INTESTINAL ENDOMETRIOSIS: OUTCOMES FROM A MULTIDISCIPLINARY SPECIALIZED REFERRAL CENTER.

BACKGROUND: Deep penetrating endometriosis (DE) can affect abdominal and pelvic organs like the bowel and bladder, requiring treatment to alleviate symptoms. AIMS: To study and investigate clinical and surgical outcomes in patients diagnosed with DE involving the intestines, aiming to analyze the effectiveness of surgical treatments. METHODS: All cases treated from January 2021 to July 2023 were included, focusing on patients aged 18 years or older with the disease affecting the intestines. Patients without intestinal involvement and those with less than six months of post-surgery follow-up were excluded. Intestinal involvement was defined as direct invasion of the intestinal wall or requiring adhesion lysis for complete resection. Primary outcomes were adhesion lysis, rectal shaving, disc excision (no-colectomy group), and segmental resection (colectomy group) along with surgical complications like anastomotic leak and fistulas, monitored for up to 30 days. RESULTS: Out of 169 patients with DE surgically treated, 76 met the inclusion criteria. No colectomy treatment was selected for 50 (65.7%) patients, while 26 (34.2%) underwent rectosigmoidectomy (RTS). Diarrhea during menstruation was the most prevalent symptom in the RTS group (19.2 vs. 6%, p<0.001). Surgical outcomes indicated longer operative times and hospital stays for the segmental resection group, respectively 186.5 vs. 104 min (p<0.001) and 4 vs. 2 days, (p<0.001). Severe complications (Clavien-Dindo ≥3) had an overall prevalence of 6 (7.9%) cases, without any difference between the groups. There was no mortality reported. Larger lesions and specific symptoms like dyschezia and rectal bleeding were associated with a higher likelihood of RTS. Bayesian regression highlighted diarrhea close to menstruation as a strong predictor of segmental resection. CONCLUSIONS: In patients with DE involving the intestines, symptoms such as dyschezia, rectal bleeding, and menstrual period-related diarrhea predict RTS. However, severe complication rates did not differ significantly between the segmental resection group and no-colectomy group.

Intestinal endometriosis: outcomes from a multidisciplinary specialized referral center / Endometriose intestinal: resultados de um centro de referência multidiscipilinar especializado

ABSTRACT BACKGROUND: Deep penetrating endometriosis (DE) can affect abdominal and pelvic organs like the bowel and bladder, requiring treatment to alleviate symptoms. AIMS: To study and investigate clinical and surgical outcomes in patients diagnosed with DE involving the intestines, aiming to analyze the effectiveness of surgical treatments. METHODS: All cases treated from January 2021 to July 2023 were included, focusing on patients aged 18 years or older with the disease affecting the intestines. Patients without intestinal involvement and those with less than six months of post-surgery follow-up were excluded. Intestinal involvement was defined as direct invasion of the intestinal wall or requiring adhesion lysis for complete resection. Primary outcomes were adhesion lysis, rectal shaving, disc excision (no-colectomy group), and segmental resection (colectomy group) along with surgical complications like anastomotic leak and fistulas, monitored for up to 30 days. RESULTS: Out of 169 patients with DE surgically treated, 76 met the inclusion criteria. No colectomy treatment was selected for 50 (65.7%) patients, while 26 (34.2%) underwent rectosigmoidectomy (RTS). Diarrhea during menstruation was the most prevalent symptom in the RTS group (19.2 vs. 6%, p<0.001). Surgical outcomes indicated longer operative times and hospital stays for the segmental resection group, respectively 186.5 vs. 104 min (p<0.001) and 4 vs. 2 days, (p<0.001). Severe complications (Clavien-Dindo ≥3) had an overall prevalence of 6 (7.9%) cases, without any difference between the groups. There was no mortality reported. Larger lesions and specific symptoms like dyschezia and rectal bleeding were associated with a higher likelihood of RTS. Bayesian regression highlighted diarrhea close to menstruation as a strong predictor of segmental resection. CONCLUSIONS: In patients with DE involving the intestines, symptoms such as dyschezia, rectal bleeding, and menstrual period-related diarrhea predict RTS. However, severe complication rates did not differ significantly between the segmental resection group and no-colectomy group.

