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    Radiation Therapy for Local or Biochemical Recurrence Following Radica

    Introduction

    Radical prostatectomy is a standard treatment for localized prostate cancer.1,2 A subsequently rising prostate specific antigen (PSA) level occurs in a significant proportion of patients with localized prostate cancer following radical prostatectomy. Patients with biochemical recurrence—some of whom already have metastases—include those whose metastatic sites remain undetectable, as well as those in whom local recurrence cannot be identified through conventional imaging techniques.

    Current guidelines recommend local radiation therapy, with or without androgen deprivation therapy (ADT), for patients without metastases who experience biochemical recurrence following radical prostatectomy.3–5

    We investigated the clinical conditions and outcomes of patients with biochemical or local recurrence, without distant metastasis, who received radiation therapy targeting the prostate bed at our hospital following radical prostatectomy for prostate cancer. Our results underscore the need for more accurate diagnostic methods to detect PSA recurrence following radical prostatectomy.

    Patients and Methods

    This study was conducted with institutional review board approval (E2024000201).

    Patients

    After radical prostatectomy, patients are regularly monitored using PSA tests and other procedures. Here, those with suspected recurrence after radical prostatectomy, indicated by an increase in PSA levels or other factors, were evaluated through imaging tests for local recurrence and distant metastasis. For patients not undergoing androgen deprivation therapy (ADT), imaging was conducted when the PSA level exceeded 0.2 ng/mL. For those receiving ADT, evaluations were carried out on an individual basis. CT, bone scans, and whole-body MRI were utilized to confirm the presence or absence of metastasis. Multiparametric MRI was applied to evaluate local recurrence in the prostate bed. The multiparametric MRI images were interpreted exclusively by Y.I.

    PSA Doubling Time (PSADT)

    PSADT can be utilized to predict changes in PSA levels over time and as an indicator of biochemical and clinical progression. It was calculated as the natural log of 2 (0.693) divided by the slope of the linear regression of the natural log of PSA levels vs the time of PSA measurement in months. If the PSA level slope was 0 (constant PSA level) or negative (decreasing PSA level after initial increase), PSADT was arbitrarily set to 100.6

    Radiotherapy

    Patients who showed no local recurrence or metastasis, as determined by imaging evaluation, received salvage radiotherapy to the prostate bed at a dose of 64.8 Gy, delivered in 36 fractions. Patients with local recurrence and no distant metastases, as determined by imaging evaluation, received radiotherapy of 70.8 Gy to the site of local recurrence and 64.8 Gy to the prostate bed. One patient with pelvic lymph node recurrence underwent whole pelvic radiation therapy at a dose of 50.4 Gy.

    Radiotherapy-Related Gastrointestinal (GI) Toxicities

    Radiotherapy-related GI toxicities were retrospectively graded according to Radiation Therapy Oncology Group (RTOG) acute and late toxicity criteria. In both cases, 0 indicates the absence of radiation effects and 5 means the effects were fatal. The severity of reactions was graded from 1 to 4. (Grade 0: No change, 1:Increased frequency or change in quality of bowel habits not requiring medication/rectal discomfort not requiring analgesics, Grade 2: Diarrhea requiring parasympatholytic drugs (eg, Lomotil)/mucous discharge not necessitating sanitary pads/rectal or abdominal pain requiring analgesics, Grade 3: Diarrhea requiring parenteral support/severe mucous or blood discharge necessitating sanitary pads/abdominal distention (flat plate radiograph demonstrates distended bowel loops), Grade 4:Acute or subacute obstruction, fistula or perforation; GI bleeding requiring transfusion; abdominal pain or tenesmus requiring tube decompression or bowel diversion).7

    Follow-up After Radiation Therapy

    Patients are regularly monitored using PSA tests and other procedures following radiation therapy. Patients underwent re-evaluation imaging when their PSA levels exceeded 1 ng/mL during follow-up after radiation therapy. In the present study, patients with suspected recurrence after radiation therapy, indicated by an increase in PSA levels or other factors, were evaluated through imaging tests for local recurrence and distant metastasis. Any suspicion of recurrence following radiotherapy was evaluated on an individual basis. If no recurrence was detected on imaging, PSADT and other factors were considered before initiating ADT, with shared decision-making involving the patients.

    Statistical Analysis

    The PSA recurrence rate after radiation therapy was calculated using the Kaplan-Meier method, and significance was assessed using the Log rank test. Differences were considered significant at a P-value <0.05. Statistical analyses were performed using commercial statistical software (SPSS, version 28.0; IBM Corp, SPSS, Inc., Chicago, IL, USA).

    Results

    Patient Characteristics

    The study included 76 patients who received local radiation therapy following prostatectomy between the opening of our hospital in June 2015 and April 2024. (Table 1) Eleven patients who underwent radical prostatectomy at other hospitals were subsequently referred to our hospital for follow-up observation. The age of patients at the time of radical prostatectomy ranged from 56 to 79 years, with a mean age of 67 years. The time from radical prostatectomy to radiation therapy for all patients ranged from five to 211 months, with a median of 32 months.

    Table 1 Patient Characteristics

    The average PSA level at the time of prostate cancer diagnosis was 15.7 ng/mL, ranging from 3.68 to 79.64 ng/mL. In three patients, PSA values at the time of diagnosis were not reported when they were referred to our hospital. The pathological grade group at the time of radical prostatectomy was classified as follows: grade 1, 4 cases; grade 2, 20 cases; grade 3, 11 cases; grade 4, 19 cases; and grade 5, 16 cases. Additionally, there were 6 cases in which the grade group was not reported at the time of referral to our hospital, or the grade group was not evaluated due to the patient undergoing hormone therapy. The pathological stage at radical prostatectomy was: pT2 or lower, 36 cases; pT3a, 31 cases; pT3b, 9 cases; pN0, 75 cases; pN1, 1 case.

    Sixty-eight patients did not receive ADT at the time of radical prostatectomy. Among the patients observed in this study, eight received ADT perioperatively following radical prostatectomy. One patient underwent bilateral orchiectomy, five patients had been treated with ADT prior to surgery, and two patients began ADT immediately after the procedure.

    Biochemical Recurrence Following Radical Prostatectomy

    The interval between radical prostatectomy and radiation therapy ranged from 6 to 211 months, with a mean duration of 44 months. Following radical prostatectomy, local recurrence was/was not observed in 19 and 57 patients, respectively.

    Thirty-five and 41 patients did not/did receive ADT during radiation therapy, respectively. Among those who received ADT, 28 patients were treated with short-term ADT (LHRH agonist (3-month formulation) administered twice at three-month intervals), and 13 patients received long-term ADT (ADT had exceeded six months).

    Patients with Local Recurrence

    Local recurrence following radical prostatectomy was observed in 19 patients. (Table 2) Local radiation therapy was not used in combination with ADT in nine patients. It was applied in combination with short- and long-term ADT in three and seven patients, respectively. Three out of nine patients who did not receive ADT experienced recurrence following local radiation therapy. In contrast, none of the ten patients who received ADT during radiation therapy developed recurrence after treatment. No significant difference was observed in clinical recurrence-free survival between patients receiving radiation therapy alone and those receiving ADT during radiation therapy (p = 0.302) (Figure 1).

