An autopsy report with a diagnostic clinical profile on fatal overdose of life-saving iron supplement.

Ferrous sulfate is a commonly prescribed drug for prophylaxis and treatment purposes, particularly in women and adolescent girls. However, its easy availability, potential toxicity at higher doses, and vague clinical presentation make it a drug of concern when evaluating a case of poisoning. We present the case of a 28-year-old female who allegedly consumed 60 ferrous sulfate (60 mg of elemental iron in 200 mg of ferrous sulfate) tablets in a suicidal attempt. She presented with gastrointestinal disturbances on the same day to a tertiary care health facility. Investigations revealed deranged liver function tests, serum iron levels ten times the normal range, and high levels of saturated transferrin. Despite treatment, she succumbed to the poisoning 4 days after the incident. Autopsy showed features of liver failure, which was confirmed by histopathology. Chemical examination detected free ferrous and chloride ions. This fatal case of adult iron toxicity highlights the different causes of death in various stages of iron toxicity, providing a wider perspective on clinical management and aiding in the determination of the cause of death during an autopsy. This article adds a rare fatal iron poisoning case in adults to the literature, emphasizing the necessity for regulating iron tablet supplementation and raising public awareness of the toxicity of iron, which could save millions of lives.

Fatal anabolic androgenic steroid overdose in an amateur bodybuilder: a clinical and autopsy report.

Stanozolol is a synthetic anabolic-androgenic steroid commonly used by bodybuilders to increase muscle mass. However, its use can lead to serious adverse effects on the liver, including cholestasis, hepatic necrosis, and even death. In this case report, we describe a fatal case of stanozolol overdose in an otherwise healthy 35-year-old amateur bodybuilder. The patient presented with general malaise, jaundice, and a history of hematemesis after taking stanozolol tablets orally for 3 months. Upon admission, his liver function tests were significantly abnormal, and he succumbed within 48 h despite symptomatic treatment. The autopsy revealed sub-massive hepatic necrosis, focal macro-vesicular steatosis, and a cholestatic pattern of acute liver injury, with the chemical examination confirming the presence of stanozolol in the blood, liver, and kidneys. The cause of death was determined to be hepatic necrosis as a complication of stanozolol overdose. The overuse of anabolic steroids like stanozolol can cause hepatotoxicity, resulting in reversible cholestatic hepatitis or, in rare cases, fatal liver injury. The mechanism of anabolic androgenic steroid (AAS) drug-induced liver injury is obscure, but proposed mechanisms include oxidative stress and cholestasis. In this case, the recent overuse of stanozolol, a 17 alpha-alkylated (oral) AAS led to sub-massive hepatic necrosis and subsequent liver failure, proving fatal. It is imperative that healthcare providers and the public are informed about the dangers of AAS use, especially since AAS usage has increased recently due to easy online access, to prevent potentially life-threatening consequences.

Descriptive study of the histopathological subtypes and programmed death-ligand 1 in metaplastic breast carcinoma.

Metaplastic Breast Carcinoma (MBC) is a rare heterogeneous group of tumors, the incidence of which is less than 1% of breast tumors. These are a unique set of tumors with varying subtypes, poor prognosis, and an increased chance of distant metastasis. We aimed to study the clinical, histomorphological, and immunohistochemical (IHC) features of Metaplastic Breast Carcinoma (MBC). This was a descriptive study of cases diagnosed as MBC at a tertiary care center in Southern India from January 2015 to December 2019. A total of 20 cases were diagnosed whose clinical, histomorphological, and IHC features were studied. PD-L1and CD8 IHC were performed and analyzed in 12 cases. The median age of presentation was 50 years. Seventy percent (14/20) patients were postmenopausal women. On excision, 75% (15/20) showed mixed typed MBC, the remainder showing epithelial type MBC. Metastasis to axillary lymph node was seen only in 20% (4/20) of the cases. Thirty percent (6/20) of the cases belonged to stage 3 disease and 5% (1/20) of the cases belonged to stage 4 disease with liver metastasis. Estrogen receptor (ER), Progesterone receptor (PR) were negative in all the cases, Her2neu was positive in three cases. Ki67 labeling index was greater than 14% in all the cases. PD-L1was positive in 41.5% of the cases and intratumoral CD8 positive lymphocytes were increased in 83.3% of the cases. MBCs are tumors occurring in elderly postmenopausal women, presenting with large tumor size, have lesser chances of lymph node metastasis, and a higher chance of recurrence and hematogenous spread. They are negative for ER, PR, Her-2 neu, with a high Ki67 index and a strong PDL-1 expression.

