Use of Endpoints in Phase III Randomized Controlled Trials for Hematopoietic Stem Cell Transplantation Over the Last 15 Years: A Systematic Review.

This systematic review aimed to evaluate the proportion of primary and secondary endpoints in hematopoietic stem cell transplant (HSCT) phase III randomized clinical trials (RCTs) and analyze their trends in time and study sponsorship status. The Chi-square test and logistic regression analyses were performed using SPSS version 28. A total of 147 HSCT phase III RCTs from 2006 to 2021 reported 197 primary and 600 secondary endpoints. Overall survival (OS, 17 %), progression-free survival (PFS, 15 %), graft versus host disease (GVHD, 8 %), event-free survival (EFS, 8 %), and organ function (8 %) were the most common primary endpoints. GVHD (12.3 %, n = 74), safety/toxicity/adverse events (11.8 %, n = 71), OS (11.5 %, n = 69), PFS (9.3 %, n = 56), and relapse rate (RR; 7.5 %, n = 45) were the most common secondary endpoints during 2006-2021. After 2013, an increase was noted in the use of PFS as a primary endpoint (12 %-18 %, p = 0.196), while the use of OS as a primary endpoint declined (20 %-13 %, p = 0.170). An increase was observed in using the secondary endpoints RR (5 %-10 %, p = 0.047) and NRM (3 %-6 %, p = 0.047). EFS was used more (14 % vs. 4 %, p = 0.012) than ORR (11 % vs. 2 %, p = 0.003) as a primary endpoint in pharmaceutical-compared to non-pharmaceutical-sponsored studies. As secondary endpoints, the use of EFS (4 % vs. 1 %, p = 0.013) and ORR (4 % vs. 1 %, p = 0.028) was higher, whereas that of organ systems/functions (1.5 % vs. 5.5 %, p = 0.022) and GVHD (6.5 % vs. 15 %, p = 0.002) was lower in pharmaceutical-compared to non-pharmaceutical sponsored studies. GVHD-free relapse-free survival was reported as a primary endpoint in 2 % of studies, while only 5 % reported quality of life as a secondary endpoint. We described commonly used endpoints in HSCT phase III RCTs and patterns in their use over time by funding source and study intervention category.

Renal AL Amyloidosis: Updates on Diagnosis, Staging, and Management.

AL amyloidosis is caused by the excessive production of nonfunctional immunoglobulins, leading to the formation of amyloid fibrils that damage vital organs, especially the heart and kidneys. AL amyloidosis presents with non-specific symptoms such as fatigue, weight loss, numbness, pain, and nephrotic syndrome. Consequently, diagnosis is often delayed, and patients typically present with advanced disease at diagnosis. The Pavia renal staging model stratifies patients based on their likelihood of progressing to dialysis. Treatment with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD) was effective in inducing renal response in the landmark phase III ANDROMEDA trial and reducing early mortality. However, determining the most appropriate treatment regimen for relapsed or refractory cases remains a challenge due to various patient- and disease-related factors. Encouragingly, t(11:14) may be a positive indicator of therapy responses to the anti-BCL2 therapy venetoclax. Moreover, it is increasingly possible-for the first time-to clear AL amyloid fibrils from peripheral organs by leveraging novel anti-fibril immunotherapeutic approaches, although these medications are still under investigation in clinical trials. Given these advancements, this review provides a comprehensive overview of the current strategies for diagnosing, staging, treating, and monitoring AL amyloidosis, emphasizing renal involvement.