    Table 2 Use of ADT During Radiation Therapy in Patients with Local Recurrence

    Figure 1 Clinical Recurrence-free Survival After Local Radiation Therapy. Use of ADT During Radiation Therapy for Patients With Local Recurrence.Local recurrence following radical prostatectomy was observed in 19 patients. Local radiation therapy was not used in combination with ADT in nine patients. It was applied in combination with short- and long-term ADT in three and seven patients, respectively. Three out of nine patients who did not receive ADT experienced recurrence following local radiation therapy. In contrast, none of the ten patients who received ADT during radiation therapy developed recurrence after treatment. No difference was observed in clinical recurrence-free survival between patients receiving radiation therapy alone and those receiving ADT during radiation therapy (p=0.302).

    Patients Without Local Recurrence

    In those without local recurrence at the time of radiation therapy, 26 and 31 patients did not/did receive ADT during treatment, respectively. Among those who received ADT, 28 and three patients were treated with short- and long-term ADT, respectively. (Table 3) Of these patients with ADT, four experienced recurrence. Of the 26 patients who received local radiotherapy without ADT, 11 showed recurrence. No difference was observed in clinical recurrence-free survival between patients receiving radiation therapy alone and those receiving ADT during radiation therapy (p=0.221) (Figure 2).

    Table 3 Use of ADT During Radiation Therapy in Patients Without Local Recurrence

    Figure 2 Clinical Recurrence-free Survival After Local Radiation Therapy. Use of ADT During Radiation Therapy for Patients Without Local Recurrence.In patients without local recurrence at the time of radiation therapy, 26 did not receive ADT during treatment, while 31 patients did. Among those who received ADT, 28 were treated with short-term ADT, and three received long-term ADT. Of these patients with ADT, four experienced recurrence. Local radiation therapy without ADT was administered to 26 patients. Of these patients without ADT, 11 showed recurrence. No difference was observed in clinical recurrence-free survival between patients receiving radiation therapy alone and those administered ADT during radiation therapy (p=0.221).

    Fifty-three of the 57 patients without local recurrence were evaluated. In four of them, PSA levels could not be assessed due to ADT. Among patients without local recurrence, 26 with a PSA value that had fallen below the sensitivity threshold of 0.01 exhibited a period from radical prostatectomy to local radiation therapy ranging from 21 to 183 months, with an average of 55 months. (Table 4) Four out of the 26 patients with a PSA value below the threshold experienced recurrence after local radiation therapy. The PSA value at time of recurrence was 0.25 ng/mL (range: 0.2 to 0.46 ng/mL) and PSADT was 8.5 months (range: 2.1 to 14.9 months). In contrast, among the 27 patients whose PSA levels did not fall below the sensitivity threshold of 0.01, the time from radical prostatectomy to local radiation therapy ranged from 7 to 66 months, with a mean duration of 24 months. The PSA value at time of recurrence was 0.55 ng/mL (range: 0.21 to 1.46 ng/mL) and PSADT was 11.0 months (range: 2.8 to 14.9 months). Of these patients, eight showed recurrence. There was no difference in clinical recurrence-free survival after local radiation therapy between patients whose PSA levels declined to less than 0.01 ng/mL following radical prostatectomy and those that did not (p=0.333) (Figure 3).

    Table 4 PSA Minimum (0.01ng/Ml) in Patients Without Local Recurrence

    Figure 3 Clinical Recurrence-free Survival After Local Radiation Therapy. PSA Minimum (0.01 ng/mL) in Patients Without Local Recurrence.Four out of 26 patients with a PSA value that had fallen below detection limits experienced recurrence after local radiation therapy. In contrast, among the 27 patients whose PSA levels did not fall below the sensitivity threshold of 0.01, eight showed recurrence. There was no difference in clinical recurrence-free survival after local radiation therapy. (p=0.333).

    Fifty-six of the 57 patients without local recurrence were evaluated for PSADT. (Table 5) In one patient, PSADT could not be assessed due to ADT. In the 28 patients with PSADT of 6 months or less, the duration from radical prostatectomy to confirmation of recurrence was 29 months (range: 6 to 83 months), and the PSA level at the time of recurrence was 0.69 ng/mL (range: 0.21 to 6.25 ng/mL). Among these patients, nine experienced recurrence. In the 28 patients with PSADT of 6 months or more, the duration from radical prostatectomy to confirmation of recurrence was 46 months (range: 7 to 183 months), and the PSA level at the time of recurrence was 0.34 ng/mL (range: 0.21 to 1.46 ng/mL). Among these patients, five showed recurrence. Patients with PSADT of 6 months or more at the time of recurrence following radical prostatectomy tended to show longer clinical recurrence-free survival after local radiation therapy compared with those whose PSADT was less than 6 months (p=0.06) (Figure 4).

    Table 5 PSADT at the Time of Recurrence in Patients Without Local Recurrence

    Figure 4 Clinical Recurrence-free Survival After Local Radiation Therapy. PSADT at the Time of Recurrence in Patients Without Local Recurrence.In the 28 patients with PSADT of 6 months or less, nine experienced recurrence. In the 28 patients with PSADT of 6 months or more, five showed recurrence. Patients with PSADT of 6 months or more at the time of recurrence following radical prostatectomy tended to show longer clinical recurrence-free survival after local radiation therapy compared with those whose PSADT was less than 6 months. (p=0.06).

    Radiotherapy-Related GI Toxicities

    Patients who showed no local recurrence or metastasis received salvage radiotherapy to the prostate bed at a dose of 64.8 Gy. Patients with local recurrence and no distant metastases received radiotherapy of 70.8 Gy to the site of local recurrence. In 57 patients without local recurrence, 13 experienced GI toxicities related to radiotherapy (Grade 1 in 12 patients; Grade 2 in one patient). (Table 6) In 19 patients with local recurrence, five developed GI toxicities related to radiotherapy (Grade 1 in four patients; Grade 2 in one patient). Patients with local recurrence who were treated with escalated radiation doses did not experience any difference in the incidence of radiotherapy-related gastrointestinal toxicity compared with patients without local recurrence.

    Table 6 Radiotherapy-Related GI Toxicities

    Discussion

    This study summarizes the clinical course of local radiotherapy in 76 patients who experienced biochemical recurrence following radical prostatectomy and had no distant metastasis. Of the 76 patients who experienced PSA recurrence following radical prostatectomy, 19 (25%) exhibited local recurrence, while 57 patients did not show any signs of local recurrence. Patients received radiation therapy targeting the prostate bed and any local recurrence lesions. However, 18 have since shown signs of recurrence. ADT may be beneficial in preventing recurrence following radiation therapy for local recurrence after radical prostatectomy. PSADT may be a valuable predictor of recurrence following radiation therapy.