Coexistence of malignancy and tuberculosis: is it double disease or double hit related to COVID-19? - Experience from a tertiary care center.

BACKGROUND: Coexistent malignancy and tuberculosis (TB) are rarely encountered. Cancer patients are a highly vulnerable subgroup during this Covid crisis. Delayed treatment for malignancy because of COVID-19 pandemic leads to higher chances to get infections. PURPOSE: The present study aimed to present the clinicopathologic profile of the patients with coexistent carcinoma and TB during the COVID-19 pandemic in a tertiary care center. MATERIALS AND METHODS: This was a retrospective study conducted during the COVID-19 pandemic between April 2020 to May 2021 in the Department of Pathology of our Institute. 11 patients with coexistent malignancy and caseous necrotizing granulomatous inflammation with Langhans giant cells and or acid-fast bacilli (AFB) positivity were included in the study. Cases of ill-defined granulomas coexistent malignancy were excluded. We studied varied clinical and histopathologic features of these cases. RESULTS: Eleven cases were reported with coexistent malignancy and tuberculosis, of which 8 were reported in 2021 and 3 cases were reported in 2020. Adenocarcinoma comprised 9 cases (81.8%) and the remaining 2 were squamous cell carcinoma (18.1%). Out of 11, 10 (90.9%) were new TB cases. Of these, 10 were extrapulmonary TB and one pulmonary TB case with cancer. Regarding chemotherapy, four patients accepted that chemotherapy was delayed because of the COVID-19 crisis. CONCLUSION: In this covid pandemic, India being the 2nd most populous country and endemic for TB, there is a higher chance of latent and active TB. The coexistence of two different pathologies is rare, even in a region with a high incidence of TB. Delayed chemotherapy in a pandemic situation leads to an increased incidence of infectious diseases such as TB.

Clinicopathologic profile of gastroenteropancreatic neuroendocrine neoplasms in a referral center of South India.

BACKGROUND: The neuroendocrine system of the gastroenteropancreatic (GEP) region gives rise to unique, heterogeneous malignancies that need a high index of suspicion to make a diagnosis owing to their indolent course. AIMS: The present study aimed to find the incidence and the differences in the morphologic and immunohistochemical profile of gastroenteropancreatic neuroendocrine tumors (GEPNET) in a referral center of South India, JIPMER, Puducherry, India. METHODS: There were 55 gastroenteropancreatic region neuroendocrine neoplasms (NEN) assessed for demographic, clinical and radiological features. Gross morphological features, histopathological features, mitotic index, Ki67 proliferation index, and immunohistochemical positivity for synaptophysin, chromogranin-A, CD-56, NSE (Neuron Specific Enolase) and pan-cytokeratin (Pan-CK) were also assessed. RESULTS: The majority were nonfunctional tumors presenting with abdominal pain, gastrointestinal bleed, vomiting, jaundice, and loss of weight and appetite. The sites of involvement according to the order of frequency were duodenum, stomach, rectum, pancreas, ileum, appendix and jejunum. The endoscopic appearance of duodenal and jejunal tumors showed polypoidal, nodular and ulceroproliferative growth. These tumors were diagnosed by preoperative biopsy; 54% of them were grade-1 neuroendocrine tumors exhibiting nesting, trabecular, cord, and solid sheet patterns. All 55 cases were synaptophysin-positive with variable positivity for chromogranin, neuron-specific enolase, CD56, and Pan-CK. Mixed adenoneuroendocrine carcinomas (MANECs) involving the duodenum and stomach comprised 7.3% of all GEPNETs. Pancreatic neuroendocrine tumors constituted 9% of all tumors; one was multifocal. Lymph node metastasis was seen in 12/55 tumors; 6/12 showed liver metastasis also. All metastasizing tumors measured less than 4 cm in size. Statistical correlation of the tumor grade, mitotic count and Ki67 index as analysed by Spearman's correlation between the paired data denoted by rs in 55 tumors showed a strong correlation between mitotic count and Ki67 index; a moderate correlation was noted between the tumor grade and Ki67 index. CONCLUSION: The clinicopathologic profile of 55 GEPNET revealed a majority to be sporadic Grade 1 tumor. Tumors that showed lymph node and liver metastasis were less than 4 cm in size. MANECs were found in the duodenum and stomach.

