ATP depletion and changes in calcium concentration.

Cell transit time analysis (CTTA) is a new filtrometric technique for assessing red blood cell deformability by measuring the conductivity change caused by passage of erythrocytes through a polycarbonate filter. Most reported studies to date using CTTA have focused on the transit time (TT), the duration of passage of an individual red cell through a micropore. Bulk flow rate has not been previously measured via CTTA. The use of new enzyme based cleaning solutions make it possible to reduce clogging in micropore filters. Therefore, valid measures of the number of red cell transits per unit time (counts/s: C/S) can now be obtained. We evaluated both parameters, TT and C/S, as indicators of red cell filterability. Our goal was to evaluate the effect of metabolic changes shown by alternative techniques to affect red cell deformability. The two best established factors are changes in intracellular [ATP] and [Ca2+]. ATP depletion produces a very small increase in TT but a very marked decrease in C/S. In contrast, the addition of low concentrations of calcium produces an increase in TT with minimal decrease in C/S. The effects of calcium appear to be complex. The substantial changes in intracellular calcium induced by the ionophore A23187 result in a curvilinear pattern of increase in transit times and reduction in counts per s. Lanthanum, which inhibits egress of intracellular calcium, causes an increase in TT with a drop in C/S. We conclude that CTTA demonstrates the same changes in red cell deformability measurable by alternative filtrometric techniques; however, CTTA furnishes two separate and independent parameters which may be used to evaluate red cell deformability.

[Diagnosis and treatment of invasive cervical cancer in Cambodia (apropos of 35 cases)]. / Diagnostic et traitement du cancer invasif du col utérin au Cambodge (a propos de 35 cas).

Uterine cervix cancer is an important public health problem in developing countries. In Cambodia, incidence (24. 10-5) and mortality (12,77. 10-5) rates due to this cancer are higher than in other southeast Asian countries. 35 consecutive women with a diagnosis of invasive cervical cancer were identified from the histology laboratory of the Institut Pasteur in Phnom Penh. Information on history, clinical findings, ancillary investigations and treatment were obtained by clinical files review. Patients were from Phnom Penh, the main city and from outlying provinces. The mean age was 50 years, 2 months. They all presented with clinical symptoms at the time of diagnosis, and lesions had spread beyond the uterus in nearly half of the cases. Squamous cell carcinoma (80%) was more frequent than adenocarcinoma (14%). Microinvasive squamous cell carcinomas were rare (2.8%). Treatment was mainly surgical, but lacked standardization, as radical hysterectomy including lymphadenectomy was not systematic, even when the tumor spread beyond the uterine cervix. Few women that required adjuvant radiotherapy received it as this technique has only recently been introduced in Cambodia. Many patients were lost to follow-up. None of the cases was detected by pap smear. This technique is not in general use in the country. Cervical cancer screening could be carried out by visual inspection of the cervix with acetic acid wash that is less expensive and nearly as sensitive as pap smear. Treatments are still insufficiently standardized, due to the lack of technical means, and lack of patient compliance.

Comparison of amlodipine/valsartan/hydrochlorothiazide single pill combination and free combination: adherence, persistence, healthcare utilization and costs.

OBJECTIVES: To determine whether amlodipine/valsartan/hydrochlorothiazide single pill combination (SPC) is associated with improved persistence, adherence and reduced healthcare utilization and costs compared to the corresponding free combination (FC). METHODS: Adult (≥18 years) patients covered by commercial and Medicare Supplemental insurance in the Truven MarketScan database with hypertension (HTN) diagnosis between October 2009 and December 2011 were included. At least two filled prescriptions for the SPC cohort or two periods of minimum 15 days of concurrent use of amlodipine, valsartan and hydrochlorothiazide (HCT) for the FC cohort were required. Cohorts were propensity score matched (PSM) to balance on important confounders. Outcomes included: 1) adherence (proportion of days covered [PDC] and medication possession ratio [MPR]); 2) persistence (treatment gap >30 days); 3) all-cause and HTN-specific healthcare utilization and costs at 12 months. RESULTS: After cohort matching with PSM, patients taking SPC (N = 9221) exhibited better outcomes than FC (N = 1884): higher mean adherence (85.7% vs. 77.0%), mean PDC (73.8% vs. 60.6%) and persistence (46.8% vs. 23.6%) (all p < 0.0001). Patients taking SPC were associated with higher odds of persistence (OR: 3.51; 95% CI: 3.08-4.02), MPR ≥80% (OR: 2.72; 95% CI: 2.40-3.08) and PDC ≥80% (OR: 2.88; 95% CI: 2.55-3.26). After PSM, the SPC cohort exhibited statistically significantly lower mean number of resource utilization events compared to FC. Patients in the SPC cohort also had a statistically significantly (p < 0.05) lower percentage of patients with ≥1 all-cause hospitalization (15.0% vs. 18.2%), ≥1 all-cause emergency room (ER) visits (25.7 vs. 31.4%), and ≥1 ER HTN-specific visits (9.7% vs. 14.1%). The costs incurred by SPC cohort patients were 2.8% to 41.7% numerically lower than the FC cohort, statistically significant for all-cause ER costs ($430.6 vs. $549.5, p < 0.05). CONCLUSIONS: Real-world data indicate an association of the amlodipine/valsartan/HCT SPC with improved adherence and persistence vs. FC with no difference in overall healthcare or hypertension specific costs between the cohorts.