    Radical prostatectomy is widely regarded as the definitive curative treatment for patients with non-metastatic prostate cancer.5 After radical prostatectomy, PSA levels are monitored regularly. If PSA is detectable following prostatectomy, residual or recurrent prostate cancer should be suspected. If the PSA level exceeds a specific threshold, biochemical recurrence is diagnosed, and imaging examinations are conducted to assess distant metastasis and local recurrence. Biochemical recurrence is commonly defined as a PSA level exceeding 0.2 ng/mL; however, this definition is not based on any official guidelines.8 In a long-term retrospective study conducted by Raisa S. Pompe et al, among patients who experienced biochemical recurrence after radical prostatectomy and did not receive neoadjuvant or adjuvant therapy, 13.4% developed distant metastases, and 9.5% died from prostate cancer.9 Felix Preisser et al reported that in patients exhibiting persistent PSA levels, salvage radiotherapy improved both overall and cancer-specific survival.10 The persistence of PSA and high-risk features often serve as indicators of distant micro-metastatic disease, which cannot be effectively treated with local therapy. Ida Sonni et al suggested that 68Ga-PSMA PET may be a valuable tool for guiding salvage radiation therapy planning directed at the prostate bed in cases of postoperative biochemical persistence or recurrence.11 A systematic review conducted by the EAU Prostate Cancer Guidelines Panel confirmed that oncological outcomes vary between patients with and without biochemical recurrence.8 The authors proposed a new EAU biochemical recurrence risk stratification. A low risk of biochemical recurrence is defined by PSADT of greater than 1 year and pathological radical prostatectomy specimen Gleason score below 8 (ISUP grade group less than 4). Conversely, a high risk of biochemical recurrence is defined by PSADT of 1 year or less, or pathological radical prostatectomy specimen Gleason score of 8 to 10 (ISUP grade group 4 to 5).8 The European Association of Urology grouping for the risk of biochemical recurrence of prostate cancer after radical prostatectomy was valid when applied in a European study cohort. Salvage radiation therapy, especially when administered at a PSA level of less than 0.5 ng/mL, was highly effective in preventing metastatic progression.12

    PSA is a sensitive and specific biomarker for early disease recurrence; however, it does not indicate the disease location. Data on the performance of conventional imaging techniques, including MRI, CT, and bone scans, in the context of biochemical recurrence of prostate cancer following radical prostatectomy are heterogeneous and show low sensitivity for the detection and localization of biochemical recurrence.13 The advantages of MRI include its effectiveness in detecting local recurrence and sensitivity to early bone changes, which can help resolve discrepancies between bone scans and CT. Overall, pelvic MRI is regarded as an appropriate imaging modality.14–16 Whole-body MRI can detect lymph node and bone metastases outside of the pelvis and is also considered an appropriate imaging modality.17,18 In patients with early biochemical recurrence following radical prostatectomy, detection rates reported for PSMA-PET CT are higher than those of any other imaging modality, particularly for smaller lesions with low PSA levels.19–22 PSMA-PET has been rapidly adopted worldwide and is recognized as a viable imaging option according to the guidelines set forth by EAU, NCCN, and AUA.3,4 Although it is evident that PSMA-PET is an outstanding diagnostic tool, this test is currently unavailable in Japan. If it were available, early diagnosis of recurrence and metastasis would be possible.

    For patients experiencing biochemical recurrence following radical prostatectomy, the primary curative intervention is radiation therapy. Generally, two main approaches are utilized for the timing of radiation therapy: adjuvant and salvage radiotherapy. However, the results of a meta-analysis indicated no evidence of improved event-free survival with adjuvant radiation therapy compared with early salvage radiation therapy.23,24 In general, for patients with higher-risk characteristics, the addition of ADT to radiotherapy improves survival rates. ESTRO-ACROP recommendations for the evidence-based use of ADT in combination with external-beam radiotherapy for prostate cancer conclude that no additional ADT should be recommended for low-risk prostate cancer patients. In contrast, for intermediate- and high-risk patients, a duration of four to six months and two to three years of ADT is recommended, respectively.25–27 The guidelines from the European Association of Urology, European Society for Radiotherapy and Oncology, and International Society of Geriatric Oncology (EAU-ESTRO-SIOG) emphasize the importance of early salvage radiotherapy. This is defined as radiotherapy initiated for patients who experience biochemical recurrence following radical prostatectomy, specifically when the PSA level is less than 0.5 ng/mL.25 Felix Preisser et al demonstrated a significant survival benefit in patients with EAU high-risk biochemical recurrence who received early salvage radiotherapy compared with those who were under observation. The findings support the recommendation for early salvage radiotherapy in men with EAU high-risk biochemical recurrence. Conversely, surveillance may be appropriate for patients with low-risk biochemical recurrence.28 In the cases examined in this study, the interval between radical prostatectomy and radiation therapy was influenced by factors such as the use of ADT in combination with radical prostatectomy. The patient with the longest interval underwent surgical castration at the time of radical prostatectomy, resulting in a prolonged period before PSA recurrence was diagnosed.

    Local recurrence following radical prostatectomy was observed in 19 patients. Local radiation therapy was not used in combination with ADT in nine patients. Three of the patients experienced recurrence after local radiation therapy. However, none of the patients who received ADT during radiation treatment developed recurrence after local radiation therapy. No significant difference was observed in clinical recurrence-free survival between patients receiving radiation therapy alone and those receiving ADT during radiation therapy (p = 0.302).

    Regarding the irradiation method, conventional-dose salvage radiotherapy to the prostate bed is adequate for patients showing early biochemical progression of prostate cancer following radical prostatectomy.29 The long-term results of the RADICALS-RT trial confirm that adjuvant radiotherapy following radical prostatectomy increases the risk of urinary and bowel morbidity without significantly improving disease control. Therefore, an observation policy with salvage radiotherapy for PSA failure should be considered as the current standard of care after radical prostatectomy.30 The shorter 20-fraction schedule provides a clear advantage in terms of patient convenience, environmental considerations, and hospital capacity. Severe toxicity is rare following post-prostatectomy prostate bed radiotherapy (RT) with either 52.5 Gy in 20 fractions or 66 Gy in 33 fractions. Only modest differences were observed in toxicity and patient-reported quality of life between these two schedules.31 In our study, we utilized conventional-dose salvage radiotherapy.29

    The American Urological Association, in collaboration with the American Society for Radiation Oncology and Society of Urologic Oncology, released the 2024 clinical practice guidelines on salvage therapy for prostate cancer.3,4 These guidelines offer practical, clear, and evidence-based recommendations for managing recurrence following surgery. Based on these findings, the authors proposed a new EAU biochemical recurrence risk stratification. A low risk of biochemical recurrence is defined by PSADT of greater than 1 year and pathological radical prostatectomy specimen Gleason score below 8 (ISUP grade group <4). Conversely, a high risk of biochemical recurrence is defined by PSADT of 1 year or less, or pathological radical prostatectomy specimen Gleason score of 8 to 10 (ISUP grade group 4–5). Almost all international guidelines emphasize the importance of early salvage radiotherapy, which is defined as radiotherapy initiated for patients with biochemical recurrence following radical prostatectomy when the PSA level is less than 0.5 ng/mL. In this study, those with PSADT of 6 months or more at the time of recurrence following radical prostatectomy tended to show longer clinical recurrence-free survival after local radiation therapy compared with those whose PSADT was less than 6 months (p=0.06).

    Although there is no universally accepted definition of biochemical recurrence following salvage radiotherapy after radical prostatectomy for prostate cancer, Sung Uk Lee et al reported that a serum PSA level greater than 0.8 ng/mL serves as a reasonable threshold for defining biochemical recurrence after salvage radiotherapy.32 Furthermore, PSADT of six months or less was significantly predictive of subsequent distant metastasis, and the combined application of both parameters improved the predictive accuracy. At our hospital, we re-evaluate imaging when the PSA level exceeds 1 ng/mL during follow-up after salvage radiotherapy. If no recurrence is detected on imaging, we consider PSADT and other factors before initiating ADT, engaging in shared decision-making with the patients. Therefore, in this study, no fixed definition was employed, and recurrence was assessed based on the clinical status of each patient. Those with PSADT of 6 months or more at the time of recurrence following radical prostatectomy tended to show longer clinical recurrence-free survival after local radiation therapy compared with those whose PSADT was less than 6 months (p=0.06).