Effect of preoperative finasteride on perioperative blood loss during transurethral resection of the prostate and on microvessel density in patients with benign prostatic hyperplasia: An open label randomized controlled trial.

OBJECTIVE: Transurethral resection of the prostate (TURP) is a common procedure for the treatment of benign prostatic hyperplasia (BPH). Previous studies on the effect of 5-alpha reductase inhibitors on perioperative blood loss in TURP and microvessel density (MVD) in the prostate are equivocal. We evaluated whether pretreatment with finasteride for 2 weeks before surgery can reduce perioperative blood loss in TURP and MVD in the prostate. MATERIALS AND METHODS: Sixty-eight patients of BPH planned for TURP were randomized into two groups. The study group comprising 34 patients was treated with finasteride (5 mg/day) for 2 weeks and the placebo group comprising 34 patients received placebo for 2 weeks, before TURP. Blood loss was measured in terms of a reduction in the blood hemoglobin (Hb) and hematocrit (HCT) levels between preoperative values and 24 h after surgery. MVD was measured in the resected prostate tissue stained with anti-CD31 monoclonal antibody. RESULTS: The reduction of Hb and HCT in the finasteride group was significantly lower than the reduction in the placebo group (P < 0.05). The artery (P = 0.005), vein (P = 0.05), and gland (P = 0.008) densities were significantly less in the finasteride group than in the placebo group. There was no significant correlation between blood loss and MVD. CONCLUSIONS: Our study suggests a clear advantage of the preoperative use of finasteride for 2 weeks by reducing the perioperative blood loss in TURP in patients with BPH. While there is a significant reduction in MVD in the prostate on treatment with finasteride, it is not clear that this is the mechanism of reduction in blood loss in TURP.

Co-infection of intestinal tuberculosis and mucormycosis in a patient with Down syndrome: a unique case report with literature review.

Mucormycosis represents several unusual opportunistic infection caused by saprophytic aseptate fungi. There is a recent rise in cases of mucormycosis due to an increase in diabetic and immunodeficient patients like patients on long-term steroids, immunomodulators due to organ transplantation, malignancies, mainly haematological malignancies, and autoimmunity. Anatomically, mucormycosis can be localised most commonly as rhino-orbito-cerebral followed by pulmonary, disseminated, cutaneous and gastrointestinal, rarest being small intestinal. Patients with Down syndrome are immunodeficient due to their impaired immune response. Disseminated tuberculosis is also common in immunodeficient patients. We report a rare case of small intestinal mucormycosis in a patient with Down syndrome with coexisting intestinal tuberculosis. Due to the invasiveness of mucormycosis, the patient succumbed to death despite providing aggressive surgical debridement and medical management.

Narciclasine improves outcome in sepsis among neonatal rats via inhibition of calprotectin and alleviating inflammatory responses.

Sepsis is associated with exacerbated inflammatory response which subsequently results in multiple organ dysfunction. Sepsis accounts for high mortality and morbidity among newborns worldwide. Narciclasine is a plant alkaloid which has shown to possess anti-inflammatory properties. In this study we investigated the effect and mechanism of action of narciclasine in neonatal sepsis rat models. The excessive release of S100A8/A9 or calprotectin in neonatal sepsis could be detrimental as it could exacerbate the inflammatory responses. We found that narciclasine significantly reduced the plasma levels of S100A8/A9 and also suppressed its expression in the liver and lung. The systemic and local bacterial load was also reduced in the narciclasine treated rats. The systemic and local production of pro-inflammatory cytokines in plasma and organs (liver and lungs) was significantly reduced in the narciclasine treated rats. The histopathological studies showed that narciclasine prevents the organ damage associated with sepsis and improved the survival of neonatal rats. Sepsis increased the phosphorylated NF-κß p65 protein expression in the liver. Narciclasine suppressed the phosphorylation of NF-κß p65 and the degradation of NF-κß inhibitory protein alpha. It could also suppress the expression of adaptor proteins of the toll like receptor signaling pathway viz., myeloid differentiation factor 88 (MyD88), Interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6). These results suggest that narciclasine protects against sepsis in neonatal rats through the inhibition of calprotectin, pro-inflammatory cytokines and suppression of NF-κß signaling pathway.

