Hsiao C. Li

KIF14 Promotes AKT Phosphorylation and Contributes to Chemoresistance in Triple-Negative Breast Cancer

Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor 2-negative, triple-negative breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live-cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC.

Metastatic rectal cancer to the breast

Rectal cancer metastatic to the breast is an exceedingly rare event with around 15 cases reported in the literature. A metastatic breast deposit from the rectum signifies diffuse disseminated disease or a highly aggressive tumor such that surgical intervention other than palliation has a limited role. In the present report, we discuss a patient who presented with rectal cancer and developed a breast metastatic deposit. She soon developed progressive metastatic involvement of the lungs and the soft tissues and succumbed to the malignant course of this disease 12 months after the diagnosis of the primary rectal tumor.

Idelalisib-induced pneumonitis

A woman in her 40s with relapsed follicular lymphoma presented with a few days history of shortness of breath and cough producing yellow sputum. There were no reported toxic exposures or contacts with sick people. Medications included idelalisib initiated 5u2005months ago and a multivitamin. Vital signs were notable for tachycardia and tachypnoea, oxygen saturation was 89% on room air. The alveolar–arterial gradient was 50u2005mmu2005Hg (expected for age, 16u2005mmu2005Hg). Examination revealed diffuse crackles in bilateral lung fields. Routine biochemical investigations were unremarkable and multiple infectious studies were negative. Chest …

The neutrophil to albumin ratio as a predictor of pathological complete response in rectal cancer patients following neoadjuvant chemoradiation.

Pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), in patients with locally advanced rectal cancer, occurs in 15–27% of patients. Because blood cell counts and albumin are a direct indicator of the host environment, a response to nCRT might be predicted by these markers. This study was carried out to determine whether the neutrophil to albumin ratio (NAR) was predictive of pCR in veteran patients. Ninety-eight patients with rectal cancer who underwent standard nCRT, followed by TME were analyzed. Pre-nCRT and post-nCRT hematologic data were collected. Univariate and multivariate analyses were carried out. Kaplan–Meier curves were constructed with our primary endpoint of pCR. Male patients (99%), age 62.4±9.1 years, BMI=27.4±5.9u2009kg/m2, rectal cancer distance from anal verge=7.1±4.5u2009cm (SD), interval between nCRT and TME=8 weeks, 55% patients=low anterior resection, 95% received 5-fluorouracil, and all patients received radiation, with 15% achieving a pCR. Univariate analysis showed that pre-nCRT carcinoembryonic antigen (15.8±45.1 vs. 3.5±5.3u2009ng/dl; P=0.002) and the pre-nCRT NAR (16.4±4.8 vs. 14.2±1.6; P=0.002) were associated with pCR. On multivariate analysis, pre-nCRT carcinoembryonic antigen (odds ratio=0.41, 95% confidence interval 0.22–0.77) and pre-nCRT NAR (odds ratio=0.76, 95% confidence interval 0.60–0.97) remained independent predictors of pCR. Overall survival between nonresponders and pCR patients at 1, 5, and 10 years was 96, 62, and 44% versus 93, 85, and 61%, P=0.13, and disease-free survival was 95, 60, and 47% versus 93, 85, and 61%, P=0.17; respectively. Our study shows that the pre-nCRT NAR is an independent predictor of pCR. These findings should be applied to other cohorts to determine its validity and reliability for use as a potential predictor of pCR.

