Author: Rodrigo Arrangoiz MS, MD, FACS, FSSO

• Suppression of prostaglandin synthesis at sites of inflammation:
  • Is the primary mechanism behind the antinociceptive effects of nonsteroidal anti-inflammatory drugs (NSAIDs)
• NSAIDs inhibit the activity of the cyclooxygenase isoforms 1 and 2, and their use can decrease opioid consumption
• Opioids prescribed preoperatively can lead to long-term use
• Risk factors for chronic opioid use after surgery among opioid-naive patients include:
  • Male gender
  • Age greater than 50 years
  • Preoperative use of benzodiazepines
  • Preoperative use of antidepressants
  • Depression history
  • Alcohol abuse history
  • Drug abuse history
• A systematic review of the literature demonstrated that:
  • Co-administration of acetaminophen and NSAIDs:
    • Decreased 24-hour postoperative morphine consumption
• Multimodal regimens are thought to have synergistic and opioid-sparing effects
• Intravenous lidocaine is one such opioid-sparing agent:
  • It exerts its analgesic effect by blocking sodium channels responsible for neural transmission of pain impulses
• N-methyl-D-aspartate receptor antagonism:
  • Describes the mechanism of ketamine, an opioid-sparing agent
• Regional nerve blockade and neuraxial anesthesia is theorized to prevent persistent opioid use by preventative analgesia:
  • Directly blocking pain impulses preventing central sensitization
• Inhibition at glutamatergic synapses:
  • Describes the antinociceptive mechanism of action of magnesium
• References:
  • Brown, EN, Pavone KJ, Naranjo M. Multimodal general anesthesia: theory and practice. Anesth Analg. 2018;127(5):1246–1258.
  • Hah, JM, Bateman BT, Ratliff J, Curtin C, Sun E. Chronic opioid use after surgery: implications for perioperative management in the face of the opioid epidemic. Anesth Anal. 2017;125(5):1733–1740.
  • Dunn LK, Durieux ME. Perioperative use of intravenous lidocaine. Anesthesiology. 2017;126:729–737

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #BreastCancer #PostoperativePain #Ketorolac #NSAID #Miami #Teacher #Surgeon #MountSinaiMedicalCenter

• FAP is an autosomal dominant disorder:
  • That results from a mutation in the APC tumor suppressor gene on chromosome 5q21
• The syndrome is characterized by the development of:
  • Multiple adenomatous polyps with a high malignant potential throughout the gastrointestinal tract during early adulthood
  • PTC occurs in approximately 2% of patients with FAP:
    • Young women, however, are at highest risk of developing thyroid cancer:
      • Their chance of being affected is 160 times higher than it is for women without FAP
    • These tumors are frequently associated with a cribriform growth pattern on histologic examination

#Arrangoiz # ThyroidSurgeon #HeadandNeckSurgeon #ThyroidExpert #CancerSurgeon #SurgicalOncologist #FamilialAdenomaousPolyposis #FAP #Miami #MountSinaiMedicalCenter

• The pectoral branch of the thoraco-acromial artery can be encountered during a pectoral nerve block, or pecs block [not thoracic paravertebral nerve block (PVBs)]:
  • As it is consistently located adjacent to the lateral pectoral nerve
• The pecs block is a field block:
  • In which local anesthetic is injected in the interfacial plane between the pectoralis major and minor muscles.
• In addition to the pecs II block:
  • A modification blocking the long thoracic and thoracodorsal nerves:
    • The pecs block is an alternative to the thoracic paravertebral block in a multimodal pain management technique:
      • Intrathecal spread, intra-pleural injection and pneumothorax, bradycardia, and hypotension resulting from a sympathectomy in the neuraxis:
        • Are all known complications of thoracic paravertebral blocks
• References:
  • Blanco R. The ‘pecs block’: a novel technique for providing analgesia after breast surgery. Anesthesia 2011; 66:847–8.
  • S. Kulhari, et al. Efficacy of pectoral nerve block versus thoracic paravertebral block for postoperative analgesia after radical mastectomy: a randomized controlled trial. BrJ Anaesth. 2016;117(3):382–386.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #BreastCancer #PainManagement #Mastectomy #PectoralNerveBlock #Miami #Mexico #MountSinaiMedicalCenter