Cytologic aspects of T-cell acute lymphoblastic leukemia presenting as a massive pericardial effusion: a case report.

BACKGROUND: Acute lymphoblastic leukemia (ALL) with a clinical presentation of cardiac tamponade and the presence of blasts in the pericardial fluid is an uncommon event. A cytopathologist needs to adopt a cautious interpretive approach while dealing with a lymphoid-rich pericardial effusion in order to prevent a false negative diagnosis. CASE: A 27-year-old male presented with breathlessness, ascites, bilateral pedal edema and fever. He had mild hepatomegaly. On detailed clinical examination, a diagnosis of anemia with cardiac tamponade was made. Cytology of pericardial fluid revealed a large number of lymphoid cells in a hemorrhagic background that, under low magnification, closely resembled mature lymphocytes. However, a careful examination of May-Grünwald-Giemsa-stained cytologic smears, under an oil immersion objective (x 1,000), showed atypical lymphoid cells having blastoid morphology. Rare lymphoid cells displayed a "hand mirror" appearance. A hematologic workup was carried out to exclude leukemia/lymphoma. Complete blood count revealed pancytopenia with abnormal lymphoid cells. Bone marrow showed replacement by 90% lymphoblasts exhibiting periodic acid-Schiff stain, CD3 and terminal deoxynucleotidyl transferase positivity. A diagnosis of T-cell acute lymphoblastic leukemia (FAB L1) was offered, and the patient was started on a remission and induction regimen. However, he had a rapid downhill course and died of cardiorespiratory arrest. CONCLUSION: Both clinicians and cytopathologists need to be aware of rare instances in which ALL may present with a pericardial effusion as an initial manifestation. The abnormal lymphoid cells found in the pericardial fluid in such situations need to be interpreted cautiously, as their presence is of clinical significance.

A novel approach to decalcification in histopathology laboratory: An adaptation from the Hammersmith protocol.

AIM: Utility of modified Hammersmith protocol in the deacalcification and/or softening of tissues and samples in a histopathology laboratory were studied. The object of the study was to prepare a novel method for softening/decalcifying tissue for histopathology. MATERIALS AND METHODS: All the hard tissues received in the histopathology section were received in 10% neutral buffered formalin and then placed in freshly prepared combination of 10 mL of concentrated formaldehyde and 5 mL of 10% formic acid in 85 mL distilled water was used for decalcification. The tissue was checked for evidence of adequate decalcification/softening every 6 hours. Those which were decalcified/softened were sent for routine tissue processing and staining, while those which were not, were again placed in formalin. The process was repeated until the tissue was ready for further processing. The routine sections of these slides were reviewed for morphology and stain quality along with special stains and immunohistochemistry performed. The time taken for decalcification, the variables most likely to affect decalcification, the morphology and staining characteristics were documented. Statistical analysis was done to determine the effect of softening/decalcification process on each variable. RESULTS: A total of 201 blocks in 119 specimens from humans including 61 males and 58 females were studied. Time taken was found to have a significant correlation only with the nature of the tissue (bone vs nonbone) and not with any other parameter viz. age, gender, specimen size, type of bone, and nature of pathology. CONCLUSION: This novel and modified method has circumvented the common problems of overdecalcification, preserved morphology, and produced consistent results without interfering with special stains and immunohistochemistry.

Preoperative fine needle aspiration cytologic diagnosis of spindle cell myoepithelioma of the parotid gland: a case report.

BACKGROUND: There are only rare case reports of preoperative fine needle aspiration cytologic (FNAC) diagnosis of myoepithelioma of the salivary gland. Myoepitheliomas with pure spindle cell morphology may simulate a variety of benign or malignant spindle cell soft tissue tumors. CASE: A 54-year-old woman presented with a history of progressively increasing swelling in the right parotid region. The clinical diagnosis was parotid malignancy. Routine FNAC yielded highly particulate material. The smears were cellular, with tissue fragments, clusters of spindle cells and numerous small globules and strands of bright magenta material. High cellular yield and pure spindle cell population with an accentuated chromatin pattern in Papanicolaou-stained smears simulated a low-grade spindle cell soft tissue sarcoma. A vague resemblance to a schwannoma was also noted. However, based on the characteristic findings of the May-Grünwald-Giemsa (MGG)-stained smears, a preoperative diagnosis of myoepithelioma was made and confirmed by subsequent histopathologic examination and immunohistochemistry. CONCLUSION: Cytologically, spindle cell myoepithelioma of the salivary gland may simulate low-grade spindle cell soft tissue sarcoma or schwannoma. However, optimal sampling of the lesion and logical interpretation of the MGG-stained smears, in the appropriate clinical situation, allow a confident preoperative diagnosis of these tumors.