Breast Cancer Surgery: Less Is More

Not until the very end of the 19th century did physicians or patients think that breast cancer was curable. Women only presented when the tumors were large and had spread to the axilla and beyond. Attempts to remove these lesions failed and resected cancers recurred so fast it seemed that the surgery fueled their growth. Halstead, operating just before the turn of the 20th century (at Johns Hopkins Hospital) believed that cancer cells were like seeds and that they migrated from the original tumor through the lymphatic system to the axilla. He believed that cutting through any tissue in the lymphatic system risked contaminating the operative field with cancer cells, any one of which could develop into a new tumor. If true, the best way to control these cancers was to remove the breast in 1 large block of tissue along with everything around it, all the way down to the bone of the chest wall. It worked. In 1894, Halstead reported on a series of 50 women he treated by en bloc removal of the breast, its overlying skin, and all adjacent tissues, including the axillary lymph nodes and pectoral muscles.1 These women all lived another 1 to 3 years without having significant recurrent cancer, a remarkable outcome for the time. The outcomes for these women were so impressive that they influenced breast cancer surgery for the next 60 years. The prevailing opinion was that radical en bloc resection of the breast and almost everything else on the chest wall and in the axilla was necessary to effectively treat breast cancer. With time, breast cancers were identified earlier in the course of disease. Although less extensive disease was present, surgeons continued to perform the Halstead radical mastectomy. Generations of surgeons were taught to do it this way. But one, Fisher in Pittsburgh, Pennsylvania, thought that the radical operation might be unnecessary. Radical mastectomies were disfiguring operations that resulted in long-term complications such as lymphedema and limited range of motion of the arm on the affected side. Wondering if these radical operations were really necessary, Fisher designed a clinical trial in the 1960s in which some women with breast cancer and no palpable axillary nodes would undergo the standard radical mastectomy (n = 362) and others would only undergo a total mastectomy without axillary lymphadenectomy (n = 365). A third group would have total mastectomy with axillary radiation therapy (n = 352). This trial, National Surgical Adjuvant Breast and Bowel Project B-04 (NSABP B-04), challenged and reversed 6 decades of breast cancer treatment lore. Less invasive operations, with much better cosmetic results, had equivalent outcomes even after 25 years of follow-up compared with radical mastectomy.2 Treating the axilla with radiation was as effective as surgically removing the lymph nodes. In the mastectomy only group, only 13% of women developed local (7%) or regional (6%) recurrent disease. Deferring axillary dissection until after the appearance of axillary tumors had no effect on survival. The use of radical mastectomy waned. By the time the outcomes of the NSAPB-04 were accepted by the breast cancer treatment community, it was recognized that outcomes were better for women who had axillary cancers if they received postoperative chemotherapy. The NSAPB-04 trial clearly demonstrated that radical mastectomy was not necessary to treat breast cancer. A less morbid operation, the modified radical mastectomy in which the pectoralis muscles were not removed became the standard operation for breast cancer. Even though NSAPB-04 showed that little was lost by not removing axillary lymph nodes, the NSAPB-04 was not considered definitive enough to convince breast surgeons that axillary node removal might not be needed. In an effort to reduce the morbidity of axillary node dissection, Morton and Giuliano devised the sentinel node procedure. Surgeons could identify the specific lymph nodes by draining the breast regions containing the cancer, and full axillary node dissection was not performed if the nodes were cancer-free.3 Although this approach substantially reduced axillary dissections, Giuliano and colleagues considered the NSAPB-04 results and devised the American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011) trial. The investigators questioned how much benefit there was to removing axillary lymph nodes even when cancer was present. Giuliuano and the ACOSOG Z0011 trialists designed a clinical trial and assigned women with stage I or II breast cancer and no palpable axillary lymph nodes who were found to have cancer during sentinel lymph node biopsy to either undergo axillary lymph node dissection (n = 445) or not (n = 446). When first proposed, this study was considered risky, if not reckless—leaving behind known cancer violated long-held, surgical principles of always removing cancer when it is known to be present. The trial was plagued by low enrollment because of resistance to the notion that surgeons would willingly leave cancer behind. There were also women who simply did not want axillary dissection irrespective of the risks associated with leaving cancer in their bodies. Consequently, the ACOSOG Z0011 investigators struggled to enroll patients, Related article page 918 Opinion

Reducing Wait Time Between Admission and Chemotherapy Initiation

PURPOSEnReducing the length of stay is a high-priority objective for all health care institutions. Delays in chemotherapy initiation for planned preadmissions lead to patient dissatisfaction and prolonged length of stay.nnnPATIENTS AND METHODSnA multidisciplinary team was formed as part of the ASCO Quality Training Program. We aimed to reduce the time to initiation of chemotherapy from patient arrival at Parkland Hospital from a median of 6.2 hours at baseline to 4 hours over a 6-month period (35% reduction). The team identified inconsistency in blood work requirements, poor communication, and nonstandard patient arrival times as key causes of delay in the process. Plan-Do-Study-Act (PDSA) cycles were implemented based on identified improvement opportunities. The outcome measure was time from arrival to chemotherapy start. Data were obtained from time stamps in the electronic health record.nnnRESULTSnThe first PDSA cycle included patient reminders to arrive at specific times, improved communication using a smartphone secure messaging application, and preadmission notes by oncology fellows detailing whether fresh blood work were needed on admission. Baseline data from 36 patients and postimplementation data from 28 patients were analyzed. Median time from admission to chemotherapy initiation preprocess change was 6.2 hours; it was 3.2 hours postchange. A sustained shift in the process was apparent on a control chart.nnnCONCLUSIONnDelays in initiation of chemotherapy can be prevented using classic quality improvement methodology and a multidisciplinary team. We aim to further refine our PDSA cycles and ensure sustainability of change.