Outcomes with allogeneic hematopoietic stem cell transplantation in TP53-mutated myelodysplastic syndrome: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to evaluate outcomes after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in TP53-mutated myelodysplastic syndromes (MDS). A literature search was performed on PubMed, Cochrane, Embase, and Clinicaltrials.gov. After screening 626 articles, eight studies were included. Data were extracted following the PRISMA guidelines and analyzed using the meta-package by Schwarzer et al. We analyzed 540 patients. The pooled median 3 (1-5) year overall survival was 21% (95% CI 0.08-0.37, I2=91%, n=540). The pooled relapse rate was 58.9% (95% CI 0.38-0.77, I2=93%, n=487) at a median of 1.75 (1-3) years. The pooled 4-year progression- free survival was 34.8% (95% CI 0.15-0.57, I2=72%, n=105). Outcomes of Allo-HSCT for TP53-mutated MDS patients remain poor, with 21% OS at three years; however, Allo-HSCT confers a survival advantage as compared to non-transplant palliative therapies. Our findings suggest the need to explore novel therapeutic agents in prospective clinical trials.

Takotsubo Syndrome in Black Americans: Insights From the National Inpatient Sample.

BACKGROUND: Data on race-related differences in the clinical outcomes of Takotsubo syndrome are limited, particularly for Black patients. This study aimed to assess whether race and sex may have an additional impact on the inpatient mortality of patients with Takotsubo syndrome. METHODS: A total of 4,628 patients from the United States' National Inpatient Sample from 2012 to 2016 were identified; propensity score analysis revealed a similar propensity score between Black patients (n = 2,314) and White patients (n = 2,314), which was used to balance observed covariates. Sex and age distributions were identical between the 2 groups. The groups were also similar in baseline characteristics, including cardiovascular risk factors. White patients were compared with Black patients on in-hospital outcomes and inpatient mortality. A logistic regression analysis was conducted to measure the difference in mortality based on race and sex. RESULTS: Compared with White patients, Black patients had a higher percentage of in-hospital complications, including cerebrovascular accidents (4.9% vs 2.5%, P ≤ .01), acute kidney injury (25% vs 19%, P ≤ .01); longer lengths of stay (8 vs 7 days, P ≤ .01); and higher inpatient mortality (6.1% vs 4.5%, P < .01). When analysis was conducted with race and sex combined, inpatient mortality was higher among Black men than among White women (odds ratio, 2.7 [95% CI, 1.80-3.95]; P ≤ .01). CONCLUSION: This study showed that Black patients with Takotsubo syndrome have higher in-hospital complications and inpatient mortality rates. When race and sex were combined, inpatient mortality was significantly higher among Black men than among either White men and women or Black women.

Machine learning applications and challenges in graft-versus-host disease: a scoping review.

PURPOSE OF REVIEW: This review delves into the potential of artificial intelligence (AI), particularly machine learning (ML), in enhancing graft-versus-host disease (GVHD) risk assessment, diagnosis, and personalized treatment. RECENT FINDINGS: Recent studies have demonstrated the superiority of ML algorithms over traditional multivariate statistical models in donor selection for allogeneic hematopoietic stem cell transplantation. ML has recently enabled dynamic risk assessment by modeling time-series data, an upgrade from the static, "snapshot" assessment of patients that conventional statistical models and older ML algorithms offer. Regarding diagnosis, a deep learning model, a subset of ML, can accurately identify skin segments affected with chronic GVHD with satisfactory results. ML methods such as Q-learning and deep reinforcement learning have been utilized to develop adaptive treatment strategies (ATS) for the personalized prevention and treatment of acute and chronic GVHD. SUMMARY: To capitalize on these promising advancements, there is a need for large-scale, multicenter collaborations to develop generalizable ML models. Furthermore, addressing pertinent issues such as the implementation of stringent ethical guidelines is crucial before the widespread introduction of AI into GVHD care.

An Unexpected Diagnosis of Second Primary Malignancy in a Breast Cancer Survivor: A Case Report.