Granulomatous Response in Intracranial Germinomas: Diagnostic Problems.

Intracranial germinomas are rare and account for <0.5% of primary intracranial tumors. In contrast to the gonadal germinomas, these do not show granulomatous response within the tumor. In rare cases, the granulomatous component may obscure the tumor proper and lead to diagnostic difficulties/dilemmas. We report a case of suprasellar germinoma in a 17-year-old boy which showed granulomatous response. We discuss the differentials to be considered in such a scenario and discuss the utility of squash cytology and immunohistochemistry in these lesions.

Proximal epithelioid sarcomatous dedifferentiation in secondary chondrosarcoma in a known case of multiple osteochondromatosis.

Osteochondroma is the most common benign bone tumor. Approximately 15% of osteochondromas occur as multiple lesions. Multiple osteochondromatosis has a higher risk of developing chondrosarcomas, which are of low grade with good prognosis. About 10% of all chondrosarcomas may undergo dedifferentiated change, which has a poorer prognosis. Dedifferentiated peripheral chondrosarcoma developing within an osteochondroma is extremely rare. Dedifferentiation usually occurs in the form of osteosarcoma, malignant fibrous histiocytoma, fibrosarcoma, or rhabdomyosarcoma. We report a case of proximal epithelioid sarcomatous dedifferentiation in secondary chondrosarcoma in a 39-year-old male with multiple osteochondromatosis in bilateral arm. To the best of our knowledge, epithelioid sarcomatous dedifferentiation has not been described in the literature.

Morphologic Spectrum of Duodenal Biopsies in Malabsorption: A Study from Southern India.

INTRODUCTION: Duodenal endoscopic biopsy is a common investigation for various non-neoplastic conditions. Malabsorption is a common indication for duodenal biopsy in our setting. AIM: Our study was undertaken to study the morphologic spectrum of non-neoplastic conditions of duodenum emphasizing on Intraepithelial Lymphocytes (IELs) and to have a clinico-pathologic correlation. MATERIALS AND METHODS: This was a prospective descriptive study. Duodenal biopsies from 101 patients with symptoms of malabsorption were studied according to inclusion and exclusion criteria. Informed written consent was taken. Clinical, laboratory, endoscopic, and serological parameters were collected wherever available. Histomorphological parameters were studied on Haematoxylin and Eosin (H&E) stained sections. Intraepithelial lymphocyte counts were done on CD3, CD4 and CD8 Immunohistochemical (IHC) stained sections and correlated. RESULTS: We studied 101 duodenal biopsies. Our spectrum included 16 patients of celiac disease (CD) (15.8%), 15 autoimmune duodenitis (14%), 13 nutritional deficiency associated duodenitis (12.8%), five infectious duodenitis (5%) and 41 patients of non-specific duodenitis (40.6%) and 10.9% miscellaneous causes of duodenitis. Villous crypt architecture, IEL counts; villous tip IEL counts were statistically significant between CD and other disease groups. CONCLUSION: A constellation of clinical, serological, endoscopic and histopathologic features is essential in diagnosing CD and autoimmune duodenitis. Biopsy is also a useful tool in diagnosing infectious duodenitis that are missed in other investigations.

Emphasizing the pivotal role of fine-needle aspiration cytology in a case of recurrent malignant chondroid syringoma.

