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Metastasis-directed therapy (MDT)-local therapy that is intended to eradicate specific metastatic lesions-has hitherto been used with varying degrees of clinical efficacy and acceptance as a meaningful therapy for metastatic disease. Over the past 25 years, however, the momentum for using MDT to manage patients with metastatic solid tumours has increased, driven by several factors. Among these factors is the recognition that patients with limited metastatic burden could potentially derive survival benefits from MDT. Furthermore, although current systemic therapies are increasingly effective, they are infrequently curative. In addition, technological advances have broadened the spectrum of metastatic lesions that can be treated with ablative intent. Here we aim to briefly review the status of evidence for the clinical benefit of MDT based on current data mainly from trials in patients with oligometastatic disease, discuss the myriad of clinical states that might fall under and beyond the definition of oligometastasis, review technological advances in MDT and their applications beyond oligometastasis, and discuss the need for the continued co-evolution of MDT and systemic therapy as we seek to understand which patients with metastatic cancer can achieve durable remission and how to optimally manage those who cannot. [ABSTRACT FROM AUTHOR]

Purpose: The primary goal was to map the anatomic pattern of isolated nodal recurrences (NR) in the supraclavicular (SCV), axillary, and internal mammary nodes (IMNs) in patients with breast cancer treated with curative-intent surgery with or without radiation therapy (RT). Secondary objectives were to assess clinical and pathologic factors associated with patterns of NR and survival rates.Methods and Materials: Patients with NR after treatment at a single cancer center during 1998 to 2013 were identified. Patients with prior distant metastases or NR without correlative imaging were excluded. All NRs were overlaid onto representative axial computed tomographic images. Multivariable analysis was performed to identify clinical and pathologic characteristics associated with NR. Kaplan-Meier curves were generated to assess the rate of relapse by nodal region according to pathologic feature or radiation treatment status.Results: The locations of 243 NRs among 153 eligible patients were mapped. The majority of NR occurred in the axilla (42%; 102/243), followed by the IMN (32.5%; 79/243) and the SCV (25.5%; 62/243). Radiation Therapy Oncology Group (RTOG) or European Society for Radiation therapy and Oncology (ESTRO) clinical target volume encompassed 82% (198/243) of NRs. The majority of out-of-field NRs were located in the lateral and posterior SCV region for both RTOG (67%; 30/45) and ESTRO (89%; 49/55) guidelines. The high-risk patients who received regional RT to the SCV relapsed at a similar rate in the medial, but a higher rate in lateral SCV (P = .009), compared with low-risk patients who received no nodal RT. Lymphovascular invasion most strongly associated with IMN NR (P = .001); grade 3 disease highly associated with both IMN (P = .001) and SCV NR (P = .02). The presence of an IMN NR portended for significantly inferior overall survival (OS), compared with an axillary NR, with a 5-year OS of 59% versus 72%, respectively (P = .03).Conclusions: In this 3-dimensional image-based analysis of NR patterns in breast cancer patients treated with contemporary therapies, the lateral and posterior SCV represented a distinct site of NR that is not routinely included within current breast cancer contouring atlases. Grade 3 breast cancer and LVI were most commonly associated with the development of NR in the SCV. Modifying the CTV to encompass the lateral and posterior SCV in patients with breast cancer with these features might be justified. [ABSTRACT FROM AUTHOR]