• The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-40 trial was designed to determine whether adding capecitabine (Xeloda) or gemcitabine (Gemzar) to docetaxel, doxorubicin, and cyclophosphamide would improve the rates of pathologic complete response (pCR) in the neoadjuvant setting:
  • The trial was also designed to determine whether adding bevacizumab (Avastin) to the chemotherapy regimens would further increase pCR rates
• Recognizing that bevacizumab, capecitabine, and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer:
  • The NSABP B-40 trial was designed to determine whether adding capecitabine or gemcitabine to docetaxel, followed by anthracycline doxorubicin and cyclophosphamide (AC):
    • Would improve the outcomes in patients with operable, HER2-negative breast cancer
• The trial also sought to determine the effect of adding bevacizumab to these neoadjuvant chemotherapy regimens
• Patients were divided into three groups:
  • Docetaxel followed by AC
  • Docetaxel and capecitabine followed by AC
  • Docetaxel plus gemcitabine followed by AC
• Each of these three groups was then randomized to receive bevacizumab with the first 6 cycles of chemotherapy or not, for a total of 6 treatment arms
• The addition of capecitabine or gemcitabine to docetaxel therapy, compared to docetaxel alone:
  • Did not significantly increase the rate of pCR:
    • 29.7% and 31.8%, respectively, vs 32.7%; P=0.69
• Both capecitabine and gemcitabine were associated with increased toxic side effects such as:
  • Hand-foot syndrome, mucositis, and neutropenia
• However, the addition of bevacizumab significantly increased the rate of pCR in the breast:
  • From 28.2% to 34.5% (P=0.02)
  • This effect was more pronounced in:
    • The hormone receptor-positive subset of patients:
      • 15.1% pCR without bevacizumab vs 23.2% with bevacizumab
  • However, the addition of bevacizumab also increased rates of:
    • Hypertension, left ventricular systolic dysfunction, hand-foot syndrome, and mucositis
• References
  • Bear HD, Tang G, Rastogi P, Geyer Jr CE, Robidoux A, Atkins JN, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366(4):310-320.
  • NSABP clinical trials overview. Protocol B-40. A randomized phase III trial of neoadjuvant therapy in patients with palpable and operable breast cancer evaluating the effect on pathologic complete response (pCR) of adding capecitabine or gemcitabine to docetaxel when administered before AC with or without bevacizumab and correlative science studies attempting to identify predictors of high likelihood for pCR with each of the regimens. National Surgical Adjuvant Breast and Bowel Project website. http://www.nsabp.pitt.edu/B-40.asp. Accessed May 15, 2020.

#Arrangoiz #BreastSurgeon #CancerSurgeon #BreastCancer #SurgicalOncologist #NSABPB40 #Teacher #Surgeon

• The NSABP B14 trial was a randomized, double blind, placebo-controlled trial:
  • Of postoperative therapy with tamoxifen (10 mg BID) in 2644 patients with ER positive histologically node-negative breast cancers
  • Patients were administered the drug for at least 5 years
  • After 15 years of follow-up, compared with placebo:
    • Tamoxifen-treated patients were found to have benefited irrespective of age, menopausal status, or ER concentration for:
      • Recurrence free survival (RFS):
        • 78% tamoxifen vs. 65% placebo
      • Overall Survival (OS):
        • 71% tamoxifen vs. 65% placebo
  • A multivariate analysis indicated that all subgroups investigated showed benefit from tamoxifen treatment:
    • This included a:
      • Reduction in rate of treatment failure at local and distant sites
      • A reduction in rate of incidence of new tumors in the contralateral breast
      • A reduction in loco-regional recurrence after lumpectomy and breast irradiation
  • While NSABP B-14 is known for establishing tamoxifen as an effective adjuvant therapy in ER positive, node-negative patients:
    • Disease-free survival and OS were found to decrease over the 15-year follow-up in a subset of patients originally thought to have a favorable prognosis
    • These findings prompted researchers to find a way to optimize treatment in this group:
      • Thus, the NSABP conducted the B-20 trial to evaluate the value of adding chemotherapy to tamoxifen for treatment regimens in ER positive, node-negative patients:
        • Results from the B-20 trial after a 12-year follow-up demonstrated a significant improvement in disease-free survival with the addition of chemotherapy to tamoxifen when compared to tamoxifen alone
• NSABP B-14:

  • Randomized patients after surgery to:

    • To five years of tamoxifen or 
5 years of placebo:
      • 
To determine if there was a:

        • Significant survival advantage with the addition of endocrine therapy to:
          • 
ER-positive tumors

  • After 10 years of follow-up:

    • A statistically significant DFS benefit was derived:

      • With the use of tamoxifen for 5 years:

        • 69% vs 57%

          • P<0.0001

    • With a 37% reduction:
      • 
In the rate of contralateral breast cancer (P=0.007)

  • The most recent update of this trial:

    • Continues to demonstrate this survival benefit at 15 years:

      • Irrespective of age

      • Menopausal status
      • Tumor ER concentration

  • A follow-up question to protocol B-14:

    • Asked the recommended duration of tamoxifen therapy beyond 5 years:

      • The same patient population was then re-randomized to:

        • Five additional years of tamoxifen or 
five years of placebo

          • There was a significant disadvantage in:

            • DFS:

              • 86% vs 92%, P= 0.003 and 

            • Distant DFS:

              • 90% vs 96%, P=0.01:

                • For patients who continued tamoxifen for more than 5 years versus those who took it for only 5 years

                • The lack of benefit with additional tamoxifen use was independent of patient age
• References:
  • Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, et al. A randomized trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor positive tumors. N Engl J Med. 1989;320(8):479-484.
  • Fisher B, Jeong JH, Bryant, Anderson S, Dignam J, Fisher ER, et al. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet. 2004;364(9437):858-868.
  • Newman LA, Mamounas EP. Review of breast cancer clinical trials conducted by the National Surgical Adjuvant Breast Project. Surg Clin N Am. 2007;87(2):279-305.

• The SENTINA (SENTinel NeoAdjuvant) study:
  • Was designed to evaluate the optimum timing of sentinel node biopsy (SNB) for breast cancer patients treated with neoadjuvant chemotherapy (NAC)

• SENTINA Trial:
  • Was a four-arm, prospective, multicenter cohort study of 1,737 patients:
    • To evaluate the role of SNB in patients who had undergone NAC for invasive breast cancer
• Clinical node status was determined by palpation and ultrasound in all patients:
  • Ultrasound guided fine-needle aspiration or core biopsy was recommended but not mandatory
• Patients with clinically node-negative (cN-) disease underwent SNB before NAC (Arm A):
  • If the sentinel node (SN) was positive:
    • A second SNB and axillary lymph node dissection (ALND) was performed after NAC (Arm B)
• Women who were clinically node positive (cN+) underwent NAC, and those who converted to being cN- also had SNB and axillary lymph node dissection (Arm C)
• Only patients whose clinical nodal status remained positive (ycN1) underwent axillary dissection without sentinel lymph node biopsy (arm D)
• When SNB was done before NAC:
  • No difference in the detection rate:
    • Was found between the combined (radiocolloid and blue dye) and single agent (radiocolloid alone) detection techniques;
      • 99.5% vs. 98.8%
• However, when SNB was done after NAC:
  • The addition of blue dye;
    • Increased the detection rate and the number of nodes retrieved
  • Dual tracer detection rate was:
    • 76% after chemotherapy in patients who also had SNB prior to chemotherapy
    • 88% in those who converted from cN+ to cN- with NAC and had only one SNB
  • For patients who were confirmed node positive by SNB biopsy prior to NAC:
    • The FNR of repeat SNB after NAC was 51.6%
  • For patients who converted from cN+ to cN- with NAC:
    • FNR of SNB after NAC was 14.2%
  • However, in the cN+ to cN- group:
    • The FNR was below 10%:
      • For patients who had 3 or more lymph nodes removed and if both blue dye and radiocolloid were used
        • In these cases, the FNR was 8.6%
• References
  • Kuehn T, Bauerfeind I, Fehm T, Fleige B, Hausschild M, Helms G, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncol.2013;14(7):609-618.
  • Schwentner L, Helms G, Nekljudova V, Ataseven B, Bauerfeind I, Ditsch N, et al. Using ultrasound and palpation for predicting axillary lymph node status following neoadjuvant chemotherapy – Results from the multi-center SENTINA trial. Breast. 2017;31:202-207.