    This study had various limitations. Although it is evident that PSMA-PET is an outstanding diagnostic tool, this test is currently unavailable in Japan. Therefore, the data in this paper did not include PSMA-PET data. It was conducted at a single institution and included a limited number of patients; therefore, the sample size was not calculated or justified. This was a retrospective study. There were no established standards for diagnostic criteria or the use of ADT with radiation therapy. Thus, the data included institutional bias and non-randomized ADT use. Decisions were made on an individual basis for each patient.

    Conclusion

    Of the 76 patients who experienced PSA recurrence following radical prostatectomy, 19 (25%) exhibited local recurrence, while 57 patients did not show any signs of local recurrence. Patients received radiation therapy targeting the prostate bed and any local recurrence lesions. However, 18 have since shown signs of recurrence. ADT may be beneficial in preventing recurrence following radiation therapy for local recurrence after radical prostatectomy. When considering salvage radiation therapy for patients with biochemical recurrence following radical prostatectomy, PSADT may be useful. However, even in patients with short PSADT, PSA values alone cannot be used to determine whether the disease is local recurrence or distant metastasis. It is considered that some patients showing recurrence following radiation therapy had distant metastases prior to treatment, highlighting the need for more accurate diagnostic methods, such as PSMA-PET.

    Ethical Approval

    The present study was approved by the Ethical Committee of the Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital (approval no. E2024000201). The need for written informed consent from subjects and legally authorized representatives of deceased subjects for publication of this study was waived by the Ethical Committee of Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital. This study was conducted in accordance with the Declaration of Helsinki.

    Author Contributions

    All authors reviewed and edited the manuscript and approved its final version for submission. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

    Informed Consent

    We adopted patient-centered medical and health information management. Informed consent consisted of providing an opt-out option.

    Funding

    This research project received no specific grant from funding agencies in the public or commercial sectors for the research, authorship, and/or publication of this article.

    Disclosure

    The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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    28. Preisser F, Abrams-Pompe RS, Stelwagen PJ, et al. EAU-YAU Prostate Cancer Working Group. European association of urology biochemical recurrence risk classification as a decision tool for salvage radiotherapy-a multicenter study. Eur Urol. 2024;85(2):164–170. doi:10.1016/j.eururo.2023.05.038

    29. Ghadjar P, Hayoz S, Bernhard J, et al. Swiss Group for Clinical Cancer Research (SAKK). Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: the SAKK 09/10 Randomized Phase 3 Trial. Eur Urol. 2021;80(3):306–315. doi:10.1016/j.eururo.2021.05.033

    30. Parker CC, Petersen PM, Cook AD, et al. RADICALS investigators. Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047). Ann Oncol. 2024;35(7):656–666. doi:10.1016/j.annonc.2024.03.010

    31. Petersen PM, Cook AD, Sydes MR, et al. Salvage Radiation therapy after radical prostatectomy: analysis of toxicity by dose-fractionation in the RADICALS-RT trial. Int J Radiat Oncol Biol Phys. 117(3):624–629. doi:10.1016/j.ijrobp.2023.04.032

    32. Lee SU, Kim JS, Kim YS, et al. Optimal definition of biochemical recurrence in patients who receive salvage radiotherapy following radical prostatectomy for prostate cancer. Cancer Res Treat. 2022;54(4):1191–1199. doi:10.4143/crt.2021.985

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  • Mars Named on TIME’s World’s Best Companies 2025 List

    Mars Named on TIME’s World’s Best Companies 2025 List

    MCLEAN, Va. (September 10, 2025) – Mars, Incorporated, a global leader in confectionery, snacking, food and pet care products and services, has been included in the first edition of the World’s Best Companies 2025. This prestigious award is presented by TIME and Statista Inc., the world-leading statistics portal and industry ranking provider. The award list was announced on September 10 and can be viewed on time.com. 

    “Being named among the World’s Best Companies is a recognition of the way we do business at Mars. For more than a century, we’ve combined growth with a long-term commitment to operating responsibly,” said Poul Weihrauch, CEO of Mars, Incorporated. “This honor reflects the talent, creativity and operational capabilities of our 150,000 Associates who are helping us build a strong, sustainable business that delivers for people, pets and the planet.”

    The World’s Best Companies 2025 ranking recognizes leading global organizations that exemplify excellence in today’s corporate landscape. Companies were evaluated using three primary data sources: employee satisfaction, revenue growth and sustainability transparency. Out of hundreds of thousands of data points assessed, the top 1,000 companies were recognized for outstanding performance across these key areas. 

    Mars is an approximately $55B family-owned business that produces a portfolio of iconic global brands, including ROYAL CANIN®, PEDIGREE®, WHISKAS®, CESAR®, DOVE®, EXTRA®, M&M’S®, SNICKERS® and BEN’S ORIGINAL™. Earlier this year, Mars was named a 2025 Corporate Inductee into the AAF Advertising Hall of Fame, recognizing its legacy of iconic and culturally resonant campaigns and long-term brand identity. Mars also earned 11 Lions at the 2025 Cannes Lions Festival of Creativity, including its first-ever Titanium Award celebrating its creative excellence and cultural resonance.

    With 150,000 Associates globally, Mars is committed to supporting and advancing every aspect of their health and wellbeing, including through the Be Well Together framework – programs, benefits, resources and tools designed to support mental health, energy, nutrition, physical fitness, safety and more.

    “This recognition is a testament to our Associates. Every day, they bring our Purpose and Principles to life in ways that make Mars a great place to work, where everyone can thrive,” said Rebecca Snow, Vice President, People & Organization for Mars, Incorporated. “Associate experience is not separate from business performance – it fuels it. This award underscores that when we invest in our people, we strengthen both our culture and our results.”

    In addition to prioritizing its Associates, Mars also strives to help create a healthier planet so all people and pets can thrive. Mars recently released its annual Sustainable in a Generation Report, announcing it has continued decoupling its carbon emissions from its growth – it has grown over 69% to approximately $55B in annual net sales while reducing its carbon footprint by 16.4% compared to its 2015 baseline. As part of these efforts, Mars focuses on partnerships to advance innovative agricultural practices and deforestation-free supply chains, including Unreasonable Food™ – a three-year partnership with Unreasonable Group to accelerate entrepreneurial innovations around sustainable food systems.

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  • ‘Idhar mat dekho’: Suryakumar Yadav warns Muhammad Waseem after UAE captain’s cheeky attempt to gain advantage – Watch

    ‘Idhar mat dekho’: Suryakumar Yadav warns Muhammad Waseem after UAE captain’s cheeky attempt to gain advantage – Watch

    Updated on: Sept 10, 2025 08:26 pm IST

    Suryakumar Yadav shared a friendly moment with Muhammad Waseem at the toss ahead of their Asia Cup clash.

    A jovial Suryakumar Yadav won the toss in India’s opening game of the Asia Cup 2025, asking the United Arab Emirates to bat first in Dubai. After being introduced by Sanjay Manjrekar and asked to flip the coin while his opposite number Muhammad Waseem made the call, Suryakumar shared a nice, friendly moment with the UAE captain, leading to ear-to-ear smiles from both players.

    Indian captain Suryakumar Yadav flips the coin at the toss alongside UAE’s Muhammad Waseem.

    Right before flicking the coin into the air, Suryakumar leaned over to Waseem with a big smile on his face, covered the coin, and said, “Idhar mat dekho (don’t look here),” sharing a big smile and laugh with the UAE skipper.

    This wasn’t the only friendly interaction between the pair, as they also traded words with one another as they crossed over after SKY had spoken to Sanjay Manjrekar presenting the toss, parting with smiles and indicating that there is certainly some mutual respect for each other heading into this contest.