Fine-needle aspiration cytology (FNAC) features of malignant chondroid syringoma (MCS) are rarely documented. Here, we report a case of recurrent MCS, highlighting its interesting clinicopathologic features. Initially, we received cytology and histopathology slides (for review) of a 57-year-old woman who had undergone resection for an occipital MCS and later presented with recurrence. On reviewing the slides, cytology was consistent with recurrent MCS. However, tissue sections showed features of a malignant epithelial tumor with comedonecrosis and sebaceous differentiation owing to which a diagnosis of metastatic adenocarcinoma/malignant adnexal tumor was suggested. Due to an ambiguous histology, a repeat FNA was performed to perform immunocytochemistry (ICC) and oil-red O stains, which confirmed the diagnosis of MCS with sebaceous differentiation. Thus, in a situation where histology was inconclusive due to lack of representative sections, FNAC played a major role in resolving the diagnostic dilemma and facilitating an appropriate clinical management.

Reactive Eccrine Syringofibroadenomatosis Presenting as Bilateral Plantar Hyperkeratosis.

Eccrine syringofibroadenoma (ESFA) is a rare cutaneous tumor with eccrine differentiation with varied clinical manifestations. We report a case of reactive eccrine syringofibroadenomatosis associated with chronic bilateral plantar ulcers in a patient with diabetes mellitus presenting as plantar hyperkeratosis and verrucous growth at margins.

Role of p16, CK17, p63, and human papillomavirus in diagnosis of cervical intraepithelial neoplasia and distinction from its mimics.

BACKGROUND: Diagnosis of cervical intraepithelial neoplasia (CIN), the precursor forms of cervical cancer, can be tricky and it has led to discrepancy between pathologists in distinguishing them from its mimics such as atypical immature metaplasia (AIM), immature squamous metaplasia (ISM), reactive atypia (RA), atrophy, and basal cell hyperplasia (BCH). To overcome this problem this study aims at using immunohistochemical (IHC) markers p16, p63, CK17, and human papillomavirus (HPV) to differentiate CIN from its mimics. MATERIALS AND METHODS: This study analyzed 350 cervical samples with histomorphological diagnosis of CIN and its mimics and the utility of IHC markers p16, p63, CK17, and HPV in distinction was analyzed. RESULTS: p16 showed 67.76% sensitivity and 99.4% specificity whereas HPV showed 57.9% sensitivity and 91.6% specificity in detecting CIN. CK17 and p63 did not show any significance in distinguishing CIN from its mimics. After IHC of AIM cases, 66.7% were reclassified as CIN III, 27.8% as ISM with reactive atypia (ISMRA), and 5.5% case as immature condyloma. In total, 3.7% of diagnosis was upgraded to CIN and 0.6% of pre-IHC diagnosis was downgraded from CIN to reactive lesions. CONCLUSION: IHC panel comprising p16, p63, CK17, and HPV are useful adjuncts in distinguishing CIN from its mimics particularly when histomorphology has overlapping morphological features.

Study of tumour cellularity in locally advanced breast carcinoma on neo-adjuvant chemotherapy.

BACKGROUND: Breast cancer is the most common invasive malignancy which occurs in women worldwide. The advent of neoadjuvant chemotherapy has radically changed the management of locally advanced breast cancer and a complete response is reported to significantly improve disease free survival. Traditionally, clinical response is assessed on basis of tumour size. In this study, an attempt was made to check whether tumour cellularity could be a better prognostic factor and also to check as to what impact the correlation of tumour size with cellularity had on the response assessment in locally advanced breast cancer patients. MATERIALS AND METHODS: Thirty seven patients with locally advanced breast cancer, who were treated by neoadjuvant chemotherapy during the period of December 2008 to May 2009, were selected for the study and from their case records, tumour size, clinical response and demographic details were gathered. Tumour cellularity was assessed prior to chemotherapy in core needle biopsy sections and it was matched with that seen in subsequent mastectomy specimens. Tumour size and cellularity were then correlated with the different treatment response groups and they were statistically analyzed by using the SPSS, version 13.0 software. RESULTS: After neoadjuvant chemotherapy, the tumour size and cellularity were found to be significantly reduced in breast carcinomas (p<0.05, paired t-test). The relative changes in cellularity which were seen were highly variable between individual patients and different clinical response groups, particularly in the partial response and no response categories. The product of cellularity and size dramatically changed the distribution of residual tumour pathology, thus causing a shift towards a complete response. CONCLUSION: The current study showed that the product of tumour size and cellularity may be a better prognostic indicator of clinical response in patients with neoadjuvant chemotherapy treated locally advanced breast cancer and that it would enable a new definition for clinical response in the future.