Abstract Purpose The treatment paradigm for uterine clear cell carcinoma is often linked to serous carcinoma. This study compares oncologic outcomes between women with uterine clear cell and serous carcinoma. Methods and Materials We reviewed 114 women with stage I–II uterine clear cell carcinoma (n = 17, 15%) or serous carcinoma (n = 97, 85%) who underwent hysterectomy and salpingo-oophorectomy at our institution from April 1992 to December 2011; 86 (76%) had stage IA, 14 (12%) had stage IB, and 14 (12%) had stage II disease. Median followup was 57 months. Results Patients with uterine clear cell and serous carcinoma did not differ significantly by age ≥60 years, stage, or rate of lymphovascular invasion. There was no difference in the number of patients with clear cell or serous histology who received adjuvant radiotherapy (71% vs. 84%, respectively; p = 0.31); however, significantly fewer patients with clear cell histology received adjuvant chemotherapy (35% vs. 67%, respectively; p = 0.02). At 5 years, there were no significant differences in disease-free survival (94% vs. 84%, respectively; p = 0.27), disease-specific survival (100% vs. 92%, respectively; p = 0.20), or overall survival (100% vs. 89%, respectively; p = 0.34). The differences in chemotherapy utilization did not impact pattern of relapse, specifically peritoneal spread (7% vs. 6%, respectively; p = 0.92) or other distant sites (0% vs. 9%, respectively; p = 0.17). Conclusions Oncologic outcomes and recurrence patterns of women with stage I–II uterine clear cell carcinoma compared favorably with those of women with serous carcinoma, despite significantly less adjuvant chemotherapy use. Potential reduction in adjuvant therapy in women with clear cell carcinoma should be studied prospectively. [ABSTRACT FROM AUTHOR]

Purpose: Lung cancer remains the most common cause of both cancer mortality and brain metastases (BM). The purpose of this study was to assess the effect of gene alterations and tyrosine kinase inhibition (TKI) on median survival (MS) and cause of death (CoD) in patients with BM from lung adenocarcinoma (L-adeno).Methods: A multi-institutional retrospective database of patients with L-adeno and newly diagnosed BM between 2006 and 2014 was created. Demographics, gene alterations, treatment, MS, and CoD were analyzed. The treatment patterns and outcomes were compared with those in prior trials.Results: Of 1521 L-adeno patients, 816 (54%) had known alteration status. The gene alteration rates were 29%, 10%, and 26% for EGFR, ALK, and KRAS, respectively. The time from primary diagnosis to BM for EGFR-/+ was 10/15 months (P=.02) and for ALK-/+ was 10/20 months (P<.01), respectively. The MS for the group overall (n=1521) was 15 months. The MS from first treatment for BM for EGFR and ALK-, EGFR+, ALK+ were 14, 23 (P<.01), and 45 (P<.0001) months, respectively. The MS after BM for EGFR+ patients who did/did not receive TKI before BM was 17/30 months (P<.01), respectively, but the risk of death was not statistically different between TKI-naïve patients who did/did not receive TKI after the diagnosis of BM (EGFR/ALK hazard ratios: 1.06 [P=.84]/1.60 [P=.45], respectively). The CoD was nonneurologic in 82% of patients with known CoD.Conclusion: EGFR and ALK gene alterations are associated with delayed onset of BM and longer MS relative to patients without these alterations. The CoD was overwhelmingly nonneurologic in patients with known CoD. [ABSTRACT FROM AUTHOR]

Background With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patients with limited brain metastases (BM), clinicians need more specific prognostic tools. We investigated clinical predictors of outcomes in patients with limited breast cancer BM treated with SRS alone. Methods and Materials We identified 136 patients with breast cancer and 1-3 BM who underwent definitive SRS for 186 BM between 2000 and 2012. The Kaplan-Meier method was used to assess overall survival (OS), regional failure (RF), and local failure (LF). Associations between clinical factors and outcomes were tested using Cox regression. A point scoring system was used to stratify patients based on OS, and the predictive power was tested with concordance probability estimate (CPE). Results The median OS was 17.6 months. The 12-month RF and LF rates were 45% and 10%, respectively. On multivariate analysis, >1 lesion (hazard ratio [HR] = 1.6, P =.02), triple-negative (TN) disease (HR=2.0, P =.006), and active extracranial disease (ED) (HR=2.7, P <.0001) were significantly associated with worse OS. The point score system was defined using proportional simplification of the multivariate Cox proportional hazards regression function. The median OS for patients with 3.0-4.0 points (n=37), 4.5-5.5 points (n=28), 6.0-6.5 points (n=37), and 8-8.5 points (n=34) were 9.2, 15.6, 25.1, and 45.1 months, respectively ( P <.0001, CPE = 0.72). Active ED (HR=2.4, P =.0007) was significantly associated with RF. Higher risk for LF was significantly associated with larger BM size (HR=3.1, P =.0001). Conclusion Patients with >1 BM, active ED, and TN had the highest risk of death after SRS. Active ED is an important prognostic factor for OS and intracranial control. [ABSTRACT FROM AUTHOR]