#Arrangoiz #BreastSurgeon #BreastCancer #CancerSurgeon #SurgicalOncologist #Miami #MountSinaiMedicalCenter #Mexico #SENTINATRIAL

• In the NSABP B-27 trial:
  • 2,411 women with operable breast cancer were randomly assigned to receive:
    • Preoperative AC followed by surgery
    • AC followed by docetaxel then surgery
    • AC followed by surgery and then docetaxel
  • Tamoxifen was initiated concurrently with chemotherapy
  • The addition of docetaxel, preoperatively or postoperatively:
    • Did not significantly improve OS or DFS
  • The sample size of the study was deemed insufficient to yield significance for the moderate improved DFS
  • However, in the subset of patients with a clinical partial response to AC:
    • The addition of preoperative docetaxel (but not postoperative docetaxel):
      • Resulted in a significant increase in DFS compared with AC alone (hazard ratio, 0.71; 95% confidence interval, 0.55–0.91; P=.007)
    • There was a significant decrease in the cumulative incidence of all local recurrence as first events in the two groups treated with docetaxel:
      • Approximately half of which was accounted for by ipsilateral breast tumor recurrences in women treated with breast-conserving therapy
• References:
  • Bear HD, Anderson S, Smith RE, Geyer Jr CE, Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006;24(13):2019-2027.
  • NSABP clinical trials overview. Protocol B-27. A randomized trial comparing preoperative doxorubicin (adriamycin) cyclophosphamide (AC) to preoperative AC followed by preoperative docetaxel (taxotere) and to preoperative ac followed by postoperative docetaxel in patients with operable carcinoma of the breast. National Surgical Adjuvant Breast and Bowel Project website. http://www.nsabp.pitt.edu/B-27.asp. Accessed May 15, 2020.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #NSABPB27 #Chemotherapy #Miami #MountSinaiMedicalCenter #Mexico #Surgeon #Teacher

• The NSABP B-51 / RTOG 1304 trial:
  • Is a phase 3 randomized clinical trial currently accruing patients, which is designed to evaluate the role of regional nodal radiotherapy (RT) in patients who had documented positive axillary lymph nodes prior to undergoing NAC who subsequently convert to pathologically negative axillary nodes after the administration of NAC
  • The primary endpoint is:
    • To determine if regional nodal RT significantly reduces the rate of in-breast cancer recurrence free interval
  • Node positivity will be documented by either FNA or core needle biopsy prior to the administration of NAC
  • Patients will undergo standard NAC with the addition of anti-HER2 therapy for patients with HER2-positive tumors
  • Patients can have either mastectomy or breast-conserving therapy
  • Mastectomy patients will be randomized to:
    • Either no RT or regional nodal RT and chest wall RT
  • Breast conservation patients will be randomized to either whole-breast RT or whole-breast RT plus regional nodal RT
• A companion trial is being undertaken by The Alliance for Clinical Trials in Oncology:
  • The A11202 trial is enrolling patients that were axillary node positive prior to NAC, have a normal axilla on physical exam after NAC, but have microscopic disease on sentinel lymph node biopsy
  • This trial randomizes patients to completion axillary node dissection or sentinel lymph node biopsy only in addition to radiation therapy for both arms
• References
  • NSABP clinical trials overview. Protocol B-27. A randomized trial comparing preoperative doxorubicin (adriamycin) cyclophosphamide (ac) to preoperative ac followed by preoperative docetaxel (taxotere) and to preoperative ac followed by postoperative docetaxel in patients with operable carcinoma of the breast. National Surgical Adjuvant Breast and Bowel Project website. http://www.nsabp.pitt.edu/b-51.asp. Accessed May 15, 2020.
  • NRG-alias protocol information. https://www.nrgoncology.org/Clinical-Trials/Protocol/nsabp-b-51-rtog-1304?filter=nsabp-b-51-rtog-1304. Accessed September 11, 2020.
  • Comparison of axillary lymph node dissection with axillary radiation for patients with node-positive breast cancer treated with chemotherapy. NIH ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01901094. Accessed May 15, 2020.

#Arrangoiz #BreastSurgeon #BreastCancer #CancerSurgeon #NSABPB51 #RTOG1304 #Miami #Mexico #MountSinaiMedicalCenter #SurgicalOncologist

• The CALGB 9343 study:
  • Enrolled 647 patients from 1994 until 1999
  • Long-term follow-up data were published in 2013:
    • With a median follow-up of 12.6 years
  • Women age 70 years or older with clinical stage I (T1,N0,M0) ER positive breast cancer treated by lumpectomy were randomly assigned to receive:
    • Tamoxifen plus radiation therapy (TamRT) or Tam alone
  • At 10 years:
    • 98% of women receiving TamRT were free from local and regional recurrences, compared to 91% of those receiving Tam
  • The 10-year estimates of overall survival (OS) were:
    • 67% (95% confidence interval [CI], 62–72%) in the TamRT group versus 66% (95% CI, 61%–71%) in the Tam group:
      • But the difference was not statistically significant
  • In addition to concluding that while RT (in addition to Tam) reduces locoregional recurrence:
    • The authors noted that “the impact of breast cancer in this select group of older women is much smaller than that of comorbid conditions…:
      • Only 3% of women in study have died as a result of breast cancer, whereas 49% have died as a result of other causes.”²
• References
  • Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol.2013;31(19):2382-2389.
  • Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31:2382-2389.