RESUMO RACIONAL: A endometriose profunda infiltrativa (EP) pode afetar órgãos abdominais e pélvicos, tais como o intestino e a bexiga, necessitando de tratamento para aliviar os sintomas. OBJETIVOS: Estudar e investigar resultados clínicos e cirúrgicos em pacientes com diagnóstico de EP envolvendo o intestino, visando analisar a eficácia dos tratamentos cirúrgicos. MÉTODOS: Foram incluídos todos os casos atendidos de janeiro de 2021 a julho de 2023, com foco em pacientes com 18 anos ou mais com a doença acometendo o intestino. Foram excluídos pacientes sem comprometimento intestinal e aqueles com menos de seis meses de acompanhamento pós-operatório. O envolvimento intestinal foi definido como invasão direta da parede intestinal ou necessidade de lise de aderências para ressecção completa. Os desfechos primários foram lise de aderências, raspagem retal e excisão discóide (grupo não colectomia), e ressecção segmentar (grupo colectomia), juntamente com complicações cirúrgicas como fístulas, monitoradas por até 30 dias. RESULTADOS: Das 169 pacientes com EP tratadas cirurgicamente, 76 preencheram os critérios de inclusão. Não foi indicado colectomia em 50 (65,7%) pacientes, enquanto 26 (34,2%) foram submetidos à retossigmoidectomia (RTS). A diarreia durante a menstruação foi o sintoma mais prevalente no grupo RTS (19,2% vs. 6,0%, p<0,001). Os resultados cirúrgicos indicaram tempos operatórios e internações hospitalares mais longos para o grupo de ressecção segmentar, respectivamente, 186,5 vs. 104 min (p<0,001) e 4 vs. 2 dias, (p<0,001). As complicações graves (Clavien-Dindo ≥3) tiveram prevalência global de 6 (7,9%) casos, sem diferença entre os grupos. Não houve mortalidade relatada. Lesões mais graves e sintomas específicos como disquezia e sangramento retal foram associados a maior probabilidade de indicação de RTS. A regressão bayesiana destacou a diarreia próxima à menstruação como um forte preditor de ressecção segmentar. CONCLUSÕES: Em pacientes com endometriose envolvendo os intestinos, sintomas como disquezia, sangramento retal e diarreia relacionada ao período menstrual predizem a indicação de RTS. No entanto, as taxas de complicações graves não diferiram significativamente entre o grupo de ressecção segmentar e o grupo sem colectomia.

Nonoperative vs Operative Management of Uncomplicated Acute Appendicitis: A Systematic Review and Meta-analysis.

Importance: Appendectomy remains the standard of care for uncomplicated acute appendicitis despite several randomized clinical trials pointing to the safety and efficacy of nonoperative management of this disease. A meta-analysis of randomized clinical trials may contribute to the body of evidence and help surgeons select which patients may benefit from surgical and nonsurgical treatment. Objective: To assess the efficacy and safety of nonoperative management vs appendectomy for acute uncomplicated appendicitis. Data Sources: A systematic review was conducted using indexed sources (Embase and PubMed) to search for published randomized clinical trials in English comparing nonoperative management with appendectomy in adult patients presenting with uncomplicated acute appendicitis. To increase sensitivity, no limits were set for outcomes reported, sex, or year of publication. All nonrandomized or quasi-randomized trials were excluded, and validated primers were used. Study Selection: Among 1504 studies imported for screening, 805 were duplicates, and 595 were excluded for irrelevancy. A further 96 were excluded after full-text review, mainly owing to wrong study design or inclusion of pediatric populations. Eight studies met the inclusion criteria and were selected for the meta-analysis. Data Extraction and Synthesis: Meta-extraction was conducted with independent extraction by multiple reviewers using the Covidence platform for systematic reviews and in accordance with PRISMA guidelines. Data were pooled by a random-effects model. Main Outcomes and Measures: Treatment success and major adverse effects at 30 days' follow-up. Results: The main outcome (treatment success proportion at 30 days of follow-up) was not significantly different in the operative and nonoperative management cohorts (risk ratio [RR], 0.85; 95% CI, 0.66-1.11). Likewise, the percentage of major adverse effects was similar in both cohorts (RR, 0.72; 95% CI, 0.29-1.79). However, in the nonoperative management group, length of stay was significantly longer (RR, 1.48; 95% CI, 1.26-1.70), and a median cumulative incidence of 18% of recurrent appendicitis was observed. Conclusions and Relevance: These results point to the general safety and efficacy of nonoperative management of uncomplicated acute appendicitis. However, this strategy may be associated with an increase in duration of hospital stay and a higher rate of recurrent appendicitis. This meta-analysis may help inform decision-making in nonoperative management of uncomplicated acute appendicitis.