BACKGROUND: Breast cancer survival rates are increasing more than ever with the development of better diagnostic and therapeutic techniques. Survivors of breast cancer have an increased risk of developing second primary malignancies, which may be mistaken for breast cancer recurrence and lead to delayed diagnosis and poor prognosis. CASE REPORT: We report a case of a 62-year-old female who presented with shortness of breath and bone pain. She had a history of left triple-positive invasive ductal carcinoma (T1N0M0) treated with bilateral skin-sparing mastectomy, adjuvant Taxotere, and trastuzumab-based therapy and then continued on trastuzumab and letrozole. She underwent imaging to explore the source of her symptoms at which new pulmonary nodules were discovered. During workup, she was found to have elevated tumor markers. They were initially suspected to be breast cancer recurrence metastases based on elevated tumor markers; however, further investigations confirmed that the nodules were a second primary lung adenocarcinoma with a different molecular profile. The patient had disease progression despite chemotherapy and eventually succumbed to her disease. CONCLUSION: This case highlights the importance of considering second primary malignancies in breast cancer survivors and utilizing advanced diagnostic modalities to efficiently diagnose such cases.

Corrigendum: Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1200941.].

Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy.

This review focuses on the immunosuppressive effects of tumor angiogenesis and coagulation on the tumor microenvironment (TME). We summarize previous research efforts leveraging these observations and targeting these processes to enhance immunotherapy outcomes. Clinical trials have documented improved outcomes when combining anti-angiogenic agents and immunotherapy. However, their overall survival benefit over conventional therapy remains limited and certain tumors exhibit poor response to anti-angiogenic therapy. Additionally, whilst preclinical studies have shown several components of the tumor coagulome to curb effective anti-tumor immune responses, the clinical studies reporting combinations of anticoagulants with immunotherapies have demonstrated variable treatment outcomes. By reviewing the current state of the literature on this topic, we address the key questions and future directions in the field, the answers of which are crucial for developing effective strategies to reprogram the TME in order to further the field of cancer immunotherapy.

Age-sex effect on in-hospital complications and mortality in patients with Takotsubo syndrome. Insights from the National Inpatient Sample.

Age and sex differences in Takotsubo syndrome (TTS) are still a matter of debate. The present study aimed to evaluate the difference in cardiovascular (CV) risk factors, CV disease, in-hospital complications, and death within different sex-age groups. Using the National Inpatient Sample database between 2012 and 2016, 32,474 patients older than 18 years of age hospitalized with the primary diagnosis of TTS were identified. A total of 32,474 patients were enrolled; 27,611 (85.04%) were female. CV risk factors were higher in females, while CV diseases and in-hospital complications were significantly higher in males. The mortality in males was twice as high as that of female patients (9.83% versus 4.58%, p<0.01), and in the logistic regression model after adjustment for confounders, the odds ratio (OR) was 1.79, the confidence interval was 1.60-2.02, and p<0.01. After dividing the group based on age, in-hospital complications were inversely related to age in both sexes, and the length of in-hospital stay was double in the youngest group compared to the oldest one. Mortality increased progressively with age in both groups but was constantly higher in males for each age group. Multiple logistic regression analysis for mortality was performed for the two sexes separately and for the three age groups, considering the youngest one as the reference group. In females, the OR was 1.59 and 2.88, respectively, for groups 2 and 3; for males, the OR was 1.92 and 3.15, all of them statistically significant (p<0.01). In-hospital complications were more common in younger patients with TTS, particularly in males. Mortality was positively correlated with age for both sexes, but mortality was higher in males compared to females in all age groups.

Use of endpoints in phase III randomized controlled trials for acute myeloid leukemia over the last 15 years: a systematic review.