Background and purpose To identify clinical and dosimetric factors associated with hematologic toxicity (HT) during chemoradiotherapy for rectal cancer. Materials and methods We analyzed 120 rectal cancer patients treated with neoadjuvant pelvic radiotherapy (PRT) with concurrent 5-fluorouracil-based chemotherapy. The coxal (ilium, ischium, and pubis) bone marrow (BM), sacral BM, and femoral BM were contoured and dose-volume parameters were extracted. Associations between cell count trend and clinical predictors were tested using repeated-measures analysis of variance (ANOVA) test. Associations between clinical variables, Vx (percentage volume receiving x Gy), and cell count ratio at nadir were tested using linear regression models. Results Nadirs for white blood cell count (WBC), absolute neutrophil count (ANC), and platelets (PLT) occurred in the second week of PRT and the fifth week for hemoglobin and absolute lymphocyte count (ALC). Using cell count ratio, patients treated with 3DCRT had a lower WBC ratio trend during PRT compared to patients treated with IMRT ( p = 0.04), and patients ⩾59 years of age had a lower hemoglobin ratio trend during PRT ( p = 0.02). Using absolute cell count, patients treated with 3DCRT had lower ANC cell count trend ( p = 0.03), and women had lower hemoglobin cell count trend compared to men ( p = 0.03). On univariate analysis, use of 3DCRT was associated with a lower WBC ratio at nadir ( p = 0.02). On multiple regression analysis using dosimetric variables, coxal BM V45 ( p = 0.03) and sacral BM V45 ( p = 0.03) were associated with a lower WBC and ANC ratio at nadir, respectively. Conclusions HT trends during PRT revealed distinct patterns: WBC, ANC, and PLT cell counts reach nadirs early and recover, while hemoglobin and ALC decline steadily. Patients who were treated with 3DCRT and older patients experienced lower cell count ratio trend during PRT. Dosimetric constraints using coxal BM V45 and sacral BM V45 can be considered. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate local control after surgical resection and postoperative stereotactic radiosurgery (SRS) for brain metastases. Methods and Materials: A total of 49 patients (50 lesions) were enrolled and available for analysis. Eligibility criteria included histologically confirmed malignancy with 1 or 2 intraparenchymal brain metastases, age ≥18 years, and Karnofsky performance status (KPS) ≥70. A Cox proportional hazard regression model was used to test for significant associations between clinical factors and overall survival (OS). Competing risks regression models, as well as cumulative incidence functions, were fit using the method of Fine and Gray to assess the association between clinical factors and both local failure (LF; recurrence within surgical cavity or SRS target), and regional failure (RF; intracranial metastasis outside of treated volume). Results: The median follow-up was 12.0 months (range, 1.0-94.1 months). After surgical resection, 39 patients with 40 lesions were treated a median of 31 days (range, 7-56 days) later with SRS to the surgical bed to a median dose of 1800 cGy (range, 1500-2200 cGy). Of the 50 lesions, 15 (30%) demonstrated LF after surgery. The cumulative LF and RF rates were 22% and 44% at 12 months. Patients who went on to receive SRS had a significantly lower incidence of LF (P=.008). Other factors associated with improved local control include non-small cell lung cancer histology (P=.048), tumor diameter <3 cm (P=.010), and deep parenchymal tumors (P=.036). Large tumors (≥3 cm) with superficial dural/pial involvement showed the highest risk for LF (53.3% at 12 months). Large superficial lesions treated with SRS had a 54.5% LF. Infratentorial lesions were associated with a higher risk of developing RF compared to supratentorial lesions (P<.001). Conclusions: Postoperative SRS is associated with high rates of local control, especially for deep brain metastases <3 cm. Tumors ≥3 cm with superficial dural/pial involvement demonstrate the highest risk of LF. [Copyright &y& Elsevier]