Influência da utilização de métodos contraceptivos sobre as taxas de gestação não planejada em mulheres brasileiras / Influence of contraceptive use on unplanned pregnancy rates in Brazilian women

Este estudo teve como objetivo primário analisar a taxa de gestações não planejadas e sua relação com o uso de métodos contraceptivos no Brasil. Secundariamente, procurou-se identificar o impacto da pandemia por SARS-CoV-2 sobre o desejo reprodutivo e a utilização de contraceptivos. Foram entrevistadas mulheres entre 16 e 45 anos que tiveram pelo menos uma gestação, por meio de questionário on-line, em todas as regiões brasileiras. Foram analisados dados de 1.000 mulheres com média etária de 34,7 anos, paridade média de 1,69 filho e número médio de 2,01 gestações. Entre as mulheres, 62% referiram ter tido pelo menos uma gestação não planejada, com maior percentual entre as mulheres que utilizam o sistema público de saúde (65%) em relação ao sistema privado (55%). Entre as mulheres que referiram ao menos uma gestação não planejada, 46% usavam algum método contraceptivo na ocasião. O uso atual de métodos contraceptivos atingiu 81% das mulheres entrevistadas, sendo os contraceptivos orais utilizados por 31%, seguidos dos preservativos (20%), laqueadura tubária (10%) e métodos de longa ação (LARC, 9%). Entre as mulheres, 53% considerariam um LARC como modalidade contraceptiva, especialmente entre as que referiram esquecimento frequente de pílulas. Durante a pandemia, 7% das mulheres entrevistadas referiram suspender o uso de contraceptivos. Para 80%, não houve mudanças no planejamento reprodutivo durante a pandemia, porém observaram-se 10% de gestações não planejadas. Em conclusão, a menor adoção de métodos contraceptivos, aliada ao uso incorreto/ falha do método, associa-se a maiores taxas de gestações não planejadas. Métodos com maior índice de eficácia são considerados por mulheres que já experimentaram gestações não planejadas. Houve pequeno impacto da pandemia sobre o uso de métodos contraceptivos e sobre o planejamento reprodutivo.(AU)

Different perceptions among women and their physicians regarding contraceptive counseling: results from the TANCO survey in Brazil / Diferentes percepções entre mulheres e seus médicos sobre o aconselhamento contraceptivo: Resultados da pesquisa TANCO no Brasil

Abstract Objective The optimal use of contraceptive methods requires that women participate in targeted choice of methods that meet their individual needs and expectations. The Thinking About Needs in Contraception (TANCO) study is a quantitative online survey of the views of health professionals and women on aspects of contraceptive counseling and contraceptive use. Methods Physicians and women attending clinics for contraception were invited to complete online questionnaires. The research explored the knowledge and use of contraceptive methods, satisfaction with the current method and interest in receiving more information on all methods. Aspects related to contraceptive practice among physicians were gathered in parallel. The results obtained in the Brazilian research were compared with those of the European research, which involved 11 countries. Results There was a high prevalence of contraceptive use and general satisfaction with the current method. A total of 63% of the women were using short-acting contraceptive (SAC) methods, and 9% were using a long-acting reversible contraceptive (LARC). Sixty-six percent of women were interested in receiving more information on all methods; 69% of women said they would consider LARC if they received more comprehensive information about it. Health professionals tend to underestimate the interest of women in receiving information about contraception in general, and more specifically about LARCs. Conclusion Despite the high levels of use and satisfaction with the current methods, women were interested in receiving more information on all contraceptive methods. Structured contraceptive counseling based on individual needs and expectations may lead to greater knowledge and a greater likelihood of proper contraceptive choice.