We systematically evaluated the primary and secondary endpoints used in acute myeloid leukemia (AML) phase III randomized controlled trials (RCTs). We included 238 phase III AML RCTs in the past 15 years that reported 279 primary endpoints and 657 secondary endpoints. Overall survival (OS), progression-free survival (PFS), event-free survival (EFS), and complete remission (CR) were primary endpoints in 120 (43%), 34 (12%), 30 (11%), and 41 (15%) studies, respectively. OS (12.5%), PFS (13.2%), CR (14%), safety (11%), and EFS (9%) were commonly reported secondary endpoints. Among primary endpoints, a higher use of OS (OR 2.03, 95%CI 1.10-3.75, p = 0.023) and lower use of PFS (OR 0.25, 95%CI 0.12-0.52, p < 0.001) was observed from 2014 to 2021 compared to 2006-2013; CR was frequently used in relapsed/refractory compared to frontline RCTs (OR 2.20, 95%CI 1.11-4.38, p = 0.025); EFS was frequently used in frontline compared to relapsed/refractory AML RCTs (OR 10.11, 95%CI 1.34-76.34, p = 0.025). A higher trend in the use of clinically meaningful and objective endpoint of OS over the last 15 years.

Contemporary review on pediatric hypertrophic cardiomyopathy: insights into detection and management.

Hypertrophic cardiomyopathy is the most common genetic cardiac disorder and is defined by the presence of left ventricular (LV) hypertrophy in the absence of a condition capable of producing such a magnitude of hypertrophy. Over the past decade, guidelines on the screening, diagnostic, and management protocols of pediatric primary (i.e., sarcomeric) HCM have undergone significant revisions. Important revisions include changes to the appropriate screening age, the role of cardiac MRI (CMR) in HCM diagnosis, and the introduction of individualized pediatric SCD risk assessment models like HCM Risk-kids and PRIMaCY. This review explores open uncertainties in pediatric HCM that merit further attention, such as the divergent American and European recommendations on CMR use in HCM screening and diagnosis, the need for incorporating key genetic and imaging parameters into HCM-Risk Kids and PRIMaCY, the best method of quantifying myocardial fibrosis and its prognostic utility in SCD prediction for pediatric HCM, devising appropriate genotype- and phenotype-based exercise recommendations, and use of heart failure medications that can reverse cardiac remodeling in pediatric HCM.

A retrospective analysis of the frequency of heparin-induced thrombocytopenia in the intensive care unit at a tertiary care center in Riyadh, Saudi Arabia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an extremely serious and potentially fatal condition that can develop in patients taking heparin-based medications, such as unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). The incidence and risk factors for HIT in critically ill patients, however, are not well defined. METHODS: We retrospectively collected data on HIT test results, route of heparin administration, age, sex, heparin type (UFH or LMWH), and date of illness from patients admitted to the intensive care unit (ICU) and regular nursing floor (non-ICU) at our hospital between January 2011 and December 2014. We screened patients for HIT using the 4T score and confirmed the diagnosis through laboratory testing (direct enzyme immunoassay immunoglobulin G [IgG] or a platelet-activating antibody). RESULTS: We screened a total of 946 patients, 56 (5.9%) of whom were positive for HIT. Among 776 patients receiving UFH and 180 receiving LMWH, 2.8 and 6.6% developed HIT, respectively (P = 0.051). We then classified our patients into two groups: ICU, and non-ICU. In the non-ICU group (n = 317), 4 (2.7%) patients receiving LMWH and 25 (5.1%) receiving UFH were positive for HIT (P = 0.221). In the ICU group (n = 639), 1 (3.1%) patient receiving LMWH and 26 (9.1%) receiving UFH were positive for HIT (P = 0.249). The ICU group, therefore, had a higher cumulative incidence rate of HIT than the non-ICU group (8.5 vs. 4.5%). CONCLUSION: HIT was more common in ICU patients than non-ICU patients and in more patients receiving UFH than LMWH, although the differences were not statistically significant. Early diagnosis and appropriate treatment are essential to prevent adverse outcomes in patients with HIT.

SARS-CoV-2 epitopes inform future vaccination strategies.