    Change of toss fortunes for India

    Captain Surya ended India’s bad run of toss form, this being the first time in 15 attempts that an Indian captain had the toss go their way in international cricket. He opted to bowl first at the Dubai International Cricket Stadium, asking opening batter Waseem to face up first as the evening sets in, and trying to take advantage of chasing under the lights.

    India’s team for their opening contest sees Shubman Gill slotting in to partner Abhishek Sharma at the top of the order, while Sanju Samson gets to try his hand at a new role in the middle order. Meanwhile, Jasprit Bumrah starts as the lone frontline seamer, expected to receive support from Hardik Pandya and potentially Shivam Dube, who continues to be favourted in the shortest format. Three spinners and a strong stock of all-rounders see out India’s combination for the opening match.

    News / Cricket News / ‘Idhar mat dekho’: Suryakumar Yadav warns Muhammad Waseem after UAE captain’s cheeky attempt to gain advantage – Watch

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  • When politics creeps into sports, everyone loses – Sport

    When politics creeps into sports, everyone loses – Sport

    Sportspersons should never be expected to carry the weight of what happened five months ago, and they should not be required to do the bidding of their governments on a cricket field.

    Around three years ago, Shaheen Shah Afridi sat on the periphery of an ICC Academy training ground in Dubai when the Indian team arrived at the venue. The images that followed would warm billions of hearts around the world.

    Shaheen’s right-leg was in a brace, a consequence of an ill-fated dive in Galle, Sri Lanka, that ruled him out of cricket for four months. He helped himself off the ground as Yuzvendra Chahal approached to meet him. Chahal enquired about Shaheen’s injury.

    The Pakistani fast bowler detailed the timeline of his full recovery and the incident to the leg-spinner, before wishing him luck for the contest against Pakistan.

    Virat Kohli had been posing for a picture with a net bowler a few yards away from the two. He came up to Shaheen and the two shook hands. Kohli wore a worried look as Shaheen revealed to him what he had earlier explained to Chahal.

    This made a beautiful image. Their battle was going to be the spiciest subplot of the 2022 India-Pakistan Asia Cup contest, but in this moment, the rivalry had taken a backseat, with empathy at the forefront.

    Rishab Pant and KL Rahul met Shaheen next. The players exchanged jokes, and Shaheen signed off each interaction by wishing them luck for the match against his country. He told Pant that he would be in the crowd to watch the match.

    Cricket needed this bonhomie as the ever-increasing friction between the two neighbours continued to create an environment of hate and distrust.

    Earlier that year, India and Pakistan players converged outside the dressing rooms after their women’s World Cup match in Tauranga, New Zealand. The shared culture, language, and interests pull people from the two countries towards each other. But, on this occasion, the force was even stronger.

    One-by-one, the Indian players gathered around Bismah Maroof, who had her newborn, Fatima, in her arms. While a bunch near Bismah continued the best of their efforts to evoke a reaction from baby Fatima, the others casually conversed with their Pakistani counterparts in the Pakistan dressing room.

    Now, though, the environment has changed. Drastically.

    Sports vs politics

    Last week, the men’s sides of Pakistan and India were back at the ICC Academy’s training facilities eight days out of their scheduled group-stage contest. Pakistan were giving themselves final touches before the tri-series final against Afghanistan the next day and India were having their first training session after arriving in Dubai for the Asia Cup.

    The players, overly cautious about the perimeters this time, remained in their designated zones to make sure there were no interactions. The upcoming India-Pakistan contest on Sep 14 comes amid the most tense geopolitical climate in recent times. There have been calls in India for the boycott of the Asia Cup match(es) against Pakistan and Indian right-wing accounts on X have already started to censure Indian players. Any friendly advance towards a player from the other team has all the potential to be viewed as treason to his country.

    Sportspersons should never be expected to carry the weight of what happened five months ago, and they should not be required to do the bidding of their governments on a cricket field.

    The joint press conference of the eight captains on the opening day of the Asia Cup was the first instance that the captains of India and Pakistan were in close proximity. Social media was ablaze with posts about the body languages of the two. The posts made one wonder whether it was a curtain raiser of a sporting event or a conclave of heads of states in the aftermath of a military conflict. My mind took me back to the recent post-Alaska summit press conference of the US and Russian presidents that I had stayed up to watch in my best attempt to read between the lines.

    Aware, or respectful, of the charged emotions of the fans back home, Salman Ali Agha and Suryakumar Yadav avoided eye-contact despite being just a few meters away. In what was perhaps the coldest of interactions between the captains of the two teams in recent times, they had a brief handshake off stage, with no smiles or eye-contact to accompany it. It was just a tick-box exercise.

    Each India-Pakistan game carries a ridiculous load on a player from either side. There are unimaginable levels of expectations that can crumble any sportsperson. We enjoy these contests because of the weight of the political rivalry that they carry. But it should not be overdone, and the last thing these players need right now is the detailed introspection of how they behave in each other’s company.

    But, these are sad times.

    Sunday’s contest will be treated as an extension of May’s military conflict as the players will be deemed to be fighting to protect the honour and integrity of their nations, instead of the two points needed to secure qualification for the next round. The members of the winning team will be put on a pedestal, and those on the losing side will be degraded on social media.

    As a former media manager of Pakistan’s men’s and women’s sides, I have seen the admiration the players from both sides have for each other.

    When Babar Azam waited for the plane to take him back to Hyderabad after the captains’ day for the 2023 ODI World Cup in Ahmedabad, Rohit Sharma, after being made aware that the Pakistan captain sat in one of the VIP lounges, came to meet him. The Indian captain, who had to travel to Chennai, was comfortable sharing the lounge with Babar, and the two talked with each other about their families, the sport, and the food in India.

    The calm of the Pallekele dressing room was punctuated by laughter during the rain break of the India-Pakistan group-stage Asia Cup match in 2023 as India’s Kohli and the Punjabi-origin Pakistan players took jibes at each other.

    When the news of Pant’s life-threatening car accident broke out, the Pakistan players were shaken by horror, and the Karachi dressing room went quiet. Pakistan were playing New Zealand in a Test match at the National Stadium. They enquired from each other whether anyone had more information about the Indian player in the hope that they would get to compete against him again.

    In Christchurch, New Zealand, before India and Pakistan flew to Tauranga for their World Cup match, Pakistan and Indian players would often have long conversations when they ran into each other at local Indian restaurants. And, when India’s Smriti Mandhana was told by the liaison officer that her missing bag might have been placed in the Pakistan team room by the hotel staff, the Pakistan players sifted through the luggage to help the Indian batter find hers.

    That’s what cricket should ever be all about.

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  • Aziz Ansari’s directorial debut ‘Good Fortune’ comes back from the brink.

    Aziz Ansari’s directorial debut ‘Good Fortune’ comes back from the brink.

    TORONTO — In introducing the Saturday night TIFF world premiere of “Good Fortune,” his feature debut as a writer-director, comedian Aziz Ansari told the audience the three words that are scary in Hollywood right now: original theatrical comedy. But the one word that is never scary is Keanu.

    Speaking from the stage of the festival’s Roy Thomson Hall, Ansari recalled that his star Keanu Reeves broke his kneecap early in production.

    “I found out he broke his kneecap and I didn’t know what was going to happen,” Ansari continued, Reeves himself standing onstage just a few feet away. “It was like, ‘Oh, my God, what is Keanu going to say? Is he going to need some time off? Is he going to drop out of the movie?’”

    “And you know what Keanu said?” Ansari added. “Nothing. He just kept showing up to work and never complained, not once,” Ansari said. “He worked through what surely must have been excruciating pain and delivered a hilarious, touching performance, and he is the soul of this movie.”