Resumo Objetivo A utilização ideal de métodos contraceptivos requer que as mulheres participem da escolha orientada sobre métodos que atendam às suas necessidades e expectativas individuais. O estudo Thinking About Needs in Contraception (TANCO)- Pensando nas Necessidades em Contracepção-é uma pesquisa quantitativa online de opiniões de profissionais de saúde e de mulheres sobre aspectos do aconselhamento contraceptivo e uso de anticoncepcionais. Métodos Médicos e mulheres que frequentam consultórios de atendimento visando contracepção foram convidados a preencher questionários online. A pesquisa explorou o conhecimento e ouso de métodos contraceptivos, a satisfação com o método atual, e o interesse em receber mais informações sobre todos os métodos. Aspectos relacionados à prática contraceptiva entre médicos foram reunidos em paralelo. Os resultados obtidos na pesquisa brasileira foram comparados aos da pesquisa europeia, que envolveu 11 países. Resultados Houve alta prevalência do uso de contraceptivos e satisfação geral com o método atual. Sessenta e três por cento das mulheres estavam usando métodos de curta duração (SAC, na sigla em inglês), e 9% estavam usando um método de longa ação (LARC, na sigla em inglês). Sessenta e seis por cento das mulheres estavam interessadas em receber mais informações sobre todos os métodos; 69% das mulheres disseram que considerariam um LARC se recebessem informações mais abrangentes sobre esse método. Os profissionais de saúde tendem a subestimar o interesse das mulheres em receber informações sobre a contracepção em geral e, mais especificamente, sobre os LARC. Conclusão Apesar dos altos níveis de uso e satisfação com os métodos atuais, as mulheres estavam interessadas em receber mais informações sobre todos os métodos contraceptivos. O aconselhamento contraceptivo estruturado, baseado nas necessidades e expectativas individuais pode levar ao maior conhecimento e à maior probabilidade de escolha contraceptiva adequada.

Reactional changes in short-term levonorgestrel-releasing intrauterine system (lng-ius) use.

OBJECTIVE: To evaluate endocervical and vaginal environment changes in women using a levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: A quasi-experimental study included sixty women who had an LNG-IUS inserted in the Family Planning Clinic of UNICAMP between April and November of 2016. Women in reproductive age, non-pregnant, without the use of antibiotics and contraceptives seeking for LNG-IUS insertion were selected for this study. All women were evaluated with regard to vaginal and endocervical pH, vaginal and endocervical Gram-stained bacterioscopy, and Pap-smear before and two months after LNG-IUS insertion. Clinical aspects such as cervical mucus, vaginal discharge, and cervical ectopy were also observed. RESULTS: After LNG-IUS insertion, there was an increase in the following parameters: endocervical pH>4.5 (p=0.02), endocervical neutrophil amount (p<0.0001), vaginal cytolysis (p=0.04). There was a decrease in vaginal discharge (p=0.01). No statistically significant changes were found in vaginal pH, neutrophils amount in the vaginal mucosa, vaginal discharge appearance, vaginal candidiasis, bacterial vaginosis, vaginal coccobacillary microbiota, cervical mucus appearance, or cervical ectopy size. CONCLUSIONS: Short-term LNG-IUS use did not increase vulvovaginal candidiasis or bacterial vaginosis, and led to diminished vaginal discharge. Notwithstanding, this device promoted reactional changes in the vaginal and endocervical environment, without modification on cervical ectopy size.

Reactional changes in short-term levonorgestrel-releasing intrauterine system (lng-ius) use

SUMMARY OBJECTIVE: To evaluate endocervical and vaginal environment changes in women using a levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: A quasi-experimental study included sixty women who had an LNG-IUS inserted in the Family Planning Clinic of UNICAMP between April and November of 2016. Women in reproductive age, non-pregnant, without the use of antibiotics and contraceptives seeking for LNG-IUS insertion were selected for this study. All women were evaluated with regard to vaginal and endocervical pH, vaginal and endocervical Gram-stained bacterioscopy, and Pap-smear before and two months after LNG-IUS insertion. Clinical aspects such as cervical mucus, vaginal discharge, and cervical ectopy were also observed. RESULTS: After LNG-IUS insertion, there was an increase in the following parameters: endocervical pH>4.5 (p=0.02), endocervical neutrophil amount (p<0.0001), vaginal cytolysis (p=0.04). There was a decrease in vaginal discharge (p=0.01). No statistically significant changes were found in vaginal pH, neutrophils amount in the vaginal mucosa, vaginal discharge appearance, vaginal candidiasis, bacterial vaginosis, vaginal coccobacillary microbiota, cervical mucus appearance, or cervical ectopy size. CONCLUSIONS: Short-term LNG-IUS use did not increase vulvovaginal candidiasis or bacterial vaginosis, and led to diminished vaginal discharge. Notwithstanding, this device promoted reactional changes in the vaginal and endocervical environment, without modification on cervical ectopy size.