All currently approved COVID-19 vaccines utilize the spike protein as their immunogen. SARS-CoV-2 variants of concern (VOCs) contain mutations in the spike protein, enabling them to escape infection- and vaccination-induced immune responses to cause reinfection. New vaccines are hence being researched intensively. Studying SARS-CoV-2 epitopes is essential for vaccine design, as identifying targets of broadly neutralizing antibody responses and immunodominant T-cell epitopes reveal candidates for inclusion in next-generation COVID-19 vaccines. We summarize the major studies which have reported on SARS-CoV-2 antibody and T-cell epitopes thus far. These results suggest that a future of pan-coronavirus vaccines, which not only protect against SARS-CoV-2 but numerous other coronaviruses, may be possible. The T-cell epitopes of SARS-CoV-2 have gotten less attention than neutralizing antibody epitopes but may provide new strategies to control SARS-CoV-2 infection. T-cells target many SARS-CoV-2 antigens other than spike, recognizing numerous epitopes within these antigens, thereby limiting the chance of immune escape by VOCs that mainly possess spike protein mutations. Therefore, augmenting vaccination-induced T-cell responses against SARS-CoV-2 may provide adequate protection despite broad antibody escape by VOCs.

Reciprocal interferences of the left ventricular assist device and the aortic valve competence.

Patients suffering from end-stage heart failure tend to have high mortality rates. With growing numbers of patients progressing into severe heart failure, the shortage of available donors is a growing concern, with less than 10% of patients undergoing cardiac transplantation (CTx). Fortunately, the use of left ventricular assist devices (LVADs), a variant of mechanical circulatory support has been on the rise in recent years. The expansion of LVADs has led them to be incorporated into a variety of clinical settings, based on the goals of therapy for patients ailing from heart failure. However, with an increase in the use of LVADs, there are a host of complications that arise with it. One such complication is the development and progression of aortic regurgitation (AR) which is noted to adversely influence patient outcomes and compromise pump benefits leading to increased morbidity and mortality. The underlying mechanisms are likely multifactorial and involve the aortic root-aortic valve (AV) complex, as well as the LVAD device, patient, and other factors, all of them alter the physiological mechanics of the heart resulting in AV dysfunction. Thus, it is imperative to screen patients before LVAD implantation for AR, as moderate or greater AR requires a concurrent intervention at the time of LVADs implantation. No current strict guidelines were identified in the literature search on how to actively manage and limit the development and/or progression of AR, due to the limited information. However, some recommendations include medical management by targeting fluid overload and arterial blood pressure, along with adjusting the settings of the LVADs device itself. Surgical interventions are to be considered depending on patient factors, goals of care, and the underlying pathology. These interventions include the closure of the AV, replacement of the valve, and percutaneous approach via percutaneous occluding device or transcatheter aortic valve implantation. In the present review, we describe the interaction between AV and LVAD placement, in terms of patient management and prognosis. Also it is provided a comprehensive echocardiographic strategy for the precise assessment of AV regurgitation severity.

A complex unit for a complex disease: the HCM-Family Unit.

Hypertrophic cardiomyopathy (HCM) is a group of heterogeneous disorders that are most commonly passed on in a heritable manner. It is a relatively rare disease around the globe, but due to increased rates of consanguinity within the Kingdom of Saudi Arabia, we speculate a high incidence of undiagnosed cases. The aim of this paper is to elucidate a systematic approach in dealing with HCM patients and since HCM has variable presentation, we have summarized differentials for diagnosis and how different subtypes and genes can have an impact on the clinical picture, management and prognosis. Moreover, we propose a referral multi-disciplinary team HCM-Family Unit in Saudi Arabia and an integrated role in a network between King Faisal Hospital and Inherited and Rare Cardiovascular Disease Unit-Monaldi Hospital, Italy (among the 24 excellence centers of the European Reference Network (ERN) GUARD-Heart).   Graphical Abstract.

Nodular lymphocyte-predominant Hodgkin lymphoma characteristics, management of primary and relapsed/refractory disease and outcome analysis: the first comprehensive report from the Middle East.