    The film opens with Reeves standing atop L.A.’s iconic Griffith Observatory with a small pair of angel wings on his back. Reeves, in a change of pace from his recent action work in the “John Wick” movies, plays Gabriel, a low-level angel given the task of stopping people from texting and driving. That is until he sees Arj (Ansari), who is struggling to make ends meet while working both at a big-box hardware store and as a food delivery driver.

    Hoping to show him the grass isn’t always greener, Gabriel switches Arj’s life with that of Jeff (Seth Rogen), an ultrarich tech investor whose days seem to largely consist of going back and forth between his sauna and his cold plunge.

    Perhaps not surprisingly, Arj much prefers Jeff’s life to his own and is reluctant to switch back. The situation becomes more complicated for Gabriel as he loses his job as an angel and must learn the tribulations and joys of being human, while still trying to fix the problem with Arj and Jeff.

    For all the film’s gentle humor and quietly humanist spirit, “Good Fortune” is also rife with a palpable anger at the income inequality that motivates its story, the reality that robots are replacing the work of humans and that the excesses of the few seem predicated on the deprivation of many.

    Aziz Ansari, left, and Keanu Reeves in the movie “Good Fortune.”

    (Eddy Chen / Lionsgate)

    The day after the film’s premiere, 42-year-old Ansari is upbeat and dapper in a gray plaid coat, black turtleneck and black slacks as he sat down for an interview in Toronto to discuss the movie and all that led up to it. After the end of his Emmy-winning series “Master of None” in 2021, Ansari had begun shooting a feature called “Being Mortal” that was shut down in 2022 a few weeks into production over allegations of misconduct by its star Bill Murray. Then production of “Good Fortune,” Ansari’s pivot away from “Being Mortal,” was delayed by the Hollywood labor strikes of 2023. Seemingly at long last, Ansari’s debut opens Oct. 17.

    When “Being Mortal” got shut down, did you feel like, “Am I ever going to get to make a movie?”

    I didn’t feel that way. Steven Spielberg has this story of — what’s the movie he did? “1941.” That didn’t do well and he was like, just immediately throw yourself in another thing. And I really thought about that, and that’s what I did. I just immediately went into “Good Fortune.” I mean, I had a couple of days where I was like,“Oh, no” and it was also so shocking. I think your mind doesn’t process it because it’s not really sinking in that this is what’s really happening. It probably still a piece of me [in which] it hasn’t really sunk in. It was definitely disappointing, but part of me is like, this is what needed to happen. This is the movie that should be out first.

    “Being Mortal,” it’s funny, but it’s heavy. The Atul Gawande book, it’s about end-of-life issues. So it’s like, “Oh, OK. It’s another heavy drama thing.” People may have just gotten pissed, like, “What’s this guy doing?” So “Good Fortune” is definitely, to me, if you like those first two seasons of “Master of None,” I feel like what you’d hope I’d do is kind of evolve that style into a feature film and raise the level of it by having Seth and Keanu and Keke [Palmer] and Sandra [Oh], and as a feature film rather than a show.

    As sweet and funny as the movie is, there also is a real righteous anger behind it. Where does that come from?

    I think I got it from when I was interviewing all these people about the subject matter in the film, when I was doing research to write the Arj character. That attitude seeps in there.

    A man in a gray blazer smiles.

    “It was definitely disappointing, but part of me is like, this is what needed to happen,” Ansari says of “Being Mortal,” his first attempt at directing a feature, one that ran into production troubles with its star, Bill Murray,

    (Christina House / Los Angeles Times)

    During the opening credits of the movie, you say the line “The American Dream is dead.”

    But that’s a frustration a lot of people like that guy Arj feel.

    But then, you are a very successful entertainer —

    Oh, yeah. Me and Seth are Jeff, no question.

    How do you reconcile that? Are you concerned some people might dismiss the movie out of hand for that simple reason?

    If you’re writing, you have to be able to write outside your own experience — for someone who’s like Arj, who doesn’t have the platform to tell these stories. When I did “Master of None,” we did an episode called “New York, I Love You.” And there was a segment about taxi drivers, a segment about a doorman and a segment about a woman who’s deaf. And doing that episode taught me a process of interviewing people and figuring out how to get these stories right when they’re not your experience. We did an episode in Season 3 about a woman going through IVF. I’d never done that or anything, and it had never been a part of my life. But I talked to all these people, and from the feedback I got, we got it right. And that’s what I did with this.

    I don’t want to spoil anything, but for a movie coming out from a Hollywood studio, Seth gives a speech at the end that is politically radical, about how rich people can’t expect to have so much without others getting angry.

    It’s kind of nuts. Some of the stuff that’s in there, I’m like, “Whoa, we really got away with something here.” Some of the stuff that’s in there, and the trailer kind of hides a little bit of that stuff, I think there are people that’d be like, “Oh, s—.”

    At the premiere, there was big applause for the line, “F— AI.” Is that your feeling as well?

    I’d rather say that I’m pro-human. I’m pro-people.

    Three men hatch a plan on a Los Angeles porch.

    Keanu Reeves, left, Seth Rogen and Aziz Ansari in the movie “Good Fortune.”

    (Eddy Chen / Lionsgate)

    The movie is very ambitious in combining the character stories and the attention to the notion of income inequality. Was it hard for you in balancing the characters and that theme? Was the work of that more when you were writing it or when you were editing what you’d shot?

    It was both. And that’s the difference between a TV show and a movie. You have a different canvas. But it was a tough thing to do. And it was my first time doing it. I remember writing a second one while I was editing, and it was such a great help because you kind of see a few moves ahead. You’re like, “Oh, wait a second, I should get to this faster.” You kind of can see your mistakes a little bit in an earlier stage because you have more experience. This is another reason I really want to get into it again and start working on the next thing because I feel like I learned a lot from it.

    That’s the thing that’s so interesting about doing stand-up and doing filmmaking. Stand-up, it’s so easy to “get to the gym,” right? If I really wanted to go to do stand-up tonight, I could do it. I could go find a club in Toronto and jump on a show. But If I wanted to go direct, that’s a big journey to get to the gym. So you have fewer opportunities to kind of get the reps in.

    Shooting a movie is in L.A. has become such an economic and political issue for the city. Was that a consideration in making the movie in Los Angeles?

    I wanted it to be in L.A., I felt like this movie had to be set in L.A. Jeff’s not going to be living in whatever place that gives you the tax credit. And L.A. really is the perfect backdrop for the story to me. And it was challenging, but you also get the benefit of working with some of the greatest technicians in the world in L.A. And I also just love being a part of the lineage of films that are set in L.A. I watched that documentary, “Los Angeles Plays itself,” and that was so fun to watch that and just see how every movie has its own L.A., whether it’s “Heat” or “Tangerine” or “Chinatown.”

    And I feel like “Good Fortune” has its L.A., and it’s exciting to show some of these neighborhoods, to see people responding to seeing Eagle Rock or Los Feliz. Whenever I was writing the movie, I always thought about that taco place in Hollywood — it’s across the street from Jitlada. I always thought about that place. I thought there was something so cinematic, and it was a hard location to clear. And our guy [location manager] Jay Traynor, he made it happen. And finding Jeff’s house was so hard. But it all came together, and I loved showing Koreatown and that Gabriel works at a Korean barbecue restaurant. Just showing all these parts of L.A.

    I want to be sure to ask you about working with Keanu. People are really responding to this role. And I’m having a hard time putting my finger on what that is about.