RESUMO OBJETIVO: Avaliar as alterações do ambiente endocervical e vaginal em mulheres usuárias de sistema intrauterino liberador de levonorgestrel (SIU-LNG). MÉTODOS: Um estudo quase-experimental incluiu 60 mulheres que inseriram o SIU-LNG na Clínica de Planejamento Familiar da UNICAMP entre abril e novembro de 2016. Mulheres em idade reprodutiva, não gestantes, sem uso de antibióticos e contraceptivos, em busca pela inserção do SIU-LNG, foram selecionadas para este estudo. Todas as mulheres foram avaliadas quanto ao pH vaginal e endocervical, bacterioscopia vaginal e endocervical por coloração de Gram, exame de Papanicolau antes e dois meses após a inserção de SIU-LNG. Aspectos clínicos como muco cervical, corrimento vaginal e ectopia cervical também foram observados. RESULTADOS: Após a inserção do SIU-LNG houve aumento nos seguintes parâmetros: pH endocervical >4,5 (p=0,02), quantidade de neutrófilos endocervicais (p<0,0001), citolise vaginal (p=0,04). Houve diminuição do conteúdo vaginal (p=0,01). Não foram encontradas alterações estatisticamente significativas no pH vaginal, na quantidade de neutrófilos na mucosa vaginal, apecto do corrimento vaginal, candidíase vaginal, vaginose bacteriana, microbiota cocobacilar vaginal, aparência de muco cervical ou tamanho da ectopia cervical. CONCLUSÃO: O uso do SIU-LNG em curto prazo não aumentou a candidíase vulvovaginal ou a vaginose bacteriana, levou à diminuição do conteúdo vaginal. No entanto, este dispositivo promoveu mudanças reacionais no ambiente vaginal e endocervical, sem modificação no tamanho da ectopia cervical.

Anticoncepção na adolescência / Contraception in adolescence

Adolescentes desejam método seguro e efetivo de contracepção, mas encontram barreiras ao conhecimento de diferentes opções e a seu acesso. A idade isoladamente não contraindica qualquer método contraceptivo. Ao contrário, adolescentes têm maior número de opções contraceptivas em virtude das condições de saúde próprias da idade. As formas mais populares de contracepção em adolescentes são preservativos e o coito interrompido, seguidos das pílulas combinadas. Observa-se, no entanto, que os métodos que dependem do uso correto das adolescentes apresentam maior número de falhas quando comparadas a mulheres adultas. Profissionais de saúde envolvidos em medidas contraceptivas devem priorizar o aconselhamento e a capacitação para a oferta dos métodos contraceptivos para adolescentes, observando aspectos culturais e éticos nessa importante fase da vida feminina.(AU)

Uso de dispositivos intrauterinos (DIU) em nulíparas / Use of intrauterine devices (IUDs) in nulliparous women

Objetivo: Avaliar as evidências para o uso de dispositivos intrauterinos (DIUs) em mulheres nulíparas. Métodos: Revisão da lteratura,com seleção de publicações relacionadas ao uso do dispositivo intrauterino de cobre e do sistema intrauterino de levonorgestrel em nulíparas no período entre 1980 e 2018. Resultados: Os DIUs utilizados em nulíparas associam-se à elevada eficácia e segurança, sem riscos adicionais de doença inflamatória pélvica e infertilidade. Não há maior risco de perfurações e expulsões em nulíparas. Os DIUs apresentam boa tolerabilidade, aceitação e continuidade de uso, embora associem-se a maior grau de dor durante a inserção quando comparados ao uso em nulíparas. Conclusão: Os dispositivos intrauterinos são eficazes e seguros para nulíparas,recomendando-se que devam ser incluídos nas opções contraceptivas oferecidas rotineiramente.