Abstract: In recent years, accelerated partial breast irradiation (APBI) has been considered an alternative to whole breast irradiation for patients undergoing breast-conserving therapy. APBI delivers higher doses of radiation in fewer fractions to the post-lumpectomy tumor bed with a 1–2cm margin, targeting the area at the highest risk of local recurrence while sparing normal breast tissue. However, there are inherent challenges in defining accurate target volumes for APBI. Studies have shown that significant interobserver variation exists among radiation oncologists defining the lumpectomy cavity, which raises the question of how to improve the accuracy and consistency in the delineation of tumor bed volumes. The combination of standardized guidelines and surgical clips significantly improves an observer’s ability in delineation, and it is the standard in multiple ongoing external-beam APBI trials. However, questions about the accuracy of the clips to mark the lumpectomy cavity remain, as clips only define a few points at the margin of the cavity. This paper reviews the techniques that have been developed so far to improve target delineation in APBI delivered by conformal external beam radiation therapy, including the use of standardized guidelines, surgical clips or fiducial markers, pre-operative computed tomography imaging, and additional imaging modalities, including magnetic resonance imaging, ultrasound imaging, and positron emission tomography/computed tomography. Alternatives to post-operative APBI, future directions, and clinical recommendations were also discussed. [Copyright &y& Elsevier]

Purpose: Guidelines recommend short-course (≤10 fractions) external-beam radiation therapy (EBRT) for bone metastases. Stereotactic body radiation therapy (SBRT) may also improve outcomes; however, routine use is not recommended outside clinical trials. We assessed national radiation therapy trends in complex techniques for bone metastases and associated expenditures.Methods and Materials: Using a claims-based Medicare data set covering 84% of beneficiaries, we assessed the relative proportion of all radiation episodes represented by bone metastases. We then evaluated use of short-course and long-course (>10 fractions) EBRT, intensity modulated radiation therapy (IMRT), and SBRT for bone metastases in hospital-affiliated outpatient (OPD) or freestanding (FREE) facilities. We assessed differences using χ2d or Wilcoxon rank sum tests for categorical and continuous variables, respectively. We identified associations with modality, fractionation, and expenditures using multivariable logistic/linear regression.Results: Among 467,781 radiation episodes for 17 cancer diagnoses, the overall proportion of episodes dedicated to bone metastases (9.4%) was stable from 2015 to 2017, although treatments were increasing in the hospital-affiliated outpatient setting (P < .005). We identified 40,993 episodes for bone metastases, of which 63% were short-course EBRT, 24% were long-course EBRT, 7% were SBRT, and 6% were IMRT. Techniques more common in the hospital-affiliated outpatient setting included short-course EBRT (OPD, 69%, vs FREE, 56%) and SBRT (OPD, 9%, vs FREE, 5%). Techniques more common among free-standing centers included long-course EBRT (OPD, 19%, vs FREE, 31%) and IMRT (OPD, 4%, vs FREE, 9%). From 2015 to 2017, long-course EBRT decreased by an absolute 8%; short-course EBRT, SBRT, and IMRT increased by 4%, 2.5%, and 1%, respectively. The SBRT/IMRT uptake did not differ by setting (P = .4). Differences in expenditures between SBRT and short-course EBRT decreased by a relative 8% in professional and 12% in technical fees.Conclusions: Approximately 1 in 4 patients received long-course EBRT, with small reductions in use largely replaced by complex treatment modalities. However, expenditures for complex modalities also decreased over time. As alternative payment models take effect, quality metrics are needed to ensure appropriate, effective, and safe delivery of complex technologies. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local control after radiation therapy (RT) for brain metastases.Methods and Materials: We retrospectively reviewed 259 patients with brain metastases treated with RT during the period 2004 to 2017 for whom tumor genetic data (MSK-IMPACT) were available for primary or metastatic lesions. Associations between clinical factors, PI3K mutations status, and local failure (LF) were evaluated with univariate and multivariate competing risks regression.Results: A total of 112 patients received whole brain radiation therapy (WBRT) to a median dose of 30 Gy in 10 fractions, and 147 patients received stereotactic radiosurgery (SRS) to 338 lesions; 276 lesions were treated with single fraction SRS (median dose 21 Gy) and 76 lesions over 3 to 5 fractions SRS (median dose 30 Gy). PI3K mutations were present in 36 WBRT patients (32%) and 44 SRS patients (30%). For WBRT, patients with PI3K mutations (hazard ratio 2.67, P < .001) were found to be at higher risk for LF on multivariable analysis, and the 1-year cumulative incidence of LF was 50% (95% confidence interval [CI] 32%-65%) for patients with PI3K mutations versus 26% (95% CI 17%-37%) for patients without PI3K mutations. For SRS lesions, while PI3K mutations positivity was not statistically significantly associated with LF, higher rate of LF was observed: 1-year LF cumulative incidence of 11% (95% CI 6%-17%) for patients with PI3K mutations versus 5% (95% CI 3%-9%) for patients without PI3K mutations.Conclusion: Patients with PI3K mutations are at higher risk for LF for brain metastases after RT. Novel therapeutic strategies to improve treatment outcomes in these patients should be considered. [ABSTRACT FROM AUTHOR]