BACKGROUND: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon variant of Hodgkin lymphoma. There is limited data on treatment, management of refractory and relapsed disease, and long-term outcome. Many registries or country-wide data reports are unable to provide detailed primary and subsequent management. We are reporting our observation on patient's characteristics, management, and outcome. METHODS: This single-institution retrospective cohort analysis includes NLPHL patients seen from 1998 to July 2019. We used Fisher's exact test, chi-square, and Kaplan-Meier (KM) method for various analyses. RESULTS: Two hundred patients were identified, (6.34% of all the HL). Male:female was 3:1. The median age at diagnosis was 22 years (4-79 years). Stage I-II in 145 (72.5%) cases. One hundred patients (50%) received chemotherapy, 68 (34%) chemotherapy + radiation therapy (RT); 87% of all chemotherapy was ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Thirteen patients (6.5%) received RT alone and 16 (8%) had surgery alone. Complete response in 82%, partial response in 5.5% and progressive disease in 10.5%. The median follow is 60 months (5-246). Median 5 and 10 years overall survival (OS) is 94.8 and 92.4% (stages I-II, 97.7 and 97.7%, stage III-IV, 94.8 and 92.4%). Median event-free survival (EFS) is 62.3 and 54% respectively (stage I-II, 72 and 64%, stage III-IV, 36.4 and 18.2%). Stage I-II vs III-IV OS (p = < 0.001) and EFS (p = < 0.001) were significant. For stage I-II, 5 year EFS of chemotherapy + RT (83.3%) was superior to chemotherapy alone (60%, p = 0.008). Five year EFS for early favorable (80%), early unfavorable (60%), and advanced (36.4%) was significant (p = < 0.001). Eleven patients (5.5%) had high-grade transformation. Twenty-nine patients underwent HDC auto-SCT, all are alive (28 in remission). 25% of patients had pathologically proved nodal hyperplasia at some point in time. CONCLUSION: OS of NLPHL is excellent and independent of treatment type. EFS is better for chemotherapy + RT than chemotherapy alone. Stem cell transplant in refractory / multiple relapses resulted in excellent disease control. There is a need to identify optimal treatment strategies accordingly to the risk stratification.

Trastuzumab, Pertuzumab, and Docetaxel as the First Line for HER-2-Positive Metastatic Breast Cancer among Arabs.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER-2) targeted therapy regimens can improve tumor response in HER-2-positive metastatic breast cancer (MBC), with overall survival benefits. OBJECTIVE: We evaluated the efficacy of dual HER-2 blockade combined with chemotherapy for HER-2-positive MBC patients as a first-line therapy in our patient population. PATIENTS AND METHODS: We identified 75 patients at King Faisal Specialist Hospital and Research Center that received trastuzumab, pertuzumab, and docetaxel as a first-line therapy in HER-2 positive MBC in 2013-2016. RESULTS: Median age at diagnosis was 45 years; 54.7% were estrogen receptor (ER)-positive. 10% of patients presented with only bone metastasis. The median follow-up time was 36 months with an objective response rate of 74.7% (complete response [CR] 18.7%; partial response [PR] 56%). The 5-year progression-free survival (PFS) and overall survival (OS) were 21% and 71.9% respectively, with a median PFS of 36 months (95% confidence interval [CI] 23.6-48.4). The 5-year OS for ER-negative and ER-positive patients was 93.9% and 59.4% respectively (p = 0.189); 23 patients experienced grade 1/2 toxicity and 2 patients had grade 3/4 toxicity. In terms of OS and PFS, the site of metastasis did not make any significant difference. CONCLUSIONS: First line pertuzumab, trastuzumab, and docetaxel for HER-2-positive MBC patients was found to be an effective and safe therapy in the Saudi population. This finding was consistent with the results seen in the CLEOPATRA trials.

Risk of hematological malignancies in the families of patients treated for nodular lymphocyte-predominant Hodgkin lymphoma.