Long-Acting Reversible Contraception / Contracepção reversível de longa ação

Abstract Unwanted pregnancy is a major public health problem both in developed and developing countries. Although the reduction in the rates of these pregnancies requires multifactorial approaches, increasing access to long-acting contraceptive methods can contribute significantly to change this scenario. In Brazil, gynecologists and obstetricians play a key role in contraceptive counseling, being decisive in the choice of long-acting reversible methods, characterized by intrauterine devices (IUDs) and the contraceptive implant. The vast scope due to the reduced number of situations to indicate long-acting methods should be emphasized in routine contraceptive counseling. On the other hand, gynecologists and obstetricians should adapt the techniques of insertion of long-acting methods, and engage in facilitating conditions to access these contraceptives through public and private health systems in Brazil. This study is part of a project called Diretrizes e Recomendações FEBRASGO (Guidelines and Recommendations of the FEBRASGO - Brazilian Federation of Gynecology and Obstetrics Associations from the Portuguese acronym). It aims to review the main characteristics of long-acting contraceptives and critically consider the current situation and future prospects to improve access to these methods, proposing practical recommendations of interest in the routine of gynecologists and obstetricians.

Resumo A gravidez não planejada representa importante problema de saúde pública tanto em países desenvolvidos quanto naqueles em desenvolvimento. Embora a redução das taxas dessas gestações requeira abordagens multifatoriais, o aumento no acesso aos métodos contraceptivos de longa ação pode contribuir de forma expressiva na mudança desse cenário. No Brasil, os ginecologistas e obstetras têm papel fundamental no aconselhamento contraceptivo, sendo decisivos na escolha dos métodos reversíveis de longa ação, caracterizados pelos dispositivos intrauterinos (DIUs) e pelo implante anticoncepcional. A grande abrangência decorrente do pequeno número de situações que contraindicam os métodos de longa ação deve ser enfatizada no aconselhamento contraceptivo de rotina. Por outro lado, os ginecologistas e obstetras devem se adaptar às técnicas de inserção dos métodos de longa ação, bem como se engajar na facilitação de condições para o acesso a esses contraceptivos por meio do sistema de saúde pública e privada no Brasil. Este estudo, parte do projeto denominado "Diretrizes e Recomendações FEBRASGO", tem por objetivo revisar as principais características dos contraceptivos de longa ação, além de considerar de forma crítica o panorama atual e as perspectivas futuras, visando melhorar o acesso a esses métodos, com recomendações práticas de interesse na rotina do ginecologista e obstetra.

Effects of an extended flexible regimen of an oral contraceptive pill containing 20 µg ethinylestradiol and 3 mg drospirenone on menstrual-related symptoms: a randomised controlled trial.

OBJECTIVES: The aim of the study was to assess the efficacy for menstrual-related symptoms of an extended flexible regimen of an oral contraceptive pill containing 20 µg ethinylestradiol and 3 mg drospirenone in comparison with a 24/4 d cyclical regimen of the same formulation. METHODS: This randomised, non-inferiority, open-label, multicentre study was conducted in women aged 18-39 years. Their menstrual-related symptoms were assessed using the Penn Daily Symptom Rating (DSR17). Participants were randomised to use an extended flexible regimen of 20 µg ethinylestradiol and 3 mg drospirenone (EE/DRSPe.flex), comprising 168 consecutive days with a 4-d hormone-free interval (HFI, allowing for management of unexpected bleeding) or a conventional 24/4 cyclical regimen of the same pill (EE/DRSP24/4). The primary measure of efficacy was the percentage change in DSR17 total score from baseline to cycle 6. The secondary measures of efficacy were the percentage changes in DSR17 total score from baseline after each 28-d interval throughout the entire study and in the scores for individual DSR17 symptoms. RESULTS: The primary analysis demonstrated that EE/DRSPe.flex was not inferior to EE/DRSP24/4 (Mean DSR17 score 9.1; 95% confidence interval (CI) - 2.5, 20.6; p = 0.123). Analysis at intervals throughout the entire evaluation period showed greater reduction in DSR17 total score for EE/DRSPe.flex than for the 24/4 regimen (p < 0.001). The decreases in individual scores for the symptoms 'poor coordination' and 'depression/feeling sad/down or blue' were greater for the extended flexible regimen than for the cyclical regimen (p < 0.05). CONCLUSION: The extended flexible regimen was not inferior to the 24/4 cyclical regimen in terms of the primary endpoint. It significantly improved symptoms in the interval analysis, and the effects on specific DSR17 symptoms, compared with the cyclical regimen.