#Arrangoiz #BreastCancer #BreastSurgeon #CancerSurgeon #SurgicalOncologist #CALGB9343Trial #Miami #MountSinaiMedicalCenter #Mexico

• HERceptin Adjuvant (HERA) trial: 
  • An international, multicenter, phase 3 randomized trial of 5,102 women with HER2-positive early breast cancer
  • After completing all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated):
    • Patients were randomly assigned to receive trastuzumab for 1 or 2 years, or to the observation group
  • Primary endpoint was disease-free survival
  • Results reported that:
    • One year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improved long-term disease-free survival, compared with observation, while two years of trastuzumab had no additional benefit
• ALTTO (Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimization) Study: 
  • Was the first trial to test the hypothesis that dual anti-HER2 blockade could further improve survival outcomes of patients with HER2-positive early breast cancer compared with adjuvant trastuzumab
  • The study compared the efficacy of the addition of lapatinib to trastuzumab (sequentially after completion of 12 weeks of trastuzumab or concurrently with 52 weeks of trastuzumab) vs. trastuzumab alone for 1 year
  • Adjuvant treatment that included lapatinib did not significantly improve survival compared with trastuzumab alone and added toxicity
• NSABP B-44, also known as the BETH Study (Treatment of HER2 Positive Breast Cancer With Chemotherapy Plus Trastuzumab vs. Chemotherapy Plus Trastuzumab Plus Bevacizumab):
  • Was a phase 3 study evaluating the addition of bevacizumab, a vascular endothelial growth factor (VEGF-A) to trastuzumab
  • Patients were randomized to 1 of 4 treatment arms in 2 cohorts: 
    • Cohort 1: 
      • The nonanthracycline regimen TCH (docetaxel, carboplatin, and trastuzumab [Herceptin]) or TCH plus bevacizumab
    • Cohort 2: 
      • Anthracycline-based therapy with T-FEC-H (docetaxel, fluorouracil, epirubicin, cyclophosphamide, plus trastuzumab) with or without bevacizumab
    • The study concluded that the addition of bevacizumab (Avastin) to adjuvant chemotherapy did not improve invasive disease-free survival or overall survival in patients with high-risk HER2-positive breast cancer
    • BETH also demonstrated that the non–anthracycline-containing chemotherapy arm was as effective in prolonging survival as the anthracycline-containing arm
• Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET) Trial: 
  • Is a multicenter, randomized, phase 3 trial designed to investigate extended adjuvant therapy with neratinib
  • Patients received one year of extended adjuvant therapy with neratinib, an irreversible pan-HER tyrosine kinase inhibitor, administered after chemotherapy and trastuzumab
  • The results showed:
    • That one year of neratinib significantly improved 5-year invasive disease-free survival without increasing the risk of long-term toxicity
• APHINITY trial (BIG 4-11): 
  • A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients with HER2-positive early breast cancer
  • In previous neoadjuvant trials:
    • Pertuzumab significantly prolonged progression free and overall survival and increased pathologic complete response (pCR) rates when added to trastuzumab and chemotherapy
  • The investigated the role of pertuzumab when added to trastuzumab after surgery and chemotherapy in the adjuvant setting
  • A small benefit in favor of the combination was observed:
    • Which was more pronounced in node-positive patients
• References
  • Cameron D, Piccart-Gebhart MJ, Gelber RD, Proctor M, Goldhirsch A, de Azambuja E, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195-1205.
  • Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol.2016;34(10):1034-1042.
  • Slamon DL, Swain SM, Buyse M, Martin M, Geyer CE. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer [Abstract]. Cancer Res. 2013;73(suppl 24): S1-03.
  • Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700.
  • von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131.

#Arrangoiz #BreastSurgeon #CancerSurgeon #SurgicalOncologist #Miami #Herceptin #Trazstuzumab #Pertuzumab #HERATrial #ALTTOTrial #NSABPB44 #BETHStudy #ExtenetTrial #APHINITYTrial