    No, I’m feeling this. Even since [the premiere], I’m feeling it. I knew people would like him, but it’s hitting on another level.

    Why do you think that is? What is the alchemy of Keanu in that role?

    I was thinking about this when I was eating lunch. If you look at the roles he’s done that are comedic, whether it’s in “Bill & Ted” or in “Parenthood,” there’s this innocence, this sweetness and this kindness that’s in there. And then Gabriel, to me, is the progression of that. And it’s also that you have Keanu at 61, where when I first met him, I was like, “Hey, there’s something about you that people are responding to and who you are as a real person that I don’t think I’ve seen onscreen. And I think you can show some of that with Gabriel.”

    It also has all of his comedy superpowers just dialed to the max. And we were just having so much fun. It just became playtime. We were coming up with bits all the time: Oh, he’s never used the internet before. Let’s just write a quick scene where he’s using the internet for the first time. What’s he gonna do? He’s gonna look at photos of baby elephants. It became such a fun joke bag. You could just make him do anything. And it was funny, the guy’s never done anything — if he takes a bite of a taco goes, “Wow!” It’s really the funniest character I’ve ever written for.

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  • Rescuers in Pakistan scramble to save residents as swollen rivers reach dangerous levels – The Washington Post

    1. Rescuers in Pakistan scramble to save residents as swollen rivers reach dangerous levels  The Washington Post
    2. Floodwaters keep south Punjab on edge  Dawn
    3. Pakistan evacuates 25,000 people from eastern city as rivers threaten flooding  AP News
    4. Town evacuated as south Punjab reels under floods  The Express Tribune
    5. Multan on red alert as Army, Navy deployed amid rising floodwaters  The Nation (Pakistan )

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  • Govt forms peace committee to frame anti-extremism narrative

    Govt forms peace committee to frame anti-extremism narrative



    Prime Minister Shehbaz Sharif chairs federal cabinet meeting on June 18, 2025. — PID

    ISLAMABAD: A National Peace Message Committee has been established to formulate a unified narrative aimed at combating extremism, terrorism, and sectarianism, functioning under the umbrella of the National Committee on Narrative Building.

    According to a notification issued by the Ministry of Information and Broadcasting, the committee will be chaired by Federal Minister Attaullah Tarar.

    Its members include Senator Hafiz Abdul Karim, Mufti Abdul Rahim, Allama Arif Hussain Wahidi, Pir Naqeeb-ur-Rehman, Allama Muhammad Hussain Akbar, and Dr Muhammad Raghib Hussain Naeemi.

    Other members comprise Maulana Tahir Mehmood Ashrafi, Maulana Tayyab Punj Piri, and Allama Ziaullah Shah Bukhari.

    Minority communities will also be represented through Bishop Azad Marshal, Rajesh Kumar Hardasani, and Sardar Ramesh Singh Arora. The notification stated that the director general of the Internal Publicity Wing of the Information Ministry will serve as secretary of the committee.

    It added that the committee will finalise detailed terms of reference (TORs) in its first meeting, which will align with those of the National Committee on Narrative Building.

    Separately, Prime Minister Shehbaz Sharif stressed the need to discourage the elements who had been churning out nefarious material on social media against the security forces, terming it “highly condemnable”.

    Addressing the federal cabinet meeting, the prime minister said it was their responsibility they single out and identify such elements and, with unwavering commitment, root them out.

    He said such a repugnant attitude towards the armed forces was unbearable and termed it a “fitna” which should be crushed.

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  • Ollie Bearman ‘sad’ after failing to score at Monza as Esteban Ocon vows to ‘come back stronger’

    Ollie Bearman ‘sad’ after failing to score at Monza as Esteban Ocon vows to ‘come back stronger’

    Haas failed to score a point at the Italian Grand Prix, with Ollie Bearman their lead driver in 12th while Esteban Ocon finished where he started in 15th. That leaves the American team losing more ground in the championship, but there were some positives to take home from Monza.
    The team opted to split strategies, starting Ocon on the hard tyre and Bearman on the medium. It meant the youngster was on the same strategy as many around him, and thus had to make up the places on the track rather than in the pits.

    That was exactly what he tried to do, but he came a cropper when battling Carlos Sainz late on. As the Williams man steamed past down the straight and seemed far enough ahead to have the corner, Bearman tried to stick with him on the inside.

    The result was a collision that tagged both drivers into a spin, leaving both with damage to boot. Bearman’s day was only made worse when the stewards deemed him responsible for the contact and handed him a 10-second time penalty.

    In the end he came home 12th, one place below where he started.

    “It’s really sad, honestly, as the car felt great today. I had to really fight as we were slow in the straights, but without the incident with Carlos Sainz, I think we could’ve been fighting for points – it’s just a big shame,” he said after the race.

    Ocon also picked up an in-race penalty on a tricky day for the team, five seconds for the Frenchman for forcing Lance Stroll wide in the Aston Martin when they were battling for position early on. That was served in his very late pit stop, Ocon trying to go as deep as possible into the race in case of a Safety Car.

    He pitted on the penultimate lap for soft tyres, and that, combined with the penalty, dropped him from ninth to 15th, a far cry from the previous race where the American outfit picked up double points.

    “We tried as a team to try and stay out and do something different. The tyres were getting better every lap, so there was no point in boxing and losing it all, so we stayed out long,” Ocon explained.

    “Unfortunately, we didn’t have the best Qualifying yesterday and that put us further back than we should be. There’s been some good learning from this weekend, and we’ll come back stronger.”

    Haas remain ninth in the Teams’ Standings, now 11 points behind Kick Sauber who managed to score in Italy courtesy of Gabriel Bortoleto’s P8.

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  • Just 1 in 4 Americans believe Trump administration vaccine shifts are based on science, Reuters/Ipsos poll finds – Reuters

    1. Just 1 in 4 Americans believe Trump administration vaccine shifts are based on science, Reuters/Ipsos poll finds  Reuters
    2. Who do you trust when it comes to vaccines and health standards? Hear what fellow Hoosiers think  WTHR
    3. Republicans, take note: Voters trust Democrats more on vaccines  statnews.com
    4. Most Americans skipping COVID-19 vaccine this fall amid policy changes: KFF poll  Cleveland.com

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  • The growing use of NGS for patients with infections

    The growing use of NGS for patients with infections

    While genomics has transformed cancer care and rare disease diagnosis, infectious disease testing is lagging behind with older methods. Often, physicians still have access only to limited or outdated technology that leaves them making decisions based on spotty or incomplete information.

    For example, it’s not uncommon for a doctor to have a postoperative patient who’s suffering from signs of infection but whose cultures are negative. “That’s the point when physicians are the most stuck and left without any insight. They know their patient has an infection, but the culture is telling them they don’t,” says Nick Sanford, PhD, vice president of Medical Affairs at MicroGenDX. “So, they believe it must be a false negative because every other thing—the lab values, their 20 years’ experience as an MD—all adds up to infection, but their primary diagnostic tool is disagreeing with them.” From there, some clinicians turn to Polymerase Chain Reaction (PCR) testing, which amplifies genetic material in the lab so it can be detected. But that method detects only the organisms whose primers are included on the particular panel used, limiting its ability to detect pathogens.

    “The next logical step,” says Sanford, “is next-generation sequencing.” As implemented by MicroGenDX, each next-generation sequencing (NGS) test includes a standardized process for amplifying universal genes for bacteria and fungi.