MRD-negative complete remission in relapsed refractory hairy cell leukemia with bendamustine and obinutuzumab

Dear Editor, We describe a 48-year-old woman who presented to our institution with relapsed hairy cell leukemia (HCL). She was diagnosed with HCL at age 42 and was treated with cladribine resulting in a complete response (CR) which lasted 2.5 years. Subsequent treatments at relapse included rituximab followed by interferon, and cladribine with rituximab. Her last treatment resulted in a partial response and was complicated by progressively worsening infusion reactions to rituximab to the point that her rituximab was discontinued prematurely. Baseline assessment at our institution was significant for splenomegaly, WBC 3.65 k/μL, Hb 9.6 g/dL, platelets 59 k/ μL, and ANC 770/μL. Bone marrow biopsy showed 80% involvement by HCL. The patient was treated with six cycles of bendamustine 90 mg/m (days 1 and 2, cycles 1–6) and obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2–6), every 4 weeks. Pegfilgrastim was given with cycle 1 but subsequently was discontinued due to an allergic reaction. End-of-treatment bone marrow biopsy showed no evidence of leukemia by morphology. Flow cytometry on marrow aspirate was negative for minimal residual disease (MRD). HCL is a rare malignancy comprising about 2% of leukemias with an estimated US incidence of 1100 new cases in 2016 [1]. Purine analogues are the mainstay of treatment in first-line and relapsed settings; however, therapeutic options beyond purine analogues and data on their comparative efficacy are quite limited [2, 3]. Combination of rituximab and bendamustine (at 70 and 90 mg/m) has been studied in relapsed and refractory HCL [4]. At 90 mg/m (on days 1 and 2), bendamustine was tolerated well and resulted in a CR in four out of six patients. Overall, half of the patients achieved an MRD(−) CR. At a median follow-up of 31 months, all MRD(−) patients had remained in CR. Obinutuzumab is a glycoengineered humanized type 2 antibody against CD20. In patients with CLL and coexisting conditions and in combination with chemotherapy, obinutuzumab resulted in superior outcomes over rituximab [5]. In addition, the GADOLIN trial demonstrated efficacy of obinutuzumab in rituximab-refractory indolent lymphomas [6]. Use of obinutuzumab as a single agent in HCL has previously been reported with limited efficacy and was associated significant infusion reaction, occurring beyond the first cycle, resulting in premature termination of treatment [7]. In our patient, we followed the dosing schedule described in the GADOLIN trial [6], but split the first dose of obinutuzumab over 2 days (100 mg on day 1 and 900 mg on day 2). Infusion reaction only occurred on day 1 of treatment. Our patient was neutropenic and thrombocytopenic at baseline and therefore, we opted not to hold treatment for cytopenias in the subsequent cycles. In summary, we present a case of relapsed refractory HCL after multiple lines of therapy including combination of cladribine and rituximab. Our patient was effectively treated with bendamustine and obinutuzumab resulting in an MRD(−) CR. Treatment was well tolerated with manageable toxicities. Considering the rarity of this entity, randomized trials to compare efficacy and toxicity of various regimens are unlikely to occur. Obinutuzumab can be considered as an adjunct to chemotherapy in HCL patients who are intolerant of, or refractory to rituximab.