Background and purpose Hypofractionated conformal radiotherapy (hfCRT) is used for larger brain metastases or metastases near critical structures. We investigated hfCRT outcomes for newly diagnosed brain metastases. Materials and methods We identified 195 patients with 1–3 brain metastases who underwent 5 × 6 Gy hfCRT for 231 lesions from 2007 to 2013. Associations among clinical factors, local control (LC), distant brain control (DC) and overall survival (OS) were tested using univariate and multivariate (MVA) Cox regression analysis and Kaplan–Meier method. Results Median follow-up was 12.8 months. One hundred forty-three (62%) lesions were treated with hfCRT post-operatively, and 88 (38%) with definitive hfCRT. LC for all lesions was 83% at 1 year. For lesions treated with post-operative hfCRT, tumor size (HR = 4.7, p = 0.04) and subtotal resection (HR = 2.7, p = 0.02) were predictive of local failure on MVA. For lesions ≥2.8 cm in size, LC was 61% at 12 months for lesions status-post subtotal resection, compared to 84% status-post gross total resection ( p = 0.004). Extracranial disease presence was associated with worse DC (HR = 1.8, p = 0.008) and OS (HR = 3.1, p < 0.001). Conclusions We showed 5 × 6 Gy hfCRT provides acceptable LC at 1 year for limited brain metastases. For large lesions not grossly resected, more aggressive strategies can be considered to improve LC. [ABSTRACT FROM AUTHOR]

Background and purpose We examined acute toxicity profiles and outcomes among rectal cancer patients treated with pre-operative chemoradiation using intensity modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3DCRT) to identify predictive clinical factors associated with increased acute toxicity. Material and methods We retrospectively reviewed records of 301 consecutive rectal cancer patients treated with pre-operative chemotherapy and radiotherapy (median dose 5000 cGy) at our institution between 2007 and 2014. Results Of the 301 patients, 203 (67.4%) were treated with IMRT and 98 (32.6%) with 3DCRT. Significantly more patients experienced ⩾grade 2 diarrhea in the 3DCRT group compared to the IMRT group (22% vs 10%, p = 0.004), and those who received 3DCRT had 2.7 times greater odds of a higher diarrhea score than those on IMRT, even after adjusting for patient characteristics and chemotherapy (OR 2.71, p = 0.01) Fewer patients experienced grade 2 genitourinary toxicity in the IMRT group (6% vs 13% 3DCRT, p = 0.04) and there was a trend toward decreased grade 2 proctitis in the IMRT group (22% vs 32% 3DCRT, p = 0.07). Patients over the age of 55 had 45% lower odds of proctitis than patients younger than 55. Conclusion The use of IMRT significantly reduced grade ⩾2 diarrhea and GU toxicity during chemoradiation. Younger patients were more likely to report grade 2 or higher proctitis. [ABSTRACT FROM AUTHOR]