    Sanford oversees Medical Affairs at MicroGenDX, an American company that has processed more than a million NGS tests from across the country as well as internationally. In the US, they’ve signed agreements with more than 100 hospital systems just since January 2024, and this April they launched a sister company, MicroGenDX EU, to receive and run samples from abroad. MicroGenDX specializes in infectious disease research and clinical testing, often working with orthopedic surgeons, pulmonologists, neurologists (for central nervous system infections), and infectious disease specialists, among other experts.

    The company recently upgraded the NGS technology in their Texas laboratory. Thanks to faster sequencing and analysis capabilities, they are reducing their sample-to-answer turnaround time from three to five days to 24 hours. They report being able to get excellent, clinical-grade data quality from a 12-hour run time, which helps them deliver results to doctors as soon as the next day after their lab receives a patient’s sample. “Now that’s diagnostics that can keep pace with clinical decision making in the hospital,” says Sanford. “With hospitals, the concern is always turnaround time.”

    Who really benefits from faster NGS testing? Receiving a precise diagnosis and treatment means that patients with sepsis or acute infections could have shorter ICU stays, avoid complications, or prevent worsening illness. Their results support providers in creating targeted treatments that help patients recover from high-risk, debilitating conditions.

    Elderly or catheterized patients suffering from recurrent UTIs could be matched with a targeted therapy, resolving symptoms faster and using fewer inappropriate antibiotics. Patients with a chronic illness might have fewer hospital visits or readmissions. Pediatric and immunocompromised patients could avoid staying in the hospital for days, waiting for results. Faster NGS testing also means lower health care expenses for families and general cost savings for hospitals and payers.

    NGS is also increasingly being used in pulmonology and otolaryngology. MicroGenDX receives bronchoalveolar samples and nasal swabs from many patients who have been cycling through antibiotics for weeks. Identifying the responsible pathogens and drug resistance markers helps doctors intervene before the infections become chronic.

    Sanford believes that, in the past, a three-to-five-day turnaround time caused doctors to consider NGS a last resort. But now that MicroGenDX has speedier lab processing, NGS testing is more attractive to providers. “Shortening that window to actionable data can mean the difference between a minor setback and a major complication,” he says.

    Research and trials

    MicroGenDX also conducts research on applications that are relevant to various critical care settings. The company just submitted a paper on a study evaluating 2000 synovial fluid samples from patients at risk of or with a chronic history of periprosthetic joint infection (PJI). “PJI is a mountain of an issue,” says Craig Tipton, PhD, MicroGenDX’s director of Biostatistics.

    Tipton routinely hears concerns from both orthopedic surgeons and infectious disease physicians. “It takes so much of their bandwidth managing these very chronic infections,” he says. MicroGenDX has been able to show the superior sensitivity of NGS over other conventional diagnostic methods for microbiological testing, such as culture or quantitative-PCR-only testing. While this particular study did not have a direct comparator, they reported 76% sensitivity for NGS compared with 63% sensitivity from culture tests across a large meta-analysis and 41%–56% sensitivity for a commonly used qPCR panel.

    “If you’re able to jump from 50% sensitivity to 76%, that’s another quarter of your patients for whom you suddenly now have actionable information with which to diagnose an infection, help guide treatment for that infection, and know whether you have to operate,” says Tipton. “Having all that extra information is huge.”

    Sanford adds that de-escalation is another benefit. For instance, if a doctor suspects that an ICU patient has a fungal infection, they may start them on an expensive empiric antifungal therapy. However, armed with the answers provided by NGS, the doctor could de-escalate much faster and reduce the patient’s antimicrobial exposure, chance of side effects, and associated costs.

    When you use only one method—and particularly only culture—you’re missing a huge spectrum of what could be there.

    Starting this month, MicroGenDX will be participating in a trial led by Indiana University in 10 to 15 trauma hospitals across the United States. The participants will be patients who have undergone at least one surgery to try to heal a broken bone from a traumatic injury, and who have suspected fracture-related infection (FRI).

    “Once an infection develops, the failure rate is extraordinarily high,” Tipton says. “And failure rates can lead to multiple surgeries trying to correct the issue and clear the infection. There are high costs with hospitalization, resource utilization, and high mortality rates—every metric you can think of.” MicroGenDX is partnering with the Major Extremity Trauma Research Consortium to coordinate the trial: In an intervention arm, patients will provide a sample for NGS. The researchers will compare the effects of incorporating NGS sampling at the time of revision surgery versus the current standard of care, which typically relies on conventional culture methods to inform treatment.

    Under this standard protocol, doctors often can’t confirm an FRI diagnosis until they go into surgery, and they may have to wait days to do so by culture. Confirming a diagnosis enables them to discharge the patient and start them on a targeted therapy, if necessary.

    The investigative team will follow patients for a year or more to monitor whether the earlier, more targeted therapy leads to faster healing, fewer surgeries, and other improvements. They’ll also track any findings that were missed by conventional diagnostics; if antibiotics are prescribed for an infection, they’ll track the medication’s management and any adverse effects.

    The culture of culture

    Both Tipton and Sanford are quick to note that the conventional culture test is still a useful tool, if an imperfect one. “We are not advocating at all for it to be taken out of the standard of care, but it has many limitations,” Tipton says. Conventional culture methods often miss an organism that doesn’t grow well in a culture dish, especially slow-growing pathogens that are anaerobes, fungi, or mycobacteria.

    “When you use only one method—and particularly only culture—you’re missing a huge spectrum of what could be there,” says Tipton, who has noticed an uptick in orders for molecular diagnostic testing, including multiplex qPCR and NGS, to compensate for the lack of data from culture. A new study led by MicroGenDX analyzed 467 synovial fluid samples that NGS had determined to be positive for PJI. And while qPCR can deliver rapid results, the study found that 44% of the dominant microbes reported in these samples were not included in a commonly used commercial multiplex qPCR panel for joint infection.

    Dominant microbes are the most abundant organisms found in at least one patient sample; they are often considered priorities for treatment in an infected joint. Missing these microbes could spell disaster for patients if their infections go unconfirmed. “It would be very difficult to ever have a qPCR panel that could capture the crazy diversity of microbes that might be causing an infection,” Tipton says. “And although you do have some ability to detect anything via culture, in theory, we know that it misses everything that is difficult to grow in culture—and that’s even more difficult if the patients have been on antibiotics. If they’re on antibiotics, you may just not see anything that’s there.”

    When they use NGS, MicroGenDX not only finds rare organisms they weren’t looking for, they find them in places no one would expect. For example, they’ve discovered the bacteria responsible for tuberculosis in synovial fluid, and Tropheryma whipplei in a lung biopsy, which aids diagnosis for atypical presentations of Whipple disease.

    The MicroGenDX team frequently hears powerful accounts from people who have spent years visiting specialists, undergoing unhelpful tests and, at times, facing skepticism—all while living with debilitating pain. They often say that nothing worked for them, neither traditional nor nontraditional methods. But when NGS testing identifies the species causing their affliction, and they receive personalized treatment, their relief is immense.

    As for those seasoned physicians scratching their heads at a negative culture result?

    The tide is starting to turn. Professional organizations have begun amending their guidelines. In 2018, the International Consensus Meeting on Infection updated their guidelines for diagnosing periprosthetic joint infection with new formal statements advocating for NGS testing. In another instance, the Infectious Disease Society of America recently released new guidance statements on potential use cases for NGS.

    “PCR works great when testing for COVID or screening a patient for Candida auris before going into surgery,” Sanford says, “But when just about anything that is a microbe could be causing your infection, I think a more agnostic method using NGS is where diagnostics will ultimately trend.”

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