Patterns of Failure in Patients With Double Hit or Double Expressor Lymphomas: Implications for Radiation Therapy

PURPOSEnLymphomas with MYC and either BLC2 or BCL6 rearrangements or MYC and BCL-2 protein overexpression, classified as double-hit (DHL) or double-expressor (DEL) lymphomas, respectively, are associated with poorer response to standard immunochemotherapy. Optimal therapy is not clear, and little information exists on the contribution of consolidative radiation therapy in these patients. This study describes the patterns of failure of DHL/DEL in relation to initial sites of disease and indications for radiation therapy in unselected diffuse large B-cell lymphoma (DLBCL).nnnMETHODS AND MATERIALSnA retrospective single-institution study of all patients with diagnoses of non-Hodgkin lymphoma between 2011 and 2015 was performed. DHL status was determined by fluorescence in-situ hybridization, and DEL status was determined by immunohistochemistry. Progression-free survival (PFS) was calculated from the end of chemotherapy using the Kaplan-Meier method. Cox modeling was used for multivariable analysis.nnnRESULTSnScreening of 275 DLBCL patients yielded a 53-patient cohort, including 32 patients with DHL, 10 with DEL, 9 with a triple rearrangement, and 2 triple expressors. Of the 26 patients whose disease progressed, 15 had primary refractory disease. The remaining 11 failures were relapses after complete response to initial chemotherapy. Of those failures, 6 (55%) occurred at initially involved site(s), and 4 (36%) were isolated initial site relapses. Consolidative radiation therapy was associated significantly with improved PFS on multivariable analysis (hazard ratio 0.17, 95% confidence interval 0.02-0.94, Pxa0=xa0.04).nnnCONCLUSIONSnDHL/DEL are associated with high relapse rates, which preferentially occur at initially involved sites. Among patients achieving complete response to chemotherapy, consolidative radiation therapy was associated with improved PFS. This provides a rationale for the continued role of radiation therapy in the treatment of DHL and DEL and requires validation in a larger cohort.

Abdominal Pain and Bloody Diarrhea

A woman in her 40s with relapsed grade 2 follicular lymphoma receiving therapy with idelalisib, 150 mg twice daily for the past 5 months, presented with 3 days of vomiting, cramping abdominal pain, and diarrhea. She initially had 10 to 12 watery bowel movements a day, which progressed to passage of bright red blood per rectum. She reported no sick contacts, recent travel, recent antibiotic exposure, or nutritional supplement intake. She denied use of tobacco, alcohol, or illicit drugs. Vital signs were notable for elevated temperature (37.9°C), tachycardia (heart rate, 112/min), respiratory rate of 16/min, and blood pressure of 105/60 mm Hg. Physical examination showed a soft nondistended abdomen without organomegaly and normal bowel sounds. She had diffuse tenderness to deep palpation. Laboratory evaluation revealed normal hematological indices, renal function, and hepatic function. Computed tomography of the abdomen and pelvis demonstrated colonic wall thickening without perforation and stable prior pelvic lymphadenopathy. No pathogenic organisms or parasitic ova were detected on stool culture. Results of a stool Clostridium difficile toxin assay were negative. Flexible sigmoidoscopy demonstrated grossly congested and erythematous mucosa in the rectosigmoid and descending colon. Histopathology from the biopsies of one of the affected areas is shown in the Figure. Figure. Colon biopsy specimen (hematoxylin-eosin, magnification ×100).

Lymphadenopathy and Jaundice

A Hispanic man in his 20swith no knownmedical history presented with worsening abdominal pain over 5 days, persistent pruritus, and scleral icterus. The patient noted swelling on the right side of the neck and a 5-kgweight loss over thepast 2months.He reported a history of moderate alcohol consumption, drinking 1 beer per day during the week and approximately 5 to 8 beers over the weekend, but denied any use of nutritional supplements or illicit drugs. Therewasno recent travel outside thestate.Human immunodeficiency virus test results on admission were negative. Physical examination revealed scleral icterus, jaundice, and a fixed right supraclavicular lymphnode conglomerate measuring 6 × 3 cm. Therewas no cervical, left supraclavicular, axillary, or inguinal lymphadenopathy. Computed tomography of the neck, chest, abdomen, and pelvis demonstrated a large right supraclavicular lymph node, extensivemediastinal lymphadenopathy, a large extracardiac mass abutting the left atrium, hepatomegaly, and multiple splenic lesions. Laboratory evaluation demonstrated a total serumbilirubin level of 10.5mg/dLwith a direct component of 8.4 mg/dL (to convert to micromoles per liter, multiply by 17.104). Renal function was normal. Mild leukopenia and slight thrombocytopenia in the absence of associatedanemiawasnotedon initial completebloodcell count. A liver biopsywasperformed, with results shown in Figure 1. Quiz at jamaoncology.com WHAT IS YOURDIAGNOSIS?