BACKGROUND: Familial clustering of lymphoid and/or hematological malignancies (FHM) provides an opportunity to study the responsible genes. The data is limited in patients with lymphoid and hematological malignancies. METHODS: The lymphoma database was used to identify patients seen in our institution from 1998 to 2019 with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We studied FHM by collecting detailed history of any malignancy in the family (FM). RESULTS: Two hundred NLPHL patients were identified. Contacting was not possible in 30 patients due to no response to the phone calls (22) and death [1]. 170/200 patients were interviewed; represented 167 families (3 patients with a family member with NLPHL). These 170 patients provided information about 8225 family members. These 167 families had a total of 329 family members with 334 malignancies (including 167 NLPHL patients and 5 members with 2 malignancies each). Of these 167 patients, 77 (46.1%) had no FM while 90 (53.9%) patients had a positive FM; 162 family members with 167 malignancies. Among these 167 families, 31 families (18.6%) had members with FHM +/- solid cancers. These 31 families had 35 family members (25 males:10 females) with 16 lymphomas: diffuse large B cell lymphoma [2], follicular center cell lymphoma [3], chronic lymphocytic leukemia/small lymphocytic lymphoma [3], non-Hodgkin lymphoma [2], classical HL [2], and NLPHL [4]. Total of 8 leukemia: acute lymphoblastic leukemia [4], acute myeloid leukemia [3], and leukemia - no subtyping [5]. These 35 FHM members are 1st [6], 2nd (16), and 3rd [7] degree relatives of 31 NLPHL patients. There are 4 families with NLPHL in family members; all these 8 NLPHL patients are male and are alive. The median total number of 1st + 2nd +3rd degree members are 81. The decrease in the age of diagnosis from 1st generation to the 2nd generation (anticipation) was noted in 13/17 patients; 2nd generation median age at diagnosis was 29.7 years vs 1st generation age 53 years (developed malignancy 23.3 years earlier). CONCLUSION: FHM is frequent in NLPHL. This study provided us many important insights for planning future studies in terms of interviewing technique, time, and resource allocation and genetic testing.

Does the Timing of Surgery after Neoadjuvant Therapy in Breast Cancer Patients Affect the Outcome?

BACKGROUND: There is a paucity of literature examining the impact of timing of surgery after neoadjuvant chemotherapy. OBJECTIVE: This study aimed to analyze the impact of the time taken to initiate surgical treatment following completion of neoadjuvant chemotherapy on patients' outcomes by evaluating their pathological response, overall survival (OS), and disease-free survival (DFS). METHODS: This is a retrospective review of 611 patients diagnosed with stage II and III breast cancer that received neoadjuvant chemotherapy and surgery between January 2004 and December 2014. The data was collected from a prospectively gathered registry. The patients were stratified into three cohorts according to the time of surgery after neoadjuvant chemotherapy: <4 weeks, 4-7 weeks, or ≥8 weeks. Outcomes were assessed using Kaplan-Meier curves, and the variables were compared using log-rank statistics. RESULTS: The 5-year OS rate was 89.6% and the 5-year DFS rate was 74%. OS and DFS were not significantly different when stratified according to timing of surgery; however, the trends of OS and DFS were poor when surgery was delayed for ≥8 weeks. Median OS and median DFS have not yet been reached. Of the 17% of patients that had surgery after ≥8 weeks, 12.9% had pathological complete response (pCR), while among those that received surgery 4-7 weeks and <4 weeks after neoadjuvant chemotherapy, 26% and 21% had pCR, respectively (p = 0.02). ER+/HER-2+ patients had a statistically significant decrease in pCR if surgery was performed after ≥8 weeks. CONCLUSION: Our patients showed improved pCR if surgery was performed within 8 weeks, especially for ER+/HER-2+ patients. All patients had better OS and DFS trends if surgery was performed between 4 and 7 weeks after neoadjuvant chemotherapy.