Purpose Although vaginal stenosis (VS) is a recognized toxicity in women who receive pelvic radiation therapy (RT), the relationship between RT dose and the volume and extent of toxicity has not been analyzed. We modeled this relationship to identify predictors of VS. Methods and Materials We evaluated 54 women, aged 29 to 78 years, who underwent pelvic RT for rectal or anal cancer during 2008 to 2011 and were enrolled in a prospective study evaluating vaginal dilator use. Maximum dilator size was measured before RT (baseline) and 1 month and 12 months after RT. Dilator use was initiated at 1 month. The difference ( D ) in dilator size before and after RT was recorded. Those with D ≤−1 were classified as having VS (n=35); those with D ≥0 were classified as having no VS (n=19 at 1 month). Dose-volume parameters were extracted, and the generalized equivalent uniform dose (gEUD) was used to build a predictive model. Results The mean vaginal doses were 50.0 Gy and 36.8 Gy for anal and rectal cancer patients, respectively. One month after RT, a gEUD model using a wide range of a values suggests that sparing of vaginal volume to a low dose may be important. When gEUD ( a = −1) was <35 Gy and the mean vaginal dose was <43 Gy, severe VS was reduced ( P =.02). A 1-year analysis suggests increasingly negative D values with increasing mean dose. However, patients with compliance <40% were more likely to have toxicity. Conclusions Vaginal stenosis is influenced by multiple RT dose-volume characteristics. Mean dose and gEUD constraints together may reduce the risk of severe VS. Patients receiving higher mean vaginal doses should have greater compliance with dilator therapy to minimize risk of toxicity. Further validation with independent datasets is needed. [ABSTRACT FROM AUTHOR]

Background: In patients with metastatic cancer, the bone is the third-most common site of involvement. Radiation to painful bone metastases results in high rates of pain control and is an integral part of bone metastases management. Up to one-third of inpatient consults are requested for painful bone metastases, and up to 60% of these patients had evidence of these lesions visible on prior imaging. Meanwhile recent advances have reduced potential side effects of radiation. Therefore, there is an opportunity to further improve outcomes for patients using prophylactic palliative radiation to manage asymptomatic bone metastases.Methods/study Design: In this trial, 74 patients with metastatic solid tumors and high-risk asymptomatic or minimally symptomatic bone metastases will be enrolled and randomized to early palliative radiation or standard of care. This will be the first trial to assess the efficacy of prophylactic palliative radiation in preventing skeletal related events (SREs), the primary endpoint. This endpoint was selected to encompass patient-centered outcomes that impact quality of life including pathologic fracture, spinal cord compression, and intervention with surgery or radiation. Secondary endpoints include hospitalizations, Bone Pain Index, pain-free survival, pain-related quality of life, and side effects of radiation therapy.Discussion: In this study, we propose a novel definition of high-risk bone metastases most likely to benefit from preventive radiation and use validated questionnaires to assess pain and impact on quality of life and health resource utilization. Observations from early patient enrollment have demonstrated robustness of the primary endpoint and need for minor modifications to Bone Pain Index and data collection for opioid use and hospitalizations. With increasing indications for radiation in the oligometastatic setting, this trial aims to improve patient-centered outcomes in the polymetastatic setting.Trial Registration: ISRCTN Number/Clinical trials.gov, ID: NCT03523351 . Registered on 14 May 2018. [ABSTRACT FROM AUTHOR]

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders. • Inhibitor THZ-P1-2 shows PI5P4K enzyme inhibition and target engagement in cells • THZ-P1-2 covalently targets unannotated cysteines outside the PI5P4K active site • AML/ALL cell lines are broadly sensitive to THZ-P1-2's covalent effects • PI5P4K inhibition causes autophagy disruption and upregulates TFEB signaling PI5P4K, an understudied kinase family, is essential in various disease contexts. Sivakumaren et al. develop and characterize PI5P4K inhibitor THZ-P1-2, which targets unique cysteines, exhibits effects in biochemical and cellular assays, displays anticancer activity in leukemia cell lines, and causes defects in autophagy similar to PI5P4K gene knockdown or deletion. [ABSTRACT FROM